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[ CAS No. 748810-28-8 ] {[proInfo.proName]}

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Chemical Structure| 748810-28-8
Chemical Structure| 748810-28-8
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Product Details of [ 748810-28-8 ]

CAS No. :748810-28-8 MDL No. :MFCD09833303
Formula : C20H32ClNO4 Boiling Point : -
Linear Structure Formula :- InChI Key :JMHYCBFEEFHTMK-IIUXMCBISA-N
M.W : 385.93 Pubchem ID :9930048
Synonyms :
RSD1235 hydrochloride;Vernakalant Hydrochloride;RSD1235, RSD-1235, RSD 1235, Vernakalant HCl, Kynapid, Brinavess;MK-6621

Calculated chemistry of [ 748810-28-8 ]

Physicochemical Properties

Num. heavy atoms : 26
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.7
Num. rotatable bonds : 7
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 109.06
TPSA : 51.16 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 3.66
Log Po/w (WLOGP) : 3.06
Log Po/w (MLOGP) : 1.92
Log Po/w (SILICOS-IT) : 2.98
Consensus Log Po/w : 2.33

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -4.25
Solubility : 0.0218 mg/ml ; 0.0000566 mol/l
Class : Moderately soluble
Log S (Ali) : -4.42
Solubility : 0.0146 mg/ml ; 0.0000377 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -4.01
Solubility : 0.0377 mg/ml ; 0.0000977 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 4.14

Safety of [ 748810-28-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H312-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 748810-28-8 ]

* 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 [ 748810-28-8 ]

[ 748810-28-8 ] Synthesis Path-Downstream   1~12

  • 1
  • [ 794466-70-9 ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
80.95% With hydrogenchloride In tetrahydrofuran; water monomer at 25 - 30℃; 1-3 To this oily substance, tetrahydrofuran (80 mL) was added, and the mixture was stirred uniformly at room temperature.Concentrated hydrochloric acid (36-38%, Wt/Wt, 2.95 g) was added to tetrahydrofuran (32 mL), mixed well, and added dropwise at 25°C to 30°C. , the filter cake was washed with tetrahydrofuran (15mL), dried in a vacuum oven at -0.10-0.095MPa, 55±5°C for 23 hours, (R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylpyrrole-3-ol hydrochloride weighed 8.25 g and had a yield of 80.95%. HPLC showed that the target molecule accounted for 99.92% (see Figure 4).
With hydrogenchloride In tert-butyl methyl ether; isopropanol at 0 - 10℃; for 4.75h; 3 Example 3; Synthesis of ( 3R) -l- { ( IR, 2R) -2- [2- (3, 4- dimethoxyphenyl) ethoxy] cyclohexyDpyrrolidinol hydrochloride(compound (7 ) );.(3R) -3-Benzyloxy-l- { (IR, 2R) -2- [2- (3, 4- dimethoxyphenyl) ethoxy] cyclohexyl jpyrrolidine (compound (5) ) (12.7 g, purity 95.6%) was dissolved in methanol (64 ml) and formic acid ( 64 ml) was added under cooling. Then, 10% palladium carbon ( 12.7 g) was added to allow reaction at 35- 400C for about 3 hr . After the completion of the reaction, palladium carbon was filtered off. Water (20 ml) was added to the filtrate and methanol was evaporated under reduced pressure . Water (20 ml) was added and the mixture was adjusted to 10-12 with 24% aqueous sodium hydroxide solution under cooling . The mixture was extracted three times with isopropyl acetate ( 64 ml ) and the organic layer was washed with water ( 64 ml ) . The organic layer was dried over magnesium sulfate and concentrated to dryness to give (3R) -l- { ( IR, 2R) -2- [2- ( 3, 4- dimethoxyphenyl ) ethoxy] cyclohexyl jpyrrolidinol (compound ( 6) ) as an oil ( 8.8 g) . The obtained oil was in dissolved in isopropyl alcohol (IPA, 88 ml) and the mixture was cooled to 0-100C . 2N Hydrochloric acid/IPA (16.4 ml) was added dropwise over about 15 min while maintaining the same temperature and then methyl-t-butyl ether (MTBE, 88 ml) was added dropwise over about 30 min . After stirring for aging at the same temperature for about 4 hr, the precipitated crystals were collected by filtration and washed with MTBE/IPA ( 1 : 1 ) mixture (35 ml ) cooled in advance . The obtained crystals were vacuum dried to give (3R) -l- { ( IR, 2R) -2- [2- ( 3, 4- dimethoxyphenyl) ethoxy] cyclohexyl jpyrrolidinol hydrochloride (compound (7) ) (7.5 g, purity 99.1%, yield based on purity 69.8%) . compound (7) : EPO MS : m/z 350 (M - HCl + H) + 1H NMR (400MHz, DMSO-d6) : δ 1.03-1.23 (3H, m) , 1.38 ( IH, in) , 1.66-1.81 (3H, m) , 1.91-2.08 (2H, m) , 2.23 ( IH, m) , 2.78 (2H, m) , 3.08-3.60 (7H, in) , 3.71 (3H, s) , 3.74 (3H, s ) , 3.78 ( IH, m) , 4.29 ( IH, s) , 5.43 ( IH, brd) , 6.76 ( IH, d, J=8.0Hz) , 6.86 ( IH, d, J=8.0Hz) , 6.87 ( IH, s)Additional tests were performed according to the same methods as in Examples 1 to 3. To compare the yield, compound A was synthesized from 4R according to the method described in WO2004/099137 (Scheme 1 ) , and the yield based on purity was calculated. The results are shown in the following.
