Hydrochloric Acid → (3R*,5S*)-3-amino-5-{[4-chloro-3-(3-methoxy-propoxy)-benzyl]-cyclopropyl-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride

HRID 1698312Notes

Reaction equation

HRID 1698312 reaction equation
[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24]C(OC(C)(C)C)=O)[CH2:21][C@H:20]([C:32](O)=[O:33])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC(=CC1=2)[Cl:49])=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:69][C:70]1[CH:80]=[CH:79][C:73]([CH2:74][NH:75][CH:76]2[CH2:78][CH2:77]2)=[CH:72][C:71]=1[O:81][CH2:82][CH2:83][CH2:84][O:85][CH3:86].Cl>C(Cl)Cl.CC#N>[ClH:49].[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:19][C@@H:20]([C:32](=[O:33])[N:75]([CH2:74][C:73]4[CH:79]=[CH:80][C:70]([Cl:69])=[C:71]([O:81][CH2:82][CH2:83][CH2:84][O:85][CH3:86])[CH:72]=4)[CH:76]4[CH2:78][CH2:77]4)[CH2:21][C@@H:22]([NH2:24])[CH2:23]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 42624899O-(6-Chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphateHCID 57870323HCID 57870323, compoundHCID 67273287N-{[4-Chloro-3-(3-methoxypropoxy)phenyl]methyl}cyclopropanamine

Product 1

HCID 131729669(3R*,5S*)-3-amino-5-{[4-chloro-3-(3-methoxy-propoxy)-benzyl]-cyclopropyl-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride

Reagents, catalysts & solvents 1

HCID 21877088Acetonitrile methylene chlorideSolvent

Procedure

A mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (1.78 g, 3.82 mmol), HCTU (1.75 g, 4.23 mmol) and DIPEA (265.3 μl, 1.55 mmol) in a 1:1 mixture of CH2Cl2/CH3CN (20 ml) is stirred for 10 min at RT. After cooling to 5° C., [4-chloro-3-(3-methoxy-propoxy)-benzyl]-cyclopropyl-amine (1.04 g, 3.86 mmol) is added in one portion. The ice-bath is removed and the mixture stirred for 14 h at RT. The reaction mixture is diluted with ethyl acetate and washed twice with K2CO3 solution. The organic layer is dried (Na2SO4) and evaporated. The crude oil thus obtained is stirred with HCl (5M in 2-propanol, 12 ml, 60 mmol) for 1 h and then evaporated to afford the title compound as a yellow oil. tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 6.31 min.

Workup

  1. temperatureAfter cooling to 5° C.
  2. customThe ice-bath is removed
  3. stirringthe mixture stirred for 14 h at RT
  4. additionThe reaction mixture is diluted with ethyl acetate
  5. washwashed twice with K2CO3 solution
  6. dry with materialThe organic layer is dried (Na2SO4)
  7. customevaporated
  8. customThe crude oil thus obtained
  9. customevaporated

Sources & evidence

ORD record
ord-f7973cdf1ef54ef7946b95ebeec86831
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

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