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Chemical Structure| 165727-45-7 Chemical Structure| 165727-45-7

Structure of 165727-45-7

Chemical Structure| 165727-45-7

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Product Details of [ 165727-45-7 ]

CAS No. :165727-45-7
Formula : C15H22ClNO3
M.W : 299.79
SMILES Code : O=C(OC(C)(C)C)N[C@H]([C@H](O)CCl)CC1=CC=CC=C1
MDL No. :MFCD02183480
Boiling Point : No data available
InChI Key :GFGQSTIUFXHAJS-QWHCGFSZSA-N
Pubchem ID :7146645

Safety of [ 165727-45-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 165727-45-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 20
Num. arom. heavy atoms 6
Fraction Csp3 0.53
Num. rotatable bonds 8
Num. H-bond acceptors 3.0
Num. H-bond donors 2.0
Molar Refractivity 80.34
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

58.56 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.95
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.92
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.72
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

2.57
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

2.83
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.8

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.23
Solubility 0.176 mg/ml ; 0.000586 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-3.81
Solubility 0.0463 mg/ml ; 0.000155 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-4.29
Solubility 0.0156 mg/ml ; 0.0000519 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.06 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.33

Application In Synthesis of [ 165727-45-7 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 165727-45-7 ]

[ 165727-45-7 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 102123-74-0 ]
  • [ 165727-45-7 ]
  • [ 162536-40-5 ]
YieldReaction ConditionsOperation in experiment
With hydrogen;Ru(S-P-Phos)Cl2(dmf)2; In methanol; at 65℃; under 15001.5 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; A series of experiments were carried out with the following ligands coordinated to ruthenium:; Some results of this study are shown in Table 1:; Table 1EntryCatalystT (°C)P(bar)Conv (percent) (HPLC)Product (HPLC)d.e (percent)config1Ru(S-Xyl-P-Phos)(acac)250io51822R.3S2Ru (S-P-Phos) Cl2 (dmf)2652089792R,3SReaction conditions: 1mmol substrate, S/C ratio = 100/1, 4mL MeOH, unoptimized reaction time 20 hrs.
With hydrogen;(R)-[RuCI2(BINAP)]n; In ethanol; at 55℃; under 3361.55 Torr; for 16h;Parr autoclave;Product distribution / selectivity; The reduction of BocChloroketone with a BINAP catalyst (R)-[RuCI2(BINAP)]n at 4.5bar hydrogen (65psi) at 55°C in ethanol, substrate/catalyst ratiol000:1 gave negligible reaction after 16h. 97.4percent starting material, 1.05percent product, de 58percent in favour of R,S (dr 3.8:1). The result suggests that Ru-BINAP is not an efficient catalyst for this conversion and the selectivity is poor.
With hydrogen;[Rh(R-PCyCo-BoPhoz)(COD)]OTf; In ethanol; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 16.Table 16EntryLigandSolventConv(percent) (HPLC)Product (HPLC)d.e (percent)config1(S-Et-BoPhoz)y MeOH94832R,3S2(S-Et-BoPhoz)THFt 52512R.3S3(S-Et-BoPhoz)BOH73422R.3S4(R-Et-BoPhoz)MeOH9545L2R,3S5(R-Et-BoPhoz)DCE15792R.3S6(S-PCyCo-BoPhoz)MeOHToo632S.3S7(S-PCyCo-BoPhoz) jTHF74392R.3S8(S-PCyCo-BoPhoz)EtOH99342S.3S9(S-PCyCo-BoPhoz)'PrOH9973h 2S.3S10(S-PCyCo-BoPhoz)DCE15142R.3S11(R-PCyCo-BoPhoz)EtOH100522R.3SaReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(S-PCyCo-BoPhoz)(COD)]OTf; In isopropyl alcohol; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 16.Table 16EntryLigandSolventConv(percent) (HPLC)Product (HPLC)d.e (percent)config1(S-Et-BoPhoz)y MeOH94832R,3S2(S-Et-BoPhoz)THFt 52512R.3S3(S-Et-BoPhoz)BOH73422R.3S4(R-Et-BoPhoz)MeOH9545L2R,3S5(R-Et-BoPhoz)DCE15792R.3S6(S-PCyCo-BoPhoz)MeOHToo632S.3S7(S-PCyCo-BoPhoz) jTHF74392R.3S8(S-PCyCo-BoPhoz)EtOH99342S.3S9(S-PCyCo-BoPhoz)'PrOH9973h 2S.3S10(S-PCyCo-BoPhoz)DCE15142R.3S11(R-PCyCo-BoPhoz)EtOH100522R.3SaReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(S-PCyCo-BoPhoz)(COD)]OTf; In ethanol; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 16.Table 16EntryLigandSolventConv(percent) (HPLC)Product (HPLC)d.e (percent)config1(S-Et-BoPhoz)y MeOH94832R,3S2(S-Et-BoPhoz)THFt 52512R.3S3(S-Et-BoPhoz)BOH73422R.3S4(R-Et-BoPhoz)MeOH9545L2R,3S5(R-Et-BoPhoz)DCE15792R.3S6(S-PCyCo-BoPhoz)MeOHToo632S.3S7(S-PCyCo-BoPhoz) jTHF74392R.3S8(S-PCyCo-BoPhoz)EtOH99342S.3S9(S-PCyCo-BoPhoz)'PrOH9973h 