1-amino-2-propanol -Drug Synthesis Database

【结构式】

【分子编号】41397

【品名】1-amino-2-propanol

【CA登记号】78-96-6

【分子式】C₃H₉NO

【分子量】75.1106

【元素组成】C 47.97% H 12.08% N 18.65% O 21.3%

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：(VIII)

Lorcaserin hydrochloride can be prepared by several different procedures. 4-Chlorophenethylamine (I) is acylated with 2-chloropropionyl chloride (II) in the presence of pyridine in CH2Cl2 to give the chloropropionamide (III), which is cyclized to the benzazepinone (IV) upon heating with AlCl3. Subsequent reduction of (IV) with either BH3 or LiAlH4 in Et2O affords the racemic lorcaserin (V) (1-3). In a related method, chloropropionamide (III) is reduced with borane in THF to yield the chloro amine (VIa), which is then cyclized to benzazepine (V) in the presence of AlCl3 (3). Alternatively, condensation of 4-chlorophenethyl bromide (VII) with 1-amino-2-propanol (VIII) provides the aminoalcohol (IX), which is converted to either the chloro amine (VIa) or the analogous bromo amine (VIb) by treatment with SOCl2 or SOBr2, respectively (3). Optical resolution of tetrahydrobenzazepine (V) either employing chiral HPLC or by crystallization with D-tartaric acid furnishes the target (R)-enantiomer (X) (1-3). This is finally converted to the title hydrochloride salt by treatment with HCl in different solvent systems (4). In a further procedure, after protection of 4-chlorophenethylamine (I) as the corresponding trifluoroacetamide (XI) by means of trifluoroacetic anhydride and pyridine in CH2Cl2, iodination with bis(pyridine)iodonium tetrafluoroborate in the presence of trifluoromethanesulfonic acid furnishes (XII). Subsequent alkylation of trifluoroacetamide (XII) with allyl bromide under phase transfer conditions leads to the iodo olefin (XIII), which undergoes intramolecular Heck cyclization in the presence of Pd(OAc)2 and PPh3 to furnish the methylene benzazepine (XIV). After reduction of (XIV) to the methyl analogue (XV) by catalytic hydrogenation over Pd/C, the N-trifluoroacetyl group is hydrolyzed with NaOH in aqueous MeOH to give 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (V) (5). Scheme 1.

参考文献中间体

合成目标

【1】 Smith, B., Smith, J., Schultz, J., Gilson, C. III (Arena Pharmaceuticals, Inc.). Benzazepine derivatives useful for the treatment of 5HT2C receptor associated diseases. EP 1633720, JP 2007516941, WO 2005003096.
【2】 Smith, B.M., Smtih, J.M., Tsai, J.H. et al. Discovery and SAR of new benzazepines as potent and selective 5-HT2C receptor agonists for the treatment of obesity. Bioorg Med Chem Lett 2005, 15(5): 1467-70.
【3】 Burbaum, B.W., Gilson, C.A. III, Aytes, S. et al. (Arena Pharmaceuticals, Inc.). Processes for preparing 3-benzazepines. EP 1636191, JP 2007521269, WO 2005019179.
【4】 Agarwal, R.K., Betts, W.L. III, Henshilwood, J.A., Kiang, Y.-H., Post, N. (Arena Pharmaceuticals, Inc.). Crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. WO 2006069363.
【5】 Smith, B., Smith, J. (Arena Pharmaceuticals, Inc.). 5HT2C receptor modulators. EP 1557409, JP 2005527579, JP 2006143751, US 2003225057, US 6953787, WO 2003086306.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIb)	65408	4-Chloro-N-(2-bromopropyl)benzeneethanamine		C₁₁H₁₅BrClN	详情	详情
(Via)	65407	4-Chloro-N-(2-chloropropyl)benzeneethanamine	897926-35-1	C₁₁H₁₅Cl₂N	详情	详情
(I)	29459	4-chlorophenethylamine; 2-(4-chlorophenyl)-1-ethanamine	156-41-2	C₈H₁₀ClN	详情	详情
(II)	12926	2-Chloropropanoyl chloride; 2-Chloropropionyl chloride	7623-09-8	C₃H₄Cl₂O	详情	详情
(III)	65404	2-chloro-n-(2-(4-chlorophenyl)ethyl)propanamide; 1-((2-(4-chlorophenyl)ethyl)amino)-1-oxo-2-chloropropane	34164-14-2	C₁₁H₁₃Cl₂NO	详情	详情
(IV)	65405	8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one	824430-77-5	C₁₁H₁₂ClNO	详情	详情
(V)	65406	Lorcaserin A; 8-Chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine	616201-80-0	C₁₁H₁₄ClN	详情	详情
(VII)	65409	4-Chlorophenethyl bromide; 1-(2-Bromoethyl)-4-chlorobenzene	6529-53-9	C₈H₈BrCl	详情	详情
(VIII)	41397	1-amino-2-propanol	78-96-6	C₃H₉NO	详情	详情
(IX)	65410	1-[[2-(4-Chlorophenyl)ethyl]amino]-2-hydroxypropane	847063-13-2	C₁₁H₁₆ClNO	详情	详情
(X)	65411	(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; Lorcaserin	616202-92-7	C₁₁H₁₄ClN	详情	详情
(XI)	65412			C₁₀H₉ClF₃NO	详情	详情
(XII)	65413			C₁₀H₈ClF₃INO	详情	详情
(XIII)	65414			C₁₃H₁₂ClF₃INO	详情	详情
(XIV)	65415			C₁₃H₁₁ClF₃NO	详情	详情
(XV)	65416			C₁₃H₁₃ClF₃NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Condensation of 3,4-dimethoxybenzylamine (I) with 3,4-dimethoxybenzaldehyde (II) afforded imine (III), that was subsequently reduced to amine (IV) by means of NaBH4. Reaction of (V) with 2,4,6,8-tetrachloropyridopyrimidine (V) in THF at room temperature produced the 4,8-diamino derivative (VI). The remaining 2- and 6-chloro groups of (VI) were then displaced by aminoalcohol (VII) in boiling THF to furnish adduct (VIII). Finally, selective cleavage of two dimethoxybenzyl groups using trifluoroacetic acid gave rise to the title compound.