With hydrogenchloride In isopropanol at 20℃; for 0.25h; 1 Synthesis of Ii?- j2R-2-(3 Λ-dimethoxy-phenylVethoxyi-cyclohexyl) - pyrrolidin-3i?-ol hydrochloride (19) from li?-{2i?-[2-(3,4-dimethoxy-phenyl)-ethoxy1- cyclohexyl}-pyrrolidin-3i?-ol (18) (Figure 2).HCl(g) was bubbled through a solution of li?-{2i?-[2-(3,4-dimethoxy-phenyl)- ethoxy]-cyclohexyl}-pyrrolidin-3i?-ol (18) (38.1 g) from the above reaction in isopropanol (150 mL) for 15 min at RT. After the addition of seeding crystals at about 25 to 35 °C the mixture was cooled to about 10 0C and kept at this temperature for 6 h. Filtration, washing of the filter residue with isopropanol (15 mL) and upon drying at about 45 °C in vacuo yielded white crystals of li?~{2i?-[2-(3,4-dimethoxy-phenyl)- ethoxy]-cyclohexyl}-pyrrolidin-3i?-ol hydrochloride (19) (37.9 g, HPLC-purity: 99.1 %).
With hydrogenchloride In diethyl ether; tert-butyl methyl ether 5a.6b.e.f (e) The solution of (19) free base in methyl t-butyl ether (10 mL) was treated with 2M HCl in diethyl ether (2 mL, 2 mmol, Aldrich cat No.455180). After the volatiles were removed in vacuo, crude (19) was obtained as a hygroscopic foam. HPLC analysis (gradient A) of this material revealed a major peak (Rt = 6.5 min).(f) Crude (19) was triturated in EtOAc (1 mL) to give an off-white solid. Chemical purity 80 area% (HPLC gradient B). Rt 6.78 min (HPLC gradient B).Isomeric impurities 0.15% (3R)-I -[(IS, 2S)-2-[2-(3, 4- dimethoxyphenyl) ethoxy] cyclohexyl] -3 -Pyrrolidinol hydrochloride,1.73% (3,S)-I -[(1S, 2S)-2-[2-(3, 4-dimethoxy- phenyl)ethoxy]cyclohexyl]-3-Pyrrolidinol hydrochloride(chiral CE, method A)1.84% (3S)-H(IR, 2R)-2-[2-(3, 4- dimethoxyphenyl)ethoxy]cyclohexyl]-3-Pyrrolidinol hydrochloride (chiral CE, method C)Wt/wt "as is basis" 62.9% (HPLC, CSK-G method) MS (ES+) 350.1 [M+H]+ 1H-NMR (D2O, 400 MHz) δ: 6.90-6.88 (m, 2H, H-13, H-14), 6.80-6.78 (m, IH, H- 15), 4.24 (broad singlet, IH, H-8), 3.93 (overlapping dt, IH, J 5.3 Hz, J 10 Hz, H-11), 3.72 & 3.71 (s, 6H, 2 x CH3, H-16, H-17), 3.54 (overlapping dt, IH, J 5.0 Hz, J 9.3 Hz, H-Il), 3.30-2.98 (m, 6H, H-I, H-2, H-7, H-IO), 2.88-2.64(m, 2H, H-12), 2.21-2.18 (m, IH, H-6), 1.95-1.85 (m, 2H, H-3, H-9), 1.70-1.60 (m, 2H, H-4, H-5), 1.28-0.97 (m, 4H, H-3, H-4, H-5, H-6). For the numbering of the protons, refer to the following structure.