2S.3S10(S-PCyCo-BoPhoz)DCE15142R.3S11(R-PCyCo-BoPhoz)EtOH100522R.3SaReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(S-PCyCo-BoPhoz)(COD)]OTf; In 1,2-dichloro-ethane; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 16.Table 16EntryLigandSolventConv(percent) (HPLC)Product (HPLC)d.e (percent)config1(S-Et-BoPhoz)y MeOH94832R,3S2(S-Et-BoPhoz)THFt 52512R.3S3(S-Et-BoPhoz)BOH73422R.3S4(R-Et-BoPhoz)MeOH9545L2R,3S5(R-Et-BoPhoz)DCE15792R.3S6(S-PCyCo-BoPhoz)MeOHToo632S.3S7(S-PCyCo-BoPhoz) jTHF74392R.3S8(S-PCyCo-BoPhoz)EtOH99342S.3S9(S-PCyCo-BoPhoz)'PrOH9973h 2S.3S10(S-PCyCo-BoPhoz)DCE15142R.3S11(R-PCyCo-BoPhoz)EtOH100522R.3SaReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(S-PCyCo-BoPhoz)(COD)]OTf; In tetrahydrofuran; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 16.Table 16EntryLigandSolventConv(percent) (HPLC)Product (HPLC)d.e (percent)config1(S-Et-BoPhoz)y MeOH94832R,3S2(S-Et-BoPhoz)THFt 52512R.3S3(S-Et-BoPhoz)BOH73422R.3S4(R-Et-BoPhoz)MeOH9545L2R,3S5(R-Et-BoPhoz)DCE15792R.3S6(S-PCyCo-BoPhoz)MeOHToo632S.3S7(S-PCyCo-BoPhoz) jTHF74392R.3S8(S-PCyCo-BoPhoz)EtOH99342S.3S9(S-PCyCo-BoPhoz)'PrOH9973h 2S.3S10(S-PCyCo-BoPhoz)DCE15142R.3S11(R-PCyCo-BoPhoz)EtOH100522R.3SaReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(S-PCyCo-BoPhoz)(COD)]OTf; In methanol; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 16.Table 16EntryLigandSolventConv(percent) (HPLC)Product (HPLC)d.e (percent)config1(S-Et-BoPhoz)y MeOH94832R,3S2(S-Et-BoPhoz)THFt 52512R.3S3(S-Et-BoPhoz)BOH73422R.3S4(R-Et-BoPhoz)MeOH9545L2R,3S5(R-Et-BoPhoz)DCE15792R.3S6(S-PCyCo-BoPhoz)MeOHToo632S.3S7(S-PCyCo-BoPhoz) jTHF74392R.3S8(S-PCyCo-BoPhoz)EtOH99342S.3S9(S-PCyCo-BoPhoz)'PrOH9973h 2S.3S10(S-PCyCo-BoPhoz)DCE15142R.3S11(R-PCyCo-BoPhoz)EtOH100522R.3SaReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;(Rp)-pseudo-o-bis(di(3,5-dimethylphenyl)phosphino)[2.2]paracyclophane; bis(cycloocta-1,5-diene)rhodium(I) trifluoromethanesulfonate; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 18:Table 18EntryRh precursorConv(percent) (HPLC)Product (HPLC)d.e (percent)config1[Rh(NBD)2]BF49961^ 2R,3S2[Rh("COD)2pTf10077h2R,3S3[Rh(ethylene)2cF|29245h2R,3S4[Rh(ethyiene)2(acac)j87h 46h 2R.3S5rRh(C6j2"(OA"CJJ2431 48t 2R,3SaReaction conditions: 1mmol substrate, catalyst generated in situ from the corresponding Rh precursor and R-Xyl-PhanePhos. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;(Rp)-pseudo-o-bis(di(3,5-dimethylphenyl)phosphino)[2.2]paracyclophane; bis(ethylene)rhodium acetylacetonate; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 18:Table 18EntryRh precursorConv(percent) (HPLC)Product (HPLC)d.e (percent)config1[Rh(NBD)2]BF49961^ 2R,3S2[Rh("COD)2pTf10077h2R,3S3[Rh(ethylene)2cF|29245h2R,3S4[Rh(ethyiene)2(acac)j87h 46h 2R.3S5rRh(C6j2"(OA"CJJ2431 48t 2R,3SaReaction conditions: 1mmol substrate, catalyst generated in situ from the corresponding Rh precursor and R-Xyl-PhanePhos. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(R-Xyl-PhanePhos)(NBD)]BF4; In methanol; at 50℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; The following ligands coordinated to rhodium were chosen for initial experimental studies.OMe OMeMeO' ^"PPh2 MeO MeO^^k ^PPh2 MeOPXyl2 PXyl2Ph2P PPh2i iNHPPh2 NHPPh2H 00OMe Xyl-P-PhosH8-BINAMPSpirOPPhanephos Xyl-Phanephos MeOXyl-Phanephos Cy-Phanephos'Pr-Phanepho"'."jf ,--'""N.^MeO^^P'Pr2 FeDIPFcMe-DUPHOSMeODIPAMPSome results of this study are shown in Table 14.Table 14EntryCatalyst(°C)P(bar)Conv (percent) (HPLC)Product . (HPLC)d.econfig1[Rh(R-Xyl-PhanePhos)(NBD)]BF4501096502R.3S2[Rh(S-MeOXyl-PhanePhos)(NBD)]BF45010100562R.3S3[Rh(R-Me-DuPhos)(COD)]OTf501015682R.3S4[Rh(R-SpirOP)(NBD)]BF4501011842R.3SReaction conditions: 1mmol substrate, S/C ratio = 100/1, 4ml_ MeOH, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(S-MeOXyl-PhanePhos)(NBD)]BF4; In methanol; at 50℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; The following ligands coordinated to rhodium were chosen for initial experimental studies.OMe OMeMeO' ^"PPh2 MeO MeO^^k ^PPh2 MeOPXyl2 PXyl2Ph2P PPh2i iNHPPh2 NHPPh2H 00OMe Xyl-P-PhosH8-BINAMPSpirOPPhanephos Xyl-Phanephos MeOXyl-Phanephos Cy-Phanephos'Pr-Phanepho"'."jf ,--'""N.