2-(3,4-Dichloro-phenylamino)-propionic Acid → 4-(3,4-Dichloro-phenyl)-1-[(s)-3-hydroxy-4-((s)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-3-methyl-piperazin-2-one

HRID 1096299Notes

Reaction equation

HRID 1096299 reaction equation
[CH2:1](OC(=O)NCC[C@H](O)CO)[C:2]1C=CC=CC=1.[NH2:18][CH2:19][CH2:20][C@H:21](O)[CH2:22][OH:23].[CH3:25]OC(OC)CNCC[C@H](O)CO.ClC1C=C(NC(C)C(O)=O)C=CC=1Cl.[Cl:52][C:53]1[CH:54]=[C:55]([NH:60][CH:61]([CH3:77])[C:62]([N:64]([CH2:71][CH2:72][C@H:73]([OH:76])[CH2:74]O)[CH2:65][CH:66](OC)OC)=[O:63])[CH:56]=[CH:57][C:58]=1[Cl:59].ClC1C=C(N2CCN(CC[C@H](O)CO)C(=O)C2C)C=CC=1Cl.Cl.C1C2(CCNC[C@H]2O)C1>>[Cl:52][C:53]1[CH:54]=[C:55]([N:60]2[CH2:66][CH2:65][N:64]([CH2:71][CH2:72][C@H:73]([OH:76])[CH2:74][N:18]3[CH2:19][CH2:20][C:21]4([CH2:2][CH2:1]4)[C@H:22]([OH:23])[CH2:25]3)[C:62](=[O:63])[CH:61]2[CH3:77])[CH:56]=[CH:57][C:58]=1[Cl:59]

Participants

8

Reactant 7

HCID 69164262-(3,4-Dichloro-phenylamino)-propionic Acid2×HCID 44541812(4S)-6-Azaspiro[2.5]octan-4-ol hydrochloride2×HCID 55281176(2S)-4-aminobutane-1,2-diolHCID 667827584-(3,4-Dichloro-phenyl)-1-((s)-3,4-dihydroxy-butyl)-3-methyl-piperazin-2-oneHCID 66782998(S)-Benzyl(3,4-dihydroxybutyl)carbamateHCID 667836492-(3,4-Dichloro-phenylamino)-n-((s)-3,4-dihydroxy-butyl)-n-(2,2-dimethoxy-ethyl)-propionamideHCID 87149782(s)-4-(2,2-Dimethoxy-ethylamino)-butane-1,2-diol

Product 1

HCID 591592614-(3,4-Dichloro-phenyl)-1-[(s)-3-hydroxy-4-((s)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-3-methyl-piperazin-2-one

Procedure

The title compound was produced in analogy with example 106, steps A-G. Thus, esterification of (S)-4-benzyloxycarbonylamino-2-hydroxy-butyric acid gave (S)-4-benzyloxycarbonylamino-2-hydroxy-butyric acid ethyl ester, which was reduced in step B, leading to ((S)-3,4-dihydroxy-butyl)-carbamic acid benzyl ester. Hydrogenation in step C led to (S)-4-amino-butane-1,2-diol, followed by reductive alkylation in step D, thus producing (S)-4-(2,2-dimethoxy-ethylamino)-butane-1,2-diol. This was coupled with 2-(3,4-dichloro-phenylamino)-propionic acid (intermediate 11) to 2-(3,4-dichloro-phenylamino)-N—((S)-3,4-dihydroxy-butyl)-N-(2,2-dimethoxy-ethyl)-propionamide in step E, followed by reductive cyclization in step F, leading to 4-(3,4-dichloro-phenyl)-1-((S)-3,4-dihydroxy-butyl)-3-methyl-piperazin-2-one. Finally, mesylation and intramolecular cyclization, followed by reaction with (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) in step G afforded 4-(3,4-dichloro-phenyl)-1-[(S)-3-hydroxy-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-3-methyl-piperazin-2-one. Light yellow foam, MS: 456.2 (M+H)+.

Sources & evidence

ORD record
ord-7eae76ffc2614a6ebadb80fe678b4498
Source dataset
uspto-grants-2012_03
Patent number
US08138175B2

Reaction notes

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