[6-(1H-Tetrazol-1-yl)pyridine-3-yl]acetic acid → (3R)-3-methyl-6-[2-(4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one

HRID 2173458Notes

Reaction equation

[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:33])[CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH:32]=[N:31][N:30]=[N:29]5)=C[CH:23]=4)[CH:16](C)[CH2:15]3)[CH:9]=2)[C:4](=[O:35])[O:3]1.[N:36]1([C:41]2[N:46]=[CH:45][C:44]([CH2:47][C:48]([OH:50])=[O:49])=[CH:43][CH:42]=2)[CH:40]=[N:39][N:38]=[N:37]1.Cl.[CH3:52][CH:53]1[CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([CH2:63][CH2:64][N:65]3[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]3)[CH:60]=2)[C:55](=[O:71])[O:54]1>>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:33])[CH2:21][C:22]4[CH:23]=[N:36][C:25]([N:28]5[CH:32]=[N:31][N:30]=[N:29]5)=[CH:26][CH:27]=4)[CH2:18][CH2:19]3)[CH:9]=2)[C:4](=[O:35])[O:3]1.[CH3:52][C@H:53]1[CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([CH2:63][CH2:64][N:65]3[CH2:66][CH2:67][N:68]([C:48](=[O:50])[CH2:47][C:44]4[CH:45]=[N:46][C:41]([N:36]5[CH:40]=[N:39][N:38]=[N:37]5)=[CH:42][CH:43]=4)[CH2:69][CH2:70]3)[CH:60]=2)[C:55](=[O:71])[O:54]1.[CH3:52][C@@H:53]1[CH2:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([CH2:63][CH2:64][N:65]3[CH2:66][CH2:67][N:68]([C:48](=[O:49])[CH2:47][C:44]4[CH:45]=[N:46][C:41]([N:36]5[CH:40]=[N:39][N:38]=[N:37]5)=[CH:42][CH:43]=4)[CH2:69][CH2:70]3)[CH:60]=2)[C:55](=[O:71])[O:54]1.[CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][N:17]([C:20](=[O:33])[CH2:21][C:22]4[CH:23]=[N:36][C:25]([N:28]5[CH:32]=[N:31][N:30]=[N:29]5)=[CH:26][CH:27]=4)[CH2:18][CH2:19]3)[CH:9]=2)[C:4](=[O:35])[O:3]1

Participants

Reactant 3

HCID 66524945[6-(1H-Tetrazol-1-yl)pyridine-3-yl]acetic acid

HCID 675156493-methyl-6-[2-(piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one hydrochloride

HCID 675180963-methyl-6-[2-(3-methyl-4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one

Product 3

HCID 69087472(3R)-3-methyl-6-[2-(4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one

HCID 86693044(3S)-3-methyl-6-[2-(4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one 3-Methyl-6-[2-(4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl] acetyl} piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one

HCID 86693045(3S)-3-methyl-6-[2-(4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one

Procedure

(3R)-3-methyl-6-[2-(4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one and (3S)-3-methyl-6-[2-(4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one 3-Methyl-6-[2-(4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one was synthesized according to the procedure described for 3-methyl-6-[2-(3-methyl-4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one, utilizing [6-(1H-tetrazol-1-yl)pyridin-3-yl]acetic acid and 3-methyl-6-[2-(piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one hydrochloride. LC-MS (IE, m/z): 462 [M+1]+. Separation of the two enantiomers was achieved by chiral preparative HPLC using a Chiralcel OD column eluting with 75% EtOH/Heptane to afford (3R)-3-methyl-6-[2-(4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one and (3S)-3-methyl-6-[2-(4-{[6-(1H-tetrazol-1-yl)pyridin-3-yl]acetyl}piperazin-1-yl)ethyl]-3,4-dihydro-1H-isochromen-1-one both having LC-MS (IE, m/z): 462 [M+1]+.

Workup

customSeparation of the two enantiomers
washeluting with 75% EtOH/Heptane

Sources & evidence

ORD record: ord-0edfd04c5a6d401fb820fb789ff0a47a
Source dataset: uspto-grants-2015_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09056859B2

Reaction notes

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