^MeO^^P'Pr2 FeDIPFcMe-DUPHOSMeODIPAMPSome results of this study are shown in Table 14.Table 14EntryCatalyst(°C)P(bar)Conv (percent) (HPLC)Product . (HPLC)d.econfig1[Rh(R-Xyl-PhanePhos)(NBD)]BF4501096502R.3S2[Rh(S-MeOXyl-PhanePhos)(NBD)]BF45010100562R.3S3[Rh(R-Me-DuPhos)(COD)]OTf501015682R.3S4[Rh(R-SpirOP)(NBD)]BF4501011842R.3SReaction conditions: 1mmol substrate, S/C ratio = 100/1, 4ml_ MeOH, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(R-Me-DuPhos)(COD)]OTf; In methanol; at 50℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; The following ligands coordinated to rhodium were chosen for initial experimental studies.OMe OMeMeO' ^"PPh2 MeO MeO^^k ^PPh2 MeOPXyl2 PXyl2Ph2P PPh2i iNHPPh2 NHPPh2H 00OMe Xyl-P-PhosH8-BINAMPSpirOPPhanephos Xyl-Phanephos MeOXyl-Phanephos Cy-Phanephos'Pr-Phanepho"'."jf ,--'""N.^MeO^^P'Pr2 FeDIPFcMe-DUPHOSMeODIPAMPSome results of this study are shown in Table 14.Table 14EntryCatalyst(°C)P(bar)Conv (percent) (HPLC)Product . (HPLC)d.econfig1[Rh(R-Xyl-PhanePhos)(NBD)]BF4501096502R.3S2[Rh(S-MeOXyl-PhanePhos)(NBD)]BF45010100562R.3S3[Rh(R-Me-DuPhos)(COD)]OTf501015682R.3S4[Rh(R-SpirOP)(NBD)]BF4501011842R.3SReaction conditions: 1mmol substrate, S/C ratio = 100/1, 4ml_ MeOH, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(S-Et-BoPhoz)(COD)]OTf; In ethanol; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 16.Table 16EntryLigandSolventConv(percent) (HPLC)Product (HPLC)d.e (percent)config1(S-Et-BoPhoz)y MeOH94832R,3S2(S-Et-BoPhoz)THFt 52512R.3S3(S-Et-BoPhoz)BOH73422R.3S4(R-Et-BoPhoz)MeOH9545L2R,3S5(R-Et-BoPhoz)DCE15792R.3S6(S-PCyCo-BoPhoz)MeOHToo632S.3S7(S-PCyCo-BoPhoz) jTHF74392R.3S8(S-PCyCo-BoPhoz)EtOH99342S.3S9(S-PCyCo-BoPhoz)'PrOH9973h 2S.3S10(S-PCyCo-BoPhoz)DCE15142R.3S11(R-PCyCo-BoPhoz)EtOH100522R.3SaReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(S-Et-BoPhoz)(COD)]OTf; In tetrahydrofuran; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 16.Table 16EntryLigandSolventConv(percent) (HPLC)Product (HPLC)d.e (percent)config1(S-Et-BoPhoz)y MeOH94832R,3S2(S-Et-BoPhoz)THFt 52512R.3S3(S-Et-BoPhoz)BOH73422R.3S4(R-Et-BoPhoz)MeOH9545L2R,3S5(R-Et-BoPhoz)DCE15792R.3S6(S-PCyCo-BoPhoz)MeOHToo632S.3S7(S-PCyCo-BoPhoz) jTHF74392R.3S8(S-PCyCo-BoPhoz)EtOH99342S.3S9(S-PCyCo-BoPhoz)'PrOH9973h 2S.3S10(S-PCyCo-BoPhoz)DCE15142R.3S11(R-PCyCo-BoPhoz)EtOH100522R.3SaReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(R-Xyl-PhanePhos)(COD)]OTf; In butan-1-ol; at 50℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 17.Table 17EntryLigandSolventConv (percent) (HPLC)Product (HPLC)d.e (percent)config1(R-Xyl-PhanePhos)MeOH100632R,3S2(R-Xyl-PhanePhos)EtOH100772R,3S3(R-Xyl-PhanePhos)10percentH2O-EtOH100802R,3S4(R-Xyl-PhanePhos)1-BuOH100792R,3S5(R-Xyl-PhanePhos)10percent H20-BuOH100842R.3SReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4mL solvent, 50°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(R-Xyl-PhanePhos)(COD)]OTf; In ethanol; at 50℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 17.Table 17EntryLigandSolventConv (percent) (HPLC)Product (HPLC)d.e (percent)config1(R-Xyl-PhanePhos)MeOH100632R,3S2(R-Xyl-PhanePhos)EtOH100772R,3S3(R-Xyl-PhanePhos)10percentH2O-EtOH100802R,3S4(R-Xyl-PhanePhos)1-BuOH100792R,3S5(R-Xyl-PhanePhos)10percent H20-BuOH100842R.3SReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4mL solvent, 50°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(R-Xyl-PhanePhos)(COD)]OTf; In methanol; at 50 - 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; The following ligands coordinated to rhodium were chosen for experimental studies:PV ,Ph PPPh2Phv fh P,PPh2 -EtPh PPh PCy2Ph. fhPPh,OY~Me ^MN~Et 0-AEt ^AHFeFeFeFeMeBoPhozEtBoPhozPCycoBoPhozProBoPhozSome results of this study are shown in Table 15.Table 15EntryLigandSolventConv(percent) (HPLC)Product (HPLC).d:e (percent) J .cqnfjg1lS-Me:BoPhc)z)MeOH98722R,3S(S-Et-BoPhoz)MeOH94832R,3SIR-Xy^PhjmePhos^MeOH10059 2R.3SReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4mL MeOH, 65°C, 10 bar, unoptimized reaction time 20 hrs.; Example 17Influence of the solvent on the hvdrogenation of BocChloroketone in the presence of fRh(COD21QTf/Xvl-PhanePhos systemsSome results of this study are shown in Table 17.Table 17EntryLigandSolventConv (percent) (HPLC)Product (HPLC)d.e (percent)config1(R-Xyl-PhanePhos)MeOH100632R,3S2(R-Xyl-PhanePhos)EtOH100772R,3S3(R-Xyl-PhanePhos)10percentH2O-EtOH100802R,3S4(R-Xyl-PhanePhos)1-BuOH100792R,3S5(R-Xyl-PhanePhos)10percent H20-BuOH100842R.3SReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4mL solvent, 50°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(R-Et-BoPhoz)(COD)]OTf; In 1,2-dichloro-ethane; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 16.Table 