  • 2
  • [ 795281-92-4 ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
75% With hydrogenchloride; hydrogen In ethanol; water at 20℃; for 5h; 3 Synthesis of liM2iH2-(3Λ-dimethoxy-phenylVethoxy'|-cyclohexyl|- Pyrrolidin-3i?-ol hydrochloride (19) (Figure 5)(a) To a Parr hydrogenator was added a solution of 3i?-benzyloxy-li?-{2i?-[2- (3,4-dimethoxy-phenyl)-ethoxy]-cyclohexyl}-pyrrolidine (17) (185 mg, 0.42 mmol) in ethanol (8 mL) and 6 M aq HCl (400 μL). The solution was stirred for 10 min after which 10% Pd-C catalyst (65 mg, Aldrich cat. No. 20,569-9) was added and the reaction vessel was evacuated and charged with H2 (60 psi). The reaction mixture was agitated under H2 at RT for 5 h, and then filtered through a plug of Celite 545 (Aldrich cat. No.41,993-1), which was pre-wetted with ethanol under suction. The Pd-C catalyst was well rinsed with ethanol. EPO (b) The acidic alcoholic solution was concentrated under reduced pressure azeotropically with toluene to give a residue which is triturated in ethyl acetate with ultrasonication for 15 min to yield the title compound 122.6 mg (75 %).(c) The crude title compound (19) (122.6 mg) was dissolved in ethanol (600 μL) and ethyl acetate was added drop wise (1 mL) and stored at about 3 to 10 0C for about 3 to 5 days. The solvent was pipetted off to leave a white residue. The residual solvent was then evaporated in vacuo to give 18 mg of the title compound. The diastereomeric excess (de) was assessed to be 84.7 % (chiral CE in 5 % highly sulfated γ-cyclodextrin in 25 mM triethylammonium-phosphate buffer (pH 2.5) and 18 kV reverse polarity) with a chemical purity of 90 % (CE in 100 mM phosphate buffer (pH 2.5) and normal polarity at 25 kV).Characterization of (19): TLC Rf 0.71 (neutral alumina, Et2NH-EtOAc, 1:4, v/v); 1H-NMR (300 MHz, CDCl3) δ 6.55 (3H, Ar), 4.10 (IH, m, CHOH), 3.55 (d, 6H, 2 x OCH3), 3.50 (m, 2H, OCH2CH2), 3.20 (m, IH), 3.00-2.50 (m, 4H), 2.35 (m, 2H), 2.25-1.90 (m, IH), 1.90-1.55 (m, 2H), 1.55-1.25 (m, 2H), 1.25-1.00 (m, 6H); 13C-NMR (75 MHz, CDCl3) δ 148.89, 147.62, 131.12, 120.57, 112.20, 111.32, 79.07, 69.29, 66.39, 56.37, 55.86, 53.37, 53.25, 35.83, 33.69, 32.34, 30.09, 28.09, 24.26, 22.98; MS (ES) M+ 350; [α ]25D -2.2° (10, CHCl3).