参考文献中间体

合成目标

【1】 Barlow, H.C.; et al.; Resistance-modifying agents. Part 7: 2,6-Disubstituted-4,8-dibenzylaminopyrimido[5,4-d]pyrimidines that inhibit nucleoside transport in the presence of alpha1-acid glycoprotein (AGP). Bioorg Med Chem Lett 2000, 10, 6, 585.

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)	13920	(3,4-Dimethoxyphenyl)methanamine; 3,4-Dimethoxybenzylamine; Veratrylamine	5763-61-1	C₉H₁₃NO₂	详情	详情
(II)	18304	3,4-Dimethoxybenzaldehyde; Veratraldehyde	120-14-9	C₉H₁₀O₃	详情	详情
(III)	41393	(3,4-dimethoxyphenyl)-N-[(E)-(3,4-dimethoxyphenyl)methylidene]methanamine; N-(3,4-dimethoxybenzyl)-N-[(E)-(3,4-dimethoxyphenyl)methylidene]amine		C₁₈H₂₁NO₄	详情	详情
(IV)	41394	N-(3,4-dimethoxybenzyl)(3,4-dimethoxyphenyl)methanamine; N,N-bis(3,4-dimethoxybenzyl)amine		C₁₈H₂₃NO₄	详情	详情
(V)	36173	2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine		C₆Cl₄N₄	详情	详情
(VI)	41395	N-[8-[bis(3,4-dimethoxybenzyl)amino]-2,6-dichloropyrimido[5,4-d]pyrimidin-4-yl]-N,N-bis(3,4-dimethoxybenzyl)amine; 2,6-dichloro-N(4),N(4),N(8),N(8)-tetrakis(3,4-dimethoxybenzyl)pyrimido[5,4-d]pyrimidine-4,8-diamine		C₄₂H₄₄Cl₂N₆O₈	详情	详情
(VII)	41397	1-amino-2-propanol	78-96-6	C₃H₉NO	详情	详情
(VIII)	41396	1-([4,8-bis[bis(3,4-dimethoxybenzyl)amino]-6-[(2-hydroxypropyl)amino]pyrimido[5,4-d]pyrimidin-2-yl]amino)-2-propanol		C₄₈H₆₀N₈O₁₀	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

Condensation of 5-bromoanthranilic acid (I) with the lithium derivative of 2-bromopyridine (II) in cold THF/ethyl ether gives the diaryl ketone (III). N-Fmoc-L-glutamic acid 5-methyl ester (IV) is chlorinated with oxalyl chloride and catalytic DMF to produce the acid chloride (V), which is then coupled with the amino ketone (III) in boiling chloroform to afford amide (VI). Base-mediated deprotection of amine (VI), followed by cyclization by treatment with AcOH in dichloroethane leads to the benzodiazepinone (VII). Subsequent treatment of lactam (VII) with bis-morpholinophosphorochloridate and NaH affords the imino phosphate (VIII), which is then condensed with 1-amino-2-propanol (IX) producing amidine (X). Finally, remimazolam is obtained by Swern oxidation of the secondary alcohol of (X), followed by cyclization under acidic conditions .

参考文献中间体

合成目标

【1】 Jung, D.K., Pacofsky, G.J., Stafford, J.A., Feldman, P.L., Kaldor, I., Tidwell, J.H. (GlaxoSmithKline plc). Short-acting benzodiazepines. EP 1183243, JP 2002544266, JP 2006151984, JP 2007197468, JP 2007197469, US 7160880, US 2007093475,US 2007135419, US 2007135420, US 2007135421, US 7435730, US 7528127, US 7473689, US 7485635, WO 2000069836

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)	31634	2-amino-5-bromobenzoic acid	5794-88-7	C₇H₆BrNO₂	详情	详情
(II)	29052	2-Bromopyridine；α-bromopyridine;α-bromoazine	109-04-6	C₅H₄BrN	详情	详情
(III)	68085	(2-amino-5-bromophenyl)(pyridin-2-yl)methanone	1563-56-0	C₁₂H₉BrN₂O	详情	详情
(IV)	68086	(R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-methoxy-5-oxopentanoic acidN-Fmoc-L-glutamic acid 5-methyl ester		C₂₁H₂₁NO₆	详情	详情
(V)	68087	(R)-methyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-chloro-5-oxopentanoate		C₂₁H₂₀ClNO₅	详情	详情
(VI)	68088	(S)-methyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-((4-bromo-2-picolinoylphenyl)amino)-5-oxopentanoate		C₃₃H₂₈BrN₃O₆	详情	详情
(VII)	68089	(S)-methyl 3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propanoate		C₁₈H₁₆BrN₃O₃	详情	详情
(VIII)	68090	(S)-methyl 3-(7-bromo-2-((dimorpholinophosphoryl)oxy)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl)propanoate		C₂₆H₃₁BrN₅O₆P	详情	详情
(IX)	41397	1-amino-2-propanol	78-96-6	C₃H₉NO	详情	详情
(X)	68091	methyl 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-yl)propanoate		C₂₁H₂₃BrN₄O₃	详情	详情

Extended Information