16EntryLigandSolventConv(percent) (HPLC)Product (HPLC)d.e (percent)config1(S-Et-BoPhoz)y MeOH94832R,3S2(S-Et-BoPhoz)THFt 52512R.3S3(S-Et-BoPhoz)BOH73422R.3S4(R-Et-BoPhoz)MeOH9545L2R,3S5(R-Et-BoPhoz)DCE15792R.3S6(S-PCyCo-BoPhoz)MeOHToo632S.3S7(S-PCyCo-BoPhoz) jTHF74392R.3S8(S-PCyCo-BoPhoz)EtOH99342S.3S9(S-PCyCo-BoPhoz)'PrOH9973h 2S.3S10(S-PCyCo-BoPhoz)DCE15142R.3S11(R-PCyCo-BoPhoz)EtOH100522R.3SaReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(R-Et-BoPhoz)(COD)]OTf; In methanol; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 16.Table 16EntryLigandSolventConv(percent) (HPLC)Product (HPLC)d.e (percent)config1(S-Et-BoPhoz)y MeOH94832R,3S2(S-Et-BoPhoz)THFt 52512R.3S3(S-Et-BoPhoz)BOH73422R.3S4(R-Et-BoPhoz)MeOH9545L2R,3S5(R-Et-BoPhoz)DCE15792R.3S6(S-PCyCo-BoPhoz)MeOHToo632S.3S7(S-PCyCo-BoPhoz) jTHF74392R.3S8(S-PCyCo-BoPhoz)EtOH99342S.3S9(S-PCyCo-BoPhoz)'PrOH9973h 2S.3S10(S-PCyCo-BoPhoz)DCE15142R.3S11(R-PCyCo-BoPhoz)EtOH100522R.3SaReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;(Rp)-pseudo-o-bis(di(3,5-dimethylphenyl)phosphino)[2.2]paracyclophane; diacetatetetracarbonyl dirhodium(I); at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 18:Table 18EntryRh precursorConv(percent) (HPLC)Product (HPLC)d.e (percent)config1[Rh(NBD)2]BF49961^ 2R,3S2[Rh("COD)2pTf10077h2R,3S3[Rh(ethylene)2cF|29245h2R,3S4[Rh(ethyiene)2(acac)j87h 46h 2R.3S5rRh(C6j2"(OA"CJJ2431 48t 2R,3SaReaction conditions: 1mmol substrate, catalyst generated in situ from the corresponding Rh precursor and R-Xyl-PhanePhos. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;(Rp)-pseudo-o-bis(di(3,5-dimethylphenyl)phosphino)[2.2]paracyclophane; bis(ethylene)rhodium(I) chloride dimer; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 18:Table 18EntryRh precursorConv(percent) (HPLC)Product (HPLC)d.e (percent)config1[Rh(NBD)2]BF49961^ 2R,3S2[Rh("COD)2pTf10077h2R,3S3[Rh(ethylene)2cF|29245h2R,3S4[Rh(ethyiene)2(acac)j87h 46h 2R.3S5rRh(C6j2"(OA"CJJ2431 48t 2R,3SaReaction conditions: 1mmol substrate, catalyst generated in situ from the corresponding Rh precursor and R-Xyl-PhanePhos. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;(Rp)-pseudo-o-bis(di(3,5-dimethylphenyl)phosphino)[2.2]paracyclophane; rhodium(I)-bis(1,5-cyclooctadiene) tetrafluoroborate; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; Some results of this study are shown in Table 18:Table 18EntryRh precursorConv(percent) (HPLC)Product (HPLC)d.e (percent)config1[Rh(NBD)2]BF49961^ 2R,3S2[Rh("COD)2pTf10077h2R,3S3[Rh(ethylene)2cF|29245h2R,3S4[Rh(ethyiene)2(acac)j87h 46h 2R.3S5rRh(C6j2"(OA"CJJ2431 48t 2R,3SaReaction conditions: 1mmol substrate, catalyst generated in situ from the corresponding Rh precursor and R-Xyl-PhanePhos. S/C ratio = 100/1, 4ml_ solvent, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With hydrogen;[Rh(S-Me-BoPhoz)(COD)]OTf; In methanol; at 65℃; under 7500.75 Torr; for 20h;Argonaut Endeavour hydrogenation unit;Product distribution / selectivity; The following ligands coordinated to rhodium were chosen for experimental studies:PV ,Ph PPPh2Phv fh P,PPh2 -EtPh PPh PCy2Ph. fhPPh,OY~Me ^MN~Et 0-AEt ^AHFeFeFeFeMeBoPhozEtBoPhozPCycoBoPhozProBoPhozSome results of this study are shown in Table 15.Table 15EntryLigandSolventConv(percent) (HPLC)Product (HPLC).d:e (percent) J .cqnfjg1lS-Me:BoPhc)z)MeOH98722R,3S(S-Et-BoPhoz)MeOH94832R,3SIR-Xy^PhjmePhos^MeOH10059 2R.3SReaction conditions: 1mmol substrate, [Rh(bisphosphine)(COD)]OTf generated in the corresponding solvent by reacting [Rh(COD)2]OTf with the bisphosphine for 30min under N2. S/C ratio = 100/1, 4mL MeOH, 65°C, 10 bar, unoptimized reaction time 20 hrs.
With isopropyl alcohol;aluminum tri-tert-butoxide; In ethyl acetate;Inert atmosphere;Product distribution / selectivity; The MPV reduction was conducted in various organic solvents as described in Example 3, where the solvent of interest was used in the place of toluene. Isopropanol (10percent) was added to each solvent for the reaction to proceed in a reasonable time.Table 1 shows the results of these reactions. The (R,S)/(S,S) ratio increased when the reaction was run in aprotic polar solvents like ethyl acetate and THF. While not limiting any embodiment by theory, it is believed that the hydrogen bonding between ketone 1 and Al(OiPr)3 may contribute to increasing the rate of reaction by keeping 1 coordinated with the aluminum center, bringing to close proximity the two reactive centers.Table 1. MPV reduction of 1 in various organic solvents