  • 3
  • [ 906802-36-6 ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
74% Stage #1: (3R)-1-(2-(3,4-dimethoxyphenethoxy)cyclohexyl)-2,5-dioxopyrrolidin-3-yl acetate With borane-THF In tetrahydrofuran at 20℃; for 18h; Stage #2: With hydrogenchloride; methanol In tetrahydrofuran 7 PREPARATION 7; Preparation of (3R)-1-[(1 R,2f?)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]- 3-pyrrolidinol (Compound of formula (Ia)); To a solution of acetic acid 1f?,2/?-(3,4-dimethoxyphenethoxy)cyclohexyl}-2,5- dioxo-pyrrolidin-3R-yl ester (6a) (0.5 g, 1.19 mmol) in anhydrous THF (2 ml_) was added borane-THF complex solution (1M, 8.0 mL) under N2. The reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was cooled to 0°C and quenched slowly by addition of a solution of MeOH (5.0 mL) saturated with HCI gas and concentrated under vacuum to give a pale yellow syrup. Trituration of the syrup in Et2O (10 mL) afforded the monohydrochloride salt of (3f?)-1-[(1f?,2R)-2-[2- (3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Ia) as an off-white solid (340 mg, 74% yield) with 79.5% HPLC purity; 1H NMR (400 MHz1 D2O): δ 7.05-7.02 (m, 2H), 6.94 (dd, 1 H, J 2 Hz, 8 Hz), 4.43-4.38 (m, 1 H), 4.11-4.04 (m, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.69 (overlapping dt, 1H, J 6 Hz, 9 Hz), 3.50-3.40 (m, 1H), 3.31-3.01 (m, 5H), 2.97-2.79 (m, 2H), 2.37-2.30 (m, 1H), 2.10-1.70 (m, 5H), 1.45-1.12 (m, 4H).Isomeric purity: 99.6% ee hydrochloride salt of (3R)-1-[(1f?,2R)-2-[2-(3,4- dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Ia) vs hydrochloride salt of (3R)-I -[(1 S,2S)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (Ib)Isomeric purity 4.02% of the hydrochloride salt of (3S)-1-[(1R,2/?)-2-[2- (S^-dimethoxyphenyOethoxyJcyclohexylJ-S-pyrrolidinol (Ic) observed.
  • 4
  • [ 822-87-7 ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: pyrrolidine; N-ethyl-N,N-diisopropylamine; zinc(II) chloride / toluene / 4 h / 90 °C 1.2: 70 °C 2.1: isopropylamine; pyridoxal 5'-phosphate / dimethyl sulfoxide / 20 - 45 °C / pH 10.5 / borate buffer 2.2: 5 - 20 °C 3.1: potassium hydrogencarbonate / ISOPROPYLAMIDE / 1 h / 20 °C 3.2: 12 h / 80 °C 3.3: 20 °C
Multi-step reaction with 4 steps 1.1: pyrrolidine; N-ethyl-N,N-diisopropylamine; zinc(II) chloride / toluene / 4 h / 90 °C 1.2: 70 °C 2.1: isopropylamine; pyridoxal 5'-phosphate / dimethyl sulfoxide / 20 - 45 °C / pH 10.5 / borate buffer 2.2: 35 °C 3.1: 1-Propyl acetate / 10.25 h / Reflux 3.2: 6 h / 70 °C 3.3: 0.08 h / 50 °C 4.1: Trimethyl borate; sodium tetrahydroborate / tetrahydrofuran / 0.58 h / 0 - 20 °C 4.2: 20 h / 0 - 40 °C 4.3: 10 - 50 °C
Multi-step reaction with 4 steps 1.1: pyrrolidine; N-ethyl-N,N-diisopropylamine; zinc(II) chloride / toluene / 4 h / 90 °C 1.2: 70 °C 2.1: isopropylamine; pyridoxal 5'-phosphate / dimethyl sulfoxide / 20 - 45 °C / pH 10.5 / borate buffer 2.2: 5 - 20 °C 3.1: potassium phosphate / water; Isopropyl acetate 3.2: 55 °C 3.3: 55 °C 4.1: Trimethyl borate; sodium tetrahydroborate / tetrahydrofuran / 0.58 h / 0 - 20 °C 4.2: 20 h / 0 - 40 °C 4.3: 10 - 50 °C
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; pyrrolidine; zinc(II) chloride / toluene / 4 h / 90 °C / Inert atmosphere 2.1: transaminase polypeptide ATA-303; pyridoxal 5'-phosphate; diisopropylamine / dimethyl sulfoxide / 45 °C / pH 10.5 / Inert atmosphere; Enzymatic reaction 2.2: 5 h / 5 - 20 °C / Inert atmosphere 3.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 3.2: 6 h / 70 °C / Inert atmosphere 4.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 4.2: 5 h / 0 - 40 °C / Inert atmosphere 4.3: 14 h / 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; pyrrolidine; zinc(II) chloride / toluene / 4 h / 90 °C / Inert atmosphere 2.1: transaminase polypeptide ATA-303; pyridoxal 5'-phosphate; diisopropylamine / dimethyl sulfoxide / 45 °C / pH 10.5 / Inert atmosphere; Enzymatic reaction 2.2: 5 h / 5 - 20 °C / Inert atmosphere 3.