HCID 23728819, compound → HCID 16117687, compound

HRID 249699Notes

Reaction equation

[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH2:5][C@@H:4]([CH3:20])[N:3]1[S:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][CH:27]([C:33]([OH:35])=[O:34])[CH2:28]2)(=[O:23])=[O:22].C[C@H]1N[C@@H](C)CN(CC2C=CC(OC(F)(F)F)=CC=2)C1>>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:18])([F:17])[F:19])=[CH:11][CH:10]=2)[CH2:5][C@@H:4]([CH3:20])[N:3]1[S:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][CH:27]([C:33]([OH:35])=[O:34])[CH2:28]2)(=[O:22])=[O:23].[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:18])([F:17])[F:19])=[CH:11][CH:10]=2)[CH2:5][C@@H:4]([CH3:20])[N:3]1[S:21]([C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH2:26][C@@H:27]([C:33]([OH:35])=[O:34])[CH2:28]2)(=[O:22])=[O:23]

Participants

Reactant 2

HCID 23728819HCID 23728819, compound

HCID 57565304HCID 57565304, compound

Product 2

HCID 16117687HCID 16117687, compound

HCID 23728819HCID 23728819, compound

Procedure

To a solution of 4-(trifluoromethoxy)-benzaldehyde (776 uL, 4.38 mmol) in methylene chloride (30 mL) was added cis-2,6-dimethyl piperazine (1.0 g, 8.77 mmol). After 1 hour sodium triacetoxy borohydride (2.45 g, 8.77 mmol) was added to the mixture. The solution was stirred at room temperature for an additional 4 hours. The reaction was concentrated in vacuo, diluted with ethyl acetate and extracted with 1N HCl (2×50 mL). The aqueous layer was then neutralized with NaOH and extracted with ethyl acetate (3×50 mL). The organic layer was dried (Na2SO4) and concentrated to provide cis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine (1.01 g, 80%). 1H NMR (400 MHz, CD3OD) δ 7.42 (d, 2H), 7.23 (d, 2H), 3.54 (s, 2H), 2.98-2.88 (m, 2H), 2.82-2.74 (m, 2H), 1.69 (t, 2H), 1.05 (d, 6H); LCMS 289.5 (M+1)+. Step 2 4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid: The compound 4-[cis-2,6-dimethyl-4-(4-trifluoromethoxyl-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was synthesized according to the procedure in Example 1 using cis-3,5-dimethyl-1-(4-trifluoromethoxy-benzyl)-piperazine. 1H NMR (400 MHz, CD3OD) δ 7.74-7.64 (m, 4H), 7.47 (d, 1H), 7.39-7.28 (m, 2H), 4.42 (s, 2H), 4.21-2.18 (m, 2H), 3.50-3.34 (m, 5H), 3.33-3.19 (m, 4H), 1.56 (d, 6H); LCMS 497.5 (M+1)+. Step 3 (S)-4-[cis-2,6-Dimethyl-4-(4-trifluoromethoxy-benzyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid: A single enantiomer of Example 2 was obtained with the following protocol. The product from example 2 Step 1 and the product from Example 1 Step 5 were reacted using the conditions outlined in Example 9 Step 6 to yield the racemic methyl ester. Chiral separation using OJ-H, 25% methanol in CO2 (100 bar), 5 mL/min followed by hydrolysis using conditions outlined in Example 1 Step 7 provided (S)-4-(cis-2,6-dimethyl-4-(3-trifluoromethoxy)benzyl)piperazin-1-ylsulfonyl)-2,3-dihydro-1H-indene-2-carboxylic acid. 1H NMR (400 MHz, CD3OD) δ 7.66 (d, 1H), 7.46 (d, 1H), 7.41 (d, 2H), 7.36-7.30 (m, 1H), 7.19 (d, 2H), 4.08-3.99 (m, 1H), 3.94-3.8 (m, 1H), 3.56-3.49 (m, 2H), 3.43 (s, 2H), 3.40-3.22 (m, 3H), 2.57 (t, 2H), 2.09-1.92 (m, 2H), 1.56 (d, 6H); LCMS 513.5

Sources & evidence

ORD record: ord-dd83cdfdcbc343079aad82f3ad0d7708
Source dataset: uspto-grants-2011_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07863276B2

Reaction notes

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