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  • 2
  • [ 102123-74-0 ]
  • [ 165727-45-7 ]
YieldReaction ConditionsOperation in experiment
95% With isopropyl alcohol;aluminum tri-tert-butoxide; In dichloromethane; at 50℃;Inert atmosphere;Product distribution / selectivity; The MPV reduction was conducted in various organic solvents as described in Example 3, where the solvent of interest was used in the place of toluene. Isopropanol (10%) was added to each solvent for the reaction to proceed in a reasonable time.Table 1 shows the results of these reactions. The (R,S)/(S,S) ratio increased when the reaction was run in aprotic polar solvents like ethyl acetate and THF. While not limiting any embodiment by theory, it is believed that the hydrogen bonding between ketone 1 and Al(OiPr)3 may contribute to increasing the rate of reaction by keeping 1 coordinated with the aluminum center, bringing to close proximity the two reactive centers.Table 1. MPV reduction of 1 in various organic solvents.
95% With aluminum sec-butoxide; In 2-methyl-propan-1-ol; toluene; at 15 - 20℃;Large scale; To 10L 4-neck flask were successively added toluene 1.7Kg, compound A (0.5Kg, 1.68mol) After stirring, the solution of isobutanol aluminum (0.246kg, 1.0mol, 0.6equiv.) Isopropanol (0.6Kg, after) was added to the reaction system, stirring was stirred at 15 ~ 20 15 ~ 20 hours.After dropping 2M hydrochloric acid after completion of the reaction to the system (1.3Kg) after quenching system, n-hexane was added 5L stirring, cooling crystallization, after a lot of white solid precipitated, filtered, and the cake was washed with water 0.5L × 6 after drying under vacuum, to give compound B. 0.46KgYield 95%, HPLC purity 95%
83% With sodium borohydrid; acetic acid; In ethanol; toluene; REFERENCE EXAMPLE 1 Production Method of (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane To (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (2.08 g) were added toluene (4.2 ml) and ethanol (16.7 ml). Sodium borohydride (133 mg) was added by portions at -10 C. and the mixture was stirred for 1 hr and 40 min. The reaction was quenched by adding acetic acid (0.40 ml). The reaction mixture was warmed to 60 C. over 1 hr and further stirred 60 C. for 30 min. The reaction mixture was then cooled to -10 C. over 1 hr and 50 min and further stirred at -10 C. for 6 hr. The obtained crystals were collected by filtration, washed with toluene (10.4 ml) and water of 0 C., and dried under reduced pressure to give the objective (2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (1.52 g, yield 83%). The obtained dry crystals were analyzed by HPLC and found to be (2S,3S):(2R,3S)=99.2:0.8 crystals.
56% With sodium borohydrid; sulfuric acid; In tetrahydrofuran; ethanol; Reference Example 1 Production of (2S,3S)1-chloro-2-hydroxy-3-(N-tert-butoxycarbonyl)amino-4-phenylbutane THF (25 ml) and 100 ml of ethanol were added to 25 g of (3S)1-chloro-2-oxo-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane, and the mixture was cooled to 10 C. To this solution was added a solution composed of 1.59 g of sodium borohydride, 25 ml of ethanol and 25 ml of THF. The mixture was stirred at 10 C. to 20 C. for 1 hour. While maintaining the inside temperature at 10 C. to 15 C., 125 ml of 1.6% (wt) aqueous sulfuric acid solution was added and the pH was adjusted to 6.5 with 30% (wt) aqueous sodium hydroxide solution. The temperature was then raised to 50 C. and, after 1 hour of stirring, the mixture was cooled to 5 C. and stirring was continued for 1 hour. The resulting crystals were collected by filtration and subjected to washing under revolving with four portions of 300-mL of a mixed solvent composed of THF/water=1/4 (v/v), two portions of 70-ml of cold ethanol and two portions of 180-mL of water. Drying under vacuum gave 14.6 g of (2S,3S)1-chloro-2-hydroxy-3-(N-tert-butoxycarbonyl)amino-4-phenylbutane as crystals (purity 95.9%, yield 56%). The crystals obtained contained, as the major impurity, 2.6 area percent of (3S)-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane and, as the next major impurity, 1.0 area percent of (2R,3S)1-chloro-2-hydroxy-3-(S)-N-(tert-butoxycarbonyl)amino-4-phenylbutane.
With diisobutylaluminium hydride; In acetone; toluene; EXAMPLE 4 Production of t-butyl [1(S)-benzyl-2(S)-hydroxy-3-chloropropyl]carbamate (I) Acetone (581 mg, 10 mmol) was added to 9.9 ml (10 mmol) of a toluene solution of DIBAH (1.02 M) at room temperature and the mixture was stirred at room temperature for 1 hour. Then, 1.489 g (5 mmol) of t-butyl [1(S)-benzyl-2-oxo-3-chloropropyl]carbamate was added and the resultant mixture was stirred at room temperature for 2 hours. After hydrolysis with 1 N hydrochloric acid, the reaction mixture was extracted with ethyl acetate. Concentration of the extract gave 1.635 g of pale-yellow crystals. The crystals obtained were subjected to quantitative analysis by HPLC and the yield and selectivity were determined.