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 4.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 4.2: 5 h / 0 - 40 °C / Inert atmosphere 4.3: 14 h / 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1.1: diethylzinc / tetrahydrofuran / 60 °C / Inert atmosphere 2.1: transaminase polypeptide ATA-303; pyridoxal 5'-phosphate; diisopropylamine / dimethyl sulfoxide / 45 °C / pH 10.5 / Inert atmosphere; Enzymatic reaction 2.2: 5 h / 5 - 20 °C / Inert atmosphere 3.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 3.2: 6 h / 70 °C / Inert atmosphere 4.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 4.2: 5 h / 0 - 40 °C / Inert atmosphere 4.3: 14 h / 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1.1: diethylzinc / tetrahydrofuran / 60 °C / Inert atmosphere 2.1: transaminase polypeptide ATA-303; pyridoxal 5'-phosphate; diisopropylamine / dimethyl sulfoxide / 45 °C / pH 10.5 / Inert atmosphere; Enzymatic reaction 2.2: 5 h / 5 - 20 °C / Inert atmosphere 3.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 4.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 4.2: 5 h / 0 - 40 °C / Inert atmosphere 4.3: 14 h / 20 °C / Inert atmosphere

  • 5
  • [ 7417-21-2 ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: pyrrolidine; N-ethyl-N,N-diisopropylamine; zinc(II) chloride / toluene / 4 h / 90 °C 1.2: 70 °C 2.1: isopropylamine; pyridoxal 5'-phosphate / dimethyl sulfoxide / 20 - 45 °C / pH 10.5 / borate buffer 2.2: 5 - 20 °C 3.1: potassium hydrogencarbonate / ISOPROPYLAMIDE / 1 h / 20 °C 3.2: 12 h / 80 °C 3.3: 20 °C
Multi-step reaction with 4 steps 1.1: pyrrolidine; N-ethyl-N,N-diisopropylamine; zinc(II) chloride / toluene / 4 h / 90 °C 1.2: 70 °C 2.1: isopropylamine; pyridoxal 5'-phosphate / dimethyl sulfoxide / 20 - 45 °C / pH 10.5 / borate buffer 2.2: 35 °C 3.1: 1-Propyl acetate / 10.25 h / Reflux 3.2: 6 h / 70 °C 3.3: 0.08 h / 50 °C 4.1: Trimethyl borate; sodium tetrahydroborate / tetrahydrofuran / 0.58 h / 0 - 20 °C 4.2: 20 h / 0 - 40 °C 4.3: 10 - 50 °C
Multi-step reaction with 4 steps 1.1: pyrrolidine; N-ethyl-N,N-diisopropylamine; zinc(II) chloride / toluene / 4 h / 90 °C 1.2: 70 °C 2.1: isopropylamine; pyridoxal 5'-phosphate / dimethyl sulfoxide / 20 - 45 °C / pH 10.5 / borate buffer 2.2: 5 - 20 °C 3.1: potassium phosphate / water; Isopropyl acetate 3.2: 55 °C 3.3: 55 °C 4.1: Trimethyl borate; sodium tetrahydroborate / tetrahydrofuran / 0.58 h / 0 - 20 °C 4.2: 20 h / 0 - 40 °C 4.3: 10 - 50 °C
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; pyrrolidine; zinc(II) chloride / toluene / 4 h / 90 °C / Inert atmosphere 2.1: transaminase polypeptide ATA-303; pyridoxal 5'-phosphate; diisopropylamine / dimethyl sulfoxide / 45 °C / pH 10.5 / Inert atmosphere; Enzymatic reaction 2.2: 5 h / 5 - 20 °C / Inert atmosphere 3.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 3.2: 6 h / 70 °C / Inert atmosphere 4.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 4.2: 5 h / 0 - 40 °C / Inert atmosphere 4.3: 14 h / 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; pyrrolidine; zinc(II) chloride / toluene / 4 h / 90 °C / Inert atmosphere 2.1: transaminase polypeptide ATA-303; pyridoxal 5'-phosphate; diisopropylamine / dimethyl sulfoxide / 45 °C / pH 10.5 / Inert atmosphere; Enzymatic reaction 2.2: 5 h / 5 - 20 °C / Inert atmosphere 3.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 4.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 4.2: 5 h / 0 - 40 °C / Inert atmosphere 4.3: 14 h / 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1.1: diethylzinc / tetrahydrofuran / 60 °C / Inert atmosphere 2.1: transaminase polypeptide ATA-303; pyridoxal 5'-phosphate; diisopropylamine / dimethyl sulfoxide / 45 °C / pH 10.5 / Inert atmosphere; Enzymatic reaction 2.2: 5 h / 5 - 20 °C / Inert atmosphere 3.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 3.2: 6 h / 70 °C / Inert atmosphere 4.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 4.2: 5 h / 0 - 40 °C / Inert atmosphere 4.3: 14 h / 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1.1: diethylzinc / tetrahydrofuran / 60 °C / Inert atmosphere 2.1: transaminase polypeptide ATA-303; pyridoxal 5'-phosphate; diisopropylamine / dimethyl sulfoxide / 45 °C / pH 10.5 / Inert atmosphere; Enzymatic reaction 2.2: 5 h / 5 - 20 °C / Inert atmosphere 3.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 4.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 4.2: 5 h / 0 - 40 °C / Inert atmosphere 4.3: 14 h / 20 °C / Inert atmosphere

