Dapoxetine, LY-210448, -Drug Synthesis Database

【结构式】

【药物名称】Dapoxetine, LY-210448

【化学名称】(S)-(+)-N,N-Dimethyl-3-(1-naphthyloxy)-1-phenylpropylamine
　　　　　　(+)-(S)-N,N-Dimethyl-alpha[2-(1-naphthyloxy)ethyl]benzylamine

【CA登记号】119356-77-3, 129938-20-1 (HCl)

【分子式】C₂₁H₂₃NO

【分子量】305.42356

【开发单位】Lilly (Originator), Dynogen Pharmaceuticals (Not Determined), Alza (Licensee), PPD GenuPro (Licensee)

【药理作用】Prevention of Premature Ejaculation, RENAL-UROLOGIC DRUGS, Treatment of Male Sexual Dysfunction, 5-HT Reuptake Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

In the original synthesis of the title compound, Knoevenagel condensation of benzaldehyde (I) with malonic acid (II) in the presence of ammonium acetate produced the beta-aminoacid (III). Reductive alkylation of the amino group of (III) with formaldehyde produced the dimethyl amine (IV). Then, Fischer esterification of (IV) with ethanolic HCl furnished the intermediate amino ester (V). Amino ester (V) was alternatively obtained by Michael addition of dimethylamine to ethyl cinnamate (VI). Reduction of the ester function of (V) provided amino alcohol (VII). The sodium alkoxide of (VII) was then coupled with 1-fluoronaphthalene (VIII) to produce the racemic amino ether, which was finally resolved into enantiomers by means of tartaric acid.

参考文献中间体

【1】 Robertson, D.W.; Thompson, D.C.; Wong, D.T. (Eli Lilly and Company); 1-Phenyl-3-naphthalenyloxypropanamines. AU 8814335; EP 0288188; JP 1988258837; US 5135947 .
【2】 Wheeler, W.J.; O'Bannon, D.D.; A chiral synthesis of dapoxetine hydrochloride, a serotonin reuptake inhibitor, and its 14C isotopomer. J Label Compd Radiopharm 1992, 31, 4, 305.

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)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(II)	12963	Malonic acid	141-82-2	C₃H₄O₄	详情	详情
(III)	59224	3-(3-Aminophenyl)propionic acid; beta-Aminohydrocinnamic acid; DL-3-Amino-3-phenylpropionic acid; 3-Amino-3-phenylpropionic acid	614-19-7	C₉H₁₁NO₂	详情	详情
(IV)	59221	N,N-dimethyl-3-phenyl-beta-alanine		C₁₁H₁₅NO₂	详情	详情
(V)	59222	ethyl 3-(dimethylamino)-3-phenylpropanoate		C₁₃H₁₉NO₂	详情	详情
(VI)	54905	Cinnamic acid ethylester; Ethyl cinnamate		C₁₁H₁₂O₂	详情	详情
(VII)	59223	3-(dimethylamino)-3-phenyl-1-propanol		C₁₁H₁₇NO	详情	详情
(VIII)	40503	1-fluoronaphthalene	321-38-0	C₁₀H₇F	详情	详情

合成路线2

An alternative synthesis starting from the chiral precursor N-Boc-(R)-phenylglycine (IX) was reported. Borane reduction of (IX) provided the N-Boc aminoalcohol (X), which was activated as the mesylate (XI) by reaction with methanesulfonyl chloride in pyridine, yielding (XI). Displacement of the mesylate group of (XI) with NaCN furnished the Boc-aminonitrile (XII). Hydrolysis of the nitrile group of (XII) with concomitant N-Boc group cleavage under acidic conditions gave aminoacid (XIII). This was reduced to amino alcohol (XIV) using borane in THF. Eschweiler-Clarke methylation of aminoalcohol (XIV) yielded the dimethyl amine (XV). This was finally condensed with 1-fluoronaphthalene (VIII) to produce the title naphthyl ether. The [14C]-labeled compound was similarly prepared employing 14C-sodium cyanide.

参考文献中间体

【1】 Wheeler, W.J.; O'Bannon, D.D.; A chiral synthesis of dapoxetine hydrochloride, a serotonin reuptake inhibitor, and its 14C isotopomer. J Label Compd Radiopharm 1992, 31, 4, 305.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	40503	1-fluoronaphthalene	321-38-0	C₁₀H₇F	详情	详情
(IX)	22613	(2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid	2900-27-8	C₁₃H₁₇NO₄	详情	详情
(X)	59225	(R)-N-(tert-Butoxycarbonyl)-phenylglycinol; N-t-BOC-D-phenylglycinol	102089-74-7	C₁₃H₁₉NO₃	详情	详情
(XI)	59226	(2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl methanesulfonate		C₁₄H₂₁NO₅S	详情	详情
(XII)	59227	tert-butyl (1S)-2-cyano-1-phenylethylcarbamate		C₁₄H₁₈N₂O₂	详情	详情
(XIII)	56272	(3R)-3-amino-3-phenylpropanoic acid		C₉H₁₁NO₂	详情	详情
(XIV)	59228	(R)-3-Amino-3-phenylpropan-1-ol		C₉H₁₃NO	详情	详情
(XV)	59229	(3S)-3-(dimethylamino)-3-phenyl-1-propanol		C₁₁H₁₇NO	详情	详情

合成路线3

The synthesis of the [11C]-labeled compound was also reported. Selective tosylation of the primary hydroxyl of (R)-1-phenyl-1,3-propanediol (XVI) provided (XVII). From this, naphthyl ether (XIX) was prepared by Williamson's synthesis with the sodium alkoxide of 1-naphthol (XVIII). The remaining hydroxyl group of (XIX) was then converted to mesylate (XX) upon treatment with methanesulfonyl chloride and DMAP. Subsequent displacement with methylamine in a sealed vessel afforded the secondary amine (XXI). This was finally alkylated with 11CH3I to yield the target 11C-labeled compound.

参考文献中间体

【1】 Livni, E.; et al.; Synthesis of [11C]dapoxetine.HCl, a serotonin re-uptake inhibitor: biodistribution in rat and preliminary PET imaging in the monkey. Nucl Med Biol 1994, 21, 4, 669.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	59233	(R)-(+)-1-phenyl-1,3-propanediol; (R)-1-Phenyl-1,3-propanediol	103548-16-9	C₉H₁₂O₂	详情	详情
(XVII)	59234	(3R)-3-hydroxy-3-phenylpropyl 4-methylbenzenesulfonate		C₁₆H₁₈O₄S	详情	详情
(XVIII)	22935	alpha-naphthol; 1-naphthol	90-15-3	C₁₀H₈O	详情	详情
(XIX)	59230	(1R)-3-(1-naphthyloxy)-1-phenyl-1-propanol		C₁₉H₁₈O₂	详情	详情
(XX)	59231	(1R)-3-(1-naphthyloxy)-1-phenylpropyl methanesulfonate		C₂₀H₂₀O₄S	详情	详情
(XXI)	59232	N-methyl-N-[(1S)-3-(1-naphthyloxy)-1-phenylpropyl]amine; (1S)-N-methyl-3-(1-naphthyloxy)-1-phenyl-1-propanamine		C₂₀H₂₁NO	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)