With diisobutylaluminium hydride; In toluene; cyclohexanol; EXAMPLE 7 Production of t-butyl [1(S)-benzyl-2(S)-hydroxy-3-chloropropyl]carbamate (I) Cyclohexanol (2.0 g, 20 mmol) and 10 ml of toluene were added to 9.8 ml (10 mmol) of a toluene solution of DIBAH (1.02 M) at room temperature and the mixture was stirred at room temperature for 1 hour. Thereto was added 1.489 g (5.0 mmol) of t-butyl [1(S)-benzyl-2-oxo-3-chloropropyl]carbamate, and the resultant mixture was stirred at room temperature for 2 hours, followed by hydrolysis with 1 N hydrochloric acid with ice cooling. Extraction with ethyl acetate and concentration gave 1.53 g of pale-yellow crystals. The crystals obtained were subjected to quantitative analysis by HPLC and the yield and selectivity were determined.
With sodium borohydrid; In tetrahydrofuran; hexane; water; ethyl acetate; Hexane (200 ml) was slowly added and the mixture was allowed to stand for 2 hours at 5 C. The solid was filtered and dried over phosphorus pentoxide under high vacuum to afford 9.58 g (first crop) of (S)-[3-chloro-2-oxo-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester. The filtrate was concentrated to dryness and the residue was again recrystallized from ethyl etherhexane to give an additional 4.41 g (second crop) of (S)-[3-chloro-2-oxo-1-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester. Sodium borohydride (1.59 g; 42 mmol) was added to a solution of (S)-[3-chloro-2-oxo-1(phenylmethyl) propyl]carbamic acid, 1,1-dimethylethyl ester (5g, 16.8 mmol) in tetrahydrofuran (84 ml) and water (9 ml) at 0 C. After stirring at 0 C. for 45 minutes the reaction mixture was concentrated to dryness. The residue was stirred at 0 C. with ethyl acetate (150 ml) and water (25 ml) while saturated potassium bisulfate solution was carefully added until the pH was about 1.5. This mixture was then diluted with ethyl acetate (350 ml) and the layers were separated. The organic layer was washed with water (100 ml) and brine (100 ml). After drying over magnesium sulfate, the organic layer was concentrated to a white solid. A portion of this solid (4.89 g) was recrystallized from hot ethyl acetate (70 ml) to afford 2.47 g of title compound as a white solid containing a small percentage of its diastereomer.
80 g With aluminum isopropoxide; In isopropyl alcohol; for 3h;Reflux; Example -1 : Preparation of [(1S, 2S)-3-chloro-2-hydroxy-1-(phenyl methyl) propyl] carbamic acid tert-butyl ester (5). The solution of (3S)-3-(tert-butoxycarbonyl) amino-1-chloro-4-phenyl-2-butanone (Chloromethyl ketone 6,100 g) and aluminium isopropoxide (35 g) in isoprpylalcohol was heated to mild reflux and maintained for 3 hours. After completion of reaction distilled off isopropyl alcohol up to 50 % under vacuum and the resultant mass was cooled to 25-35C. Water was added to the distillate, pH was adjusted to 3.0-4.0 with acetic acid and maintained the stirring for 2 hours at 25-35C. The obtained solid was filtered and washed with water. The wet cake was taken into isopropyl alcohol (400mL) and heated to reflux for 60minutes, the mass was cooled to 25-35C again maintain the stirring for 60minutes, the obtained solid was filtered and washed with isopropyl alcohol. The wet product was dried under normal drying to get title compound 5 (yield 80 g).
80 g With aluminum isopropoxide; In isopropyl alcohol; for 3h;Reflux; Example 1 Preparation of [(1S,3S)-3-chloro-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid tert-butyl ester (5) The solution of (3S)-3-(tert-butoxycarbonyl) amino-1-chloro-4-phenyl-2-butanone (Chloromethyl ketone 6, 100 g) and aluminium isopropoxide (35 g) in isoprpylalcohol was heated to mild reflux and maintained for 3 hours. After completion of reaction distilled off isopropyl alcohol up to 50% under vacuum and the resultant mass was cooled to 25-35 C. Water was added to the distillate, pH was adjusted to 3.0-4.0 with acetic acid and maintained the stirring for 2 hours at 25-35 C. The obtained solid was filtered and washed with water. The wet cake was taken into isopropyl alcohol (400 mL) and heated to reflux for 60 minutes, the mass was cooled to 25-35 C. again maintain the stirring for 60 minutes, the obtained solid was filtered and washed with isopropyl alcohol. The wet product was dried under normal drying to get title compound 5 (yield 80 g).
With C44H48FeIrNO2P(1+)*C32H12BF24(1-); hydrogen; sodium carbonate; In methanol; at 20℃; for 2h; 50 mmol of the compound of the formula (IV), 5 mmol of sodium carbonate, 0.25 mmol of ferrocene ferrocene-oxazoline catalyst (R=Me) and 300 mL of methanol were added to a strictly dry reaction flask, and nitrogen gas was introduced and replaced with nitrogen three times. Plug the stopper into the dry hydrogen at a flow rate of 20 mL/min, stir the reaction at room temperature for 2 h, stop the reaction, distill off the solvent under reduced pressure, add 100 mL of distilled water and 100 mL of ethyl acetate, stir for 0.5 h, let stand, and separate the water. The layers were washed with EtOAc. EtOAc (EtOAc m.