  • 6
  • [ 1360728-96-6 ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium phosphate / water; Isopropyl acetate 1.2: 55 °C 1.3: 55 °C 2.1: Trimethyl borate; sodium tetrahydroborate / tetrahydrofuran / 0.58 h / 0 - 20 °C 2.2: 20 h / 0 - 40 °C 2.3: 10 - 50 °C
  • 7
  • [ 1360728-87-5 ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
98% Stage #1: (3R)-1-(2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol With sodium tetrahydroborate; Trimethyl borate In tetrahydrofuran at 0 - 20℃; for 0.583333h; Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 40℃; for 20h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; iso-prpopanol at 10 - 50℃; 6.C To a mixture of hydroxysuccinimide (10.0 g) and sodium borohydride (2.89 g, 3.0 equiv) in tetrahydrofuran (50 mL, 5 vol) at 0 °C in a 200 mL 3 -neck flask was addedtnmethylborate (B(OMe)3, 2.8 mL, 1.0 equiv) over 5 min. After stirring at ambient temperature for 30 min, boron trifluoride etherate (BF30Et2, 12.6 mL, 4.0 equiv) was added over 1 h at 0 °C.This slurry was aged at ambient temperature for 2 h prior to heating at 40 °C for 17 h (-99% conv already after 2 h at 40 °C).The resulting slurry was then cooled to 0 °C and quenched with water (50 mL, 5 vol) below +10 °C. This solution was then heated at 50 °C for 24 h (>99% conv). The resulting solution was diluted with iPrOAc (100 mL, 10 vol) and 28% aqueous ammonia (25 mL, 2.5 vol).After a 50 °C phase cut, the organic layer was washed with water (20 mL, 2 vol) andconcentrated to 3 vol iPrOAc. iPrOH (30 mL, 3 vol) was added followed by 5 M HC1 in iPrOH(4.1 mL, 1.0 equiv) over 1 h at 20 °C. The resulting slurry was aged at room temperature for 14 h, cooled to 0 °C for 4 h and then filtered. Cake was washed with iPAc (50 mL, 5 vol) and dried under nitrogen to give 9.58 g of Compound A HC1 salt (98% yield, 99.5 LCAP).
85% Stage #1: (3R)-1-(2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol With sodium tetrahydroborate; Trimethyl borate In tetrahydrofuran at 0 - 20℃; for 1.58333h; Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 40℃; Stage #3: With hydrogenchloride; water In Isopropyl acetate; isopropyl alcohol at 0 - 50℃; 4 To a mixture of hydroxy succinimide vi (5 g) and sodium borohydride (1.5 g, 3 equiv) in tetrahydrofuran (THF, 25 mL) at 0° C was slowly added trimethylborate (B(OMe)3j 1.5 mL, 1 equiv) over 5 min. After stirring at ambient temperature for 1.5 h, boron trifiuoride etherate (BF3OEt2, 6.5 mL, 4 equiv) was added over 1 h at 0° C. This slurry was aged at ambient temperature for 4 h prior to heating at 40° C until >95% complete reaction was observed by HPLC (typically 12-24 h). The resulting slurry was then cooled to 0° C for addition of water (5 mL/g with respect to vi). This solution was then heated at 50° C until >98% conversion toCompound A was observed by HPLC (typically 12-24 h). The resulting solution was then diluted with iPrOAc and aqueous sodium hydroxide to pH of approximately 10. The aqueous layer was discarded and the organic layer was washed with 15% brine followed by a small amount of water and concentrated to a low volume for crystallization. To this iPrOAc solution of Compound A was added iPrOH followed by HC1 in iPrOH. The resulting slurry was aged at room temperature overnight, cooled to 0°C and then filtered to give the HC1 salt of Compound A in 85-90% yield.
