1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid [(S)-2-biphenyl-4-yl-1-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-ethyl]-amide

HRID 1264401Notes

Reaction equation

HRID 1264401 reaction equation
[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39](O)=[O:40])(=[O:13])=[O:12].[NH2:42][C@H:43]([C:57]1[N:61]([CH2:62][CH2:63][C:64]#[N:65])[N:60]=[N:59][N:58]=1)[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:47][CH:46]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:48]1([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:49]=[CH:50][C:45]([CH2:44][C@H:43]([NH:42][C:39]([C@@H:15]2[CH2:16][C@@H:17]([S:19][C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18][N:14]2[S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:12])=[O:13])=[O:40])[C:57]2[N:61]([CH2:62][CH2:63][C:64]#[N:65])[N:60]=[N:59][N:58]=2)=[CH:46][CH:47]=1

Participants

6

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 22849544(1S)-3-[5-(1-Amino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrileHCID 69428772(2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid

Product 1

HCID 86585051(2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid [(S)-2-biphenyl-4-yl-1-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-ethyl]-amideYield 81%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 520 mg (0.9 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid and 315 mg (1 mmol) (1S)-3-[5-(1-Amino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile [S. De Lombaert. Preparation of tetrazolylalkylaminomethylphosphonates as neutral endopeptidase inhibitors. U.S., 17 pp. CODEN: USXXAM. U.S. Pat. No. 5,273,990 A 931228] in 5 ml THF was cooled to 0° C. and treated with 206 mg (1.1 mmol) EDCI and 14 mg (0.09 mmol) HOBT. The reaction was stirred for 3 h at RT and partitioned between aqueous 10% KHSO4/ethyl acetate (3×). The organic phases were washed with aqueous saturated NaHCO3 solution and dried over Na2SO4. Purification by flash-chromatography on silicagel (Hexane/EtOAc 1:1) gave 639 mg (81%) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid [(S)-2-biphenyl-4-yl-1-[1-(2-cyano-ethyl)- 1H-tetrazol-5-yl]-ethyl]-amide, Mp: 122-133 slow dec, MS: 880 (MH+).

Workup

  1. custompartitioned between aqueous 10% KHSO4/ethyl acetate (3×)
  2. washThe organic phases were washed with aqueous saturated NaHCO3 solution
  3. dry with materialdried over Na2SO4
  4. customPurification by flash-chromatography on silicagel (Hexane/EtOAc 1:1)

Sources & evidence

ORD record
ord-bc71f4c16f30437c91ba0dc8c2af4627
Source dataset
uspto-grants-2003_04
Patent number
US06541638B2

Reaction notes

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