  • 3
  • [ 102123-74-0 ]
  • [ 165727-45-7 ]
  • [ 162536-40-5 ]
  • (1R,2R)[3-chloro-2-hydroxy-1-(phenylmethyl)propyl]carbamic acid 1,1-dimethylethyl ester [ No CAS ]
  • [ 923601-69-8 ]
  • 4
  • potassium bisulfite [ No CAS ]
  • [ 102123-74-0 ]
  • [ 165727-45-7 ]
YieldReaction ConditionsOperation in experiment
50% With sodium borohydrid; In tetrahydrofuran; water; ethyl acetate; EXAMPLE 3 Preparation of (S,S)-[N-(1-benzyl-2-hydroxy-3-chloro)propyl]carbamic acid t-butyl ester. A solution of (S)-[N-(1-benzyl-2-oxo-3-chloro)propyl]carbamic acid t-butyl ester prepared in Example 2 (5 g, 16.8 mmol) in 84 mL of tetrahydrofuran and 9 mL of water is treated with sodium borohydride (1.59 g, 42 mmol) at 0° C. The temperature is maintained with stirring for 45 minutes, after which the reaction mixture is concentrated to dryness. The residue is stirred at 0° C. with a mixture of 150 mL of ethyl acetate and 25 mL of water while saturated potassium bisulfite solution is carefully added until the pH of the mixture reaches about pH 1.5. The resulting mixture is diluted with 350 mL of ethyl acetate and the layers separated. The organic layer is washed with water and brine, dried over magnesium sulfate and concentrated to a white solid. The material is recrystallized from hot ethyl acetate to afford (S,S)-[N-(1-benzyl-2-hydroxy-3-chloro)propyl]carbamic acid t-butyl ester (2.57 g, 50percent). The minor amount of the (S,R) diastereomer is isolated from the mother liquor.
  • 5
  • [ 100-99-2 ]
  • [ 102123-74-0 ]
  • [ 67-63-0 ]
  • [ 165727-45-7 ]
YieldReaction ConditionsOperation in experiment
In hexane; toluene; EXAMPLE 1 Production of t-butyl [1(S)-benzyl-2(S)-hydroxy-3-chloropropyl]carbamate (I) STR13 To an ice-cooled 1.0 M solution of triisobutylaluminum in hexane (10.5 ml, 10.5 mmol) was added 0.76 ml (10 mmol) of 2-propanol, and the mixture was stirred at room temperature for 30 minutes. After dilution of the mixture with 10 ml of toluene, 0.759 g (2.5 mmol) of t-butyl [1(S)-benzyl-2-oxo-3-chloropropyl]carbamate was added and the resultant mixture was stirred at room temperature for 2 hours. Hydrolysis with 1 N hydrochloric acid, extraction with ethyl acetate and concentration gave 0.840 g of pale-yellow crystals. The crystals obtained were subjected to quantitative analysis by HPLC and the yield and selectivity were determined.
  • 6
  • [ 5419-55-6 ]
  • [ 100-99-2 ]
  • [ 102123-74-0 ]
  • [ 165727-45-7 ]
YieldReaction ConditionsOperation in experiment
In hexane; toluene; EXAMPLE 2 Production of t-butyl [1(S)-benzyl-2(S)-hydroxy-3-chloropropyl]carbamate (I) To a 1.0 M solution of triisobutylaluminum in hexane (10.5 ml, 10.5 mmol) was added 0.47 g (2.5 mmol) of triisopropoxyborane, and the mixture was heated at 170° C. for 2 hours. After cooling to 80° C., the pressure was reduced to 10 mmHg to thereby cause the excess triisobutylborane to distill off. After cooling to room temperature and dilution with 20 ml of toluene, 0.744 g (2.5 mmol) of t-butyl [1(S)-benzyl-2-oxo-3-chloropropyl]carbamate was added and the resultant mixture was stirred at room temperature for 3 hours. Hydrolysis with 1 N hydrochloric acid, extraction with ethyl acetate and concentration gave 0.995 g of pale-yellow crystals. The crystals obtained were subjected to quantitative analysis by HPLC and the yield and selectivity were determined.
  • 7
  • [ 1586-92-1 ]
  • [ 102123-74-0 ]
  • [ 165727-45-7 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In toluene; EXAMPLE 3 Production of t-butyl [1(S)-benzyl-2(S)-hydroxy-3-chloropropyl]carbamate (I) A hexane solution of diethylaluminum ethoxide (about 1 M, 10.4 ml, 10.4 mmol) was diluted with 18 ml of toluene, then 1.489 g (5 mmol) of t-butyl [1(S)-benzyl-2-keto-3-chloropropyl]carbamate was added, and the mixture was stirred at room temperature for 24 hours. After quenching with 1 N hydrochloric acid, the mixture was extracted with ethyl acetate. Concentration of the extract gave 2.560 g of pale-yellow crystals. The crystals obtained were subjected to quantitative analysis by HPLC and the yield and selectivity were determined.