9.58 g Stage #1: (3R)-1-(2-(3,4-dimethoxyphenethoxy)cyclohexyl)pyrrolidin-3-ol With sodium tetrahydroborate; Trimethyl borate In tetrahydrofuran at 0 - 20℃; for 0.583333h; Inert atmosphere; Stage #2: With boron trifluoride diethyl etherate In tetrahydrofuran at 0 - 40℃; for 5h; Inert atmosphere; Stage #3: With hydrogenchloride In isopropyl alcohol at 20℃; for 14h; Inert atmosphere;
  • 8
  • [ 1360729-06-1 ]
  • [ 1360729-08-3 ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
50% Stage #1: C2H2O4*2C16H25NO3 With potassium hydrogencarbonate In ISOPROPYLAMIDE at 20℃; for 1h; Stage #2: (R)-1,4-dibromo-2-butanol In ISOPROPYLAMIDE at 80℃; for 12h; Stage #3: With hydrogenchloride In Isopropyl acetate; isopropyl alcohol at 20℃; 5.B To a slurry of potassium bicarbonate (1 g, 4.0 equiv) in N,iV-dimethylacetamide(DMAc, 10 mL) was added the cyclohexyl amine oxalate salt iv-b (811 mg, 1.25 mmol, 0.5 equiv). The resulting suspension was stirred at RT for lh before addition of the (i?)-l,4-dibromo~ butan-2-ol vii (580 mg, 1 equiv). The suspension was then heated to 80°C for 12h or until >98% conversion to Compound A was observed by HPLC. The suspension was then allowed to cool to RT and was diluted 20 mL IP Ac, and 20 mL of saturated sodium bicarbonate was added. The aqueous layer was separated and extracted a second time with 20 mL IP Ac. The aqueous layer was then discarded and the combined organic layers were concentrated to a low volume. To this concentrated IP Ac solution of Compound A was added iPrOH followed by HC1 in iPrOH. The resulting slurry was aged at room temperature overnight, cooled to 0° C and then filtered to give the HC1 salt of Compound A in 50-60% yield.
  • 9
  • [ 1360617-31-7 ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: isopropylamine; pyridoxal 5'-phosphate / dimethyl sulfoxide / 20 - 45 °C / pH 10.5 / borate buffer 1.2: 5 - 20 °C 2.1: potassium hydrogencarbonate / ISOPROPYLAMIDE / 1 h / 20 °C 2.2: 12 h / 80 °C 2.3: 20 °C
Multi-step reaction with 3 steps 1.1: isopropylamine; pyridoxal 5'-phosphate / dimethyl sulfoxide / 20 - 45 °C / pH 10.5 / borate buffer 1.2: 35 °C 2.1: 1-Propyl acetate / 10.25 h / Reflux 2.2: 6 h / 70 °C 2.3: 0.08 h / 50 °C 3.1: Trimethyl borate; sodium tetrahydroborate / tetrahydrofuran / 0.58 h / 0 - 20 °C 3.2: 20 h / 0 - 40 °C 3.3: 10 - 50 °C
Multi-step reaction with 3 steps 1.1: isopropylamine; pyridoxal 5'-phosphate / dimethyl sulfoxide / 20 - 45 °C / pH 10.5 / borate buffer 1.2: 5 - 20 °C 2.1: potassium phosphate / water; Isopropyl acetate 2.2: 55 °C 2.3: 55 °C 3.1: Trimethyl borate; sodium tetrahydroborate / tetrahydrofuran / 0.58 h / 0 - 20 °C 3.2: 20 h / 0 - 40 °C 3.3: 10 - 50 °C
Multi-step reaction with 3 steps 1.1: transaminase polypeptide ATA-303; pyridoxal 5'-phosphate; diisopropylamine / dimethyl sulfoxide / 45 °C / pH 10.5 / Inert atmosphere; Enzymatic reaction 1.2: 5 h / 5 - 20 °C / Inert atmosphere 2.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 2.2: 6 h / 70 °C / Inert atmosphere 3.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 3.2: 5 h / 0 - 40 °C / Inert atmosphere 3.3: 14 h / 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1.1: transaminase polypeptide ATA-303; pyridoxal 5'-phosphate; diisopropylamine / dimethyl sulfoxide / 45 °C / pH 10.5 / Inert atmosphere; Enzymatic reaction 1.2: 5 h / 5 - 20 °C / Inert atmosphere 2.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 3.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 3.2: 5 h / 0 - 40 °C / Inert atmosphere 3.3: 14 h / 20 °C / Inert atmosphere