  • 8
  • [ 102123-74-0 ]
  • [ 67-63-0 ]
  • [ 165727-45-7 ]
YieldReaction ConditionsOperation in experiment
90% With diisobutylaluminium hydride; In toluene; (Reference Example 1) Method for synthesis of (2S,3S)-1-chloro-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane from (3S)-1-chloro-2-oxo-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane To 25.2 ml (25.7 mmol) of a solution of diisobutylaluminum hydride (1.02 M) in toluene was added 3.1 g of 2-propanol at room temperature, and the mixture was stirred at room temperature for 1 hour. To this was added 5.1 g (17.1 mmol) of (3S)-1-chloro-2-oxo-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane.The mixture was stirred at room temperature for 2 hours, after which hydrolysis was carried out with 1 N-hydrochloric acid under ice-cooling. This reaction mixture was extracted with ethyl acetate, the aqueous layer was separated, and the organic layer was washed with water to give 101.7 g of a solution containing 4.6 g (yield 90percent) of (2S,3S)-1-chloro-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane.
  • 9
  • [ 91-01-0 ]
  • [ 100-99-2 ]
  • [ 102123-74-0 ]
  • [ 165727-45-7 ]
YieldReaction ConditionsOperation in experiment
With methanesulfonic acid; In hexane; toluene; EXAMPLE 2 Production of [1(S)-benzyl-2(S)-hydroxy-chloropropyl]carbamic acid t-butyl ester (I) A 0.95M hexane solution of triisobutylaluminum (1.05 ml; 1.0 mmol) was diluted with 6 ml of toluene, then 100 mg (1.04 mmol) of methanesulfonic acid was added, and the mixture was stirred at room temperature for 30 minutes. Then, 393 mg (2.13 mmol) of benzhydrol was added, and the resultant mixture was stirred for 30 minutes. To the thus-prepared reducing agent was added 298 mg (1.0 mmol) of [1(S)-benzyl-2-oxo-3-chloropropyl]carbamic acid t-butyl ester, and the mixture was stirred at 25° C. for 16 hours. Hydrolysis with 1 N hydrochloric acid, extraction with ethyl acetate, drying and concentration gave 300 mg of white crystals. The crystals obtained were quantitatively analyzed by HPLC under the same conditions as used in Example 1, and the yields and selectivity were calculated.
  • 10
  • [ 369362-96-9 ]
  • [ 24424-99-5 ]
  • [ 165727-45-7 ]
  • [ 162536-40-5 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; In methanol; water; toluene; at 25℃; for 3h;pH 7.0;Product distribution / selectivity; To an aqueous solution of (2R,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutane hydrochloride (74.4 g) containing its (2S,3S)-form as a diastereomer thereof, which had been obtained in the above-mentioned step (2'f), was added toluene (378 ml), and the mixture was vigorously stirred. The mixture was adjusted to pH 7 with 4 M aqueous sodium hydroxide solution. Keeping pH 7 with 4 M aqueous sodium hydroxide solution, the mixture was added to a mixed solution of di-tert-butyldicarbonate (68.7 g) and toluene (94 ml), and the mixture was vigorously stirred at 25C for 3 hours. The organic layer (606.4 g) was separated, cooled to 0C and filtered. As a result of HPLC analysis, it was found that the filtrate contained (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (64.9 g, yield 68%), and the diastereomer ratio (2R,3S)/(2S,3S) was 95/5. In addition, the peak area ratio of other byproduct was 19.5% relative to (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane.
 

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[ 165727-45-7 ]

Chemical Structure| 923601-69-8

A230104 [923601-69-8]

tert-Butyl ((2R,3R)-4-chloro-3-hydroxy-1-phenylbutan-2-yl)carbamate

Reason: Optical isomers