  • 10
  • [ 1360728-99-9 ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 1.2: 6 h / 70 °C / Inert atmosphere 2.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 2.2: 5 h / 0 - 40 °C / Inert atmosphere 2.3: 14 h / 20 °C / Inert atmosphere
Multi-step reaction with 2 steps 1.1: butylboronic acid / 1-Propyl acetate / 10 h / Inert atmosphere; Reflux 2.1: sodium tetrahydroborate; Trimethyl borate / tetrahydrofuran / 0.58 h / 0 - 20 °C / Inert atmosphere 2.2: 5 h / 0 - 40 °C / Inert atmosphere 2.3: 14 h / 20 °C / Inert atmosphere
  • 11
  • [ 907160-68-3 ]
  • [ CAS Unavailable ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
74.7% Stage #1: (1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexan-1-amine; (R)-1,2-epichlorobutane With potassium carbonate In acetonitrile at 70 - 80℃; for 6h; Stage #2: With hydrogenchloride In methanol for 1h; 1-4 Example 2 (R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylpyrrol-3-ol hydrochloride (Venakalan hydrochloride ) PreparationIn a single-necked flask, add (1R, 2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylamine (14.0g, 50mmol), 200ml acetonitrile, magnetically stir until completely dissolved, add anhydrous Potassium carbonate (8.3g, 60mmol), add dropwise R-1,2 epichlorobutane (5.3g, 50mmol), heat up to reflux, control the system temperature 70-80, reaction time 6h, filter, filter out inorganic salt Add 5M hydrochloric acid/methanol solution (100ml) to the organic phase and stir for 1 hour until the salt is completely formed. The organic phase is evaporated to remove the solvent under reduced pressure to obtain the crude venakalan as a light-colored viscous substance, which is recrystallized by adding isopropyl acetate. , Filtered to obtain (R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylpyrrol-3-ol hydrochloride 14.41g, which was a white solid. The rate is 74.7%, the HPLC purity is 96.4%, and the isomer RSS content is 0.32%.
  • 12
  • [ 795282-03-0 ]
  • [ 748810-28-8 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride In methanol; lithium hydroxide monohydrate at 20℃; for 2h; 11-3; 11-4; 1-2 Methanol (110 mL) was added to the oil obtained in the previous step, and stirred uniformly at room temperature to form a methanol solution of Venakaran. Concentrated hydrochloric acid (36-38%, wt/wt, 3.60 g) was added to methanol (50 mL). ) to form a hydrochloric acid/methanol solution, at room temperature, add the hydrochloric acid/methanol solution dropwise to the above Venakaran methanol solution, continue to stir for 2 hours after the dropwise addition, filter, after the filter cake is washed with a small amount of methanol, vacuum dried to obtain, (R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylpyrrol-3-ol hydrochloride, (11.85g, yield : 81.70%), HPLC showed that the target molecule accounted for 99.33% (see Figure 5); Compound F, the RRS isomer of venakaran hydrochloride: the proportion was 0.09%10 g of the hydrochloride obtained in Example 11-3 was added with 50 mL of ethanol and 150 mL of isopropyl acetate, heated to 65° C. under nitrogen protection, stirred until all dissolved, cooled to room temperature, and stirred for 2 hours.filter.The obtained solid was dried in a vacuum oven at -0.10-0.095MPa, dried at 55±5°C for 23 hours, weighed 9.0 g, yield: 90%, HPLC showed that the target molecule accounted for 100%, RRS isomer: 0.07%
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