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[ CAS No. 843663-66-1 ] {[proInfo.proName]}

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Chemical Structure| 843663-66-1
Chemical Structure| 843663-66-1
Structure of 843663-66-1 * Storage: {[proInfo.prStorage]}
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Product Details of [ 843663-66-1 ]

CAS No. :843663-66-1 MDL No. :MFCD14635354
Formula : C32H31BrN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :QUIJNHUBAXPXFS-XLJNKUFUSA-N
M.W : 555.50 Pubchem ID :5388906
Synonyms :
R207910;TMC207

Calculated chemistry of [ 843663-66-1 ]

Physicochemical Properties

Num. heavy atoms : 37
Num. arom. heavy atoms : 26
Fraction Csp3 : 0.22
Num. rotatable bonds : 8
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 155.36
TPSA : 45.59 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -4.57 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.73
Log Po/w (XLOGP3) : 7.21
Log Po/w (WLOGP) : 7.02
Log Po/w (MLOGP) : 5.08
Log Po/w (SILICOS-IT) : 7.18
Consensus Log Po/w : 6.24

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 0.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.17

Water Solubility

Log S (ESOL) : -7.82
Solubility : 0.00000844 mg/ml ; 0.0000000152 mol/l
Class : Poorly soluble
Log S (Ali) : -7.99
Solubility : 0.00000568 mg/ml ; 0.0000000102 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -11.59
Solubility : 0.0000000014 mg/ml ; 0.0 mol/l
Class : Insoluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 4.39

Safety of [ 843663-66-1 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P260-P264-P270-P273-P301+P310+P330-P314-P405-P501 UN#:2811
Hazard Statements:H301-H373-H410 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 843663-66-1 ]

* 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 [ 843663-66-1 ]

[ 843663-66-1 ] Synthesis Path-Downstream   1~40

  • 2
  • [ 10320-49-7 ]
  • [ 843663-66-1 ]
  • [ 654655-80-8 ]
  • (R,S)-bedaquiline [ No CAS ]
YieldReaction ConditionsOperation in experiment
nBuLi 1.6M (0.05 mol) was added slowly at -20C under N2 flow to a solution of iV-(l-methylethyl)-2-propanamine (0.05 mol) in tetrahydrofuran (THF) (80ml) . The mixture was stirred at -20C for 15 minutes, then cooled to -70C . A solution of intermediate compound 3 (prepared according to A3 described above) (0.046 mol) in THF (150ml) was added slowly . The mixture was stirred at -70C for 30 minutes . A solution of 0.055 mol of 3-(dimethylamino)-l-(l-naphthyl)-l-propanone in THF (120ml) was added slowly . The mixture was stirred at -70C for 3 hours, hydro lyzed at -30C with ice water and extracted with EtOAc . The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated . The residue (29g) was purified by column chromatography over silica gel (eluent: CH2CyCH3OHZNH4OH; 99.5/0.5/0.1; 15-35mum) . Two fractions were collected and the solvent was evaporated, EPO <DP n="31"/>yielding 3g of fraction 1 and 4.4g of fraction 2 . Fraction 1 and 2 were crystallized separately from DIPE . The precipitate was filtered off and dried, yielding 2.2g of diastereoisomer A, i.e. final compound 14 (Yield: 9%; mp.210C) as a white solid and 4g of diastereoisomer B, i.e. final compound 15 (Yield: 16%; mp.244C) as a white solid . To obtain the corresponding enantiomers, diastereoisomer A (final compound 14) was purified by chiral chromatography over silica gel (chiralpack AD) (eluent: hexane/EtOH; 99.95/0.05) . Two fractions were collected and the solvent was evaporated . Yield: 0.233g of enantiomer Al (final compound 12) (mp. 118C, [alpha]D20 = -166.98 (c = 0.505 g/100 ml in DMF)) as a white solid and 0.287g of enantiomer A2 (final compound 13) (mp. 120C, [alpha]D20 = +167.60 (c = 0.472 g/100 ml in DMF)) as a white solid. Enantiomer Al was crystallised from EtOH to give a white solid: mp. 184C, [alpha]D20 = -188.71(c= 0.621 g/lOOml in DMF). Crystallization of enantiomer A2 from EtOH gave a solid with mp. of 175C. 0.2g of diastereoisomer B (final compound 15) was purified by chiral chromatography over silica gel (chiralpack AD) (eluent: EtOH/iPrOH/iV-ethyl-ethanamine; 50/50/0.1 ). Two fractions were collected and the solvent was evaporated . Yield: 78.2mg of enantiomer Bl and 78.8mg of enantiomer B2. Enantiomer Bl was purified by column chromatography over silica gel (eluent: CH2C12/CH3OH/NH4OH; 99/1/0.1; 15-40mum). One fraction was collected and the solvent was evaporated . Yield: 57mg of enantiomer Bl (final compound 12a) ([alpha]D20 = -42.56 (c = 0.336 g/100 ml in DMF)). Enantiomer B2 was purified by column chromatography over silica gel (eluent: CH2C12/CH3OH/NH4OH; 99/1/0.1; 15-40mum). One fraction was collected and the solvent was evaporated . Yield: 53mg of enantiomer B2 (final compound 13a) ([OC]D20 = + 43.55 (c = 0.349 g/100 ml in DMF)).
  • 3
  • rac-(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol [ No CAS ]
  • 6-bromo-α-[2-(dimethylamino)ethyl]-2-methoxy-α-1-naphthalenyl-β-phenyl-3-quinolineethanol*(11bR)-4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin 4-oxide [ No CAS ]
  • [ 843663-66-1 ]
YieldReaction ConditionsOperation in experiment
39% B. Isolation of the specific enantiomer (alphaS. betaR)-6-bromo-alpha-r2-(dimethylamino)ethyll- 2-methoxy-alpha-l-naphthalenyl-beta-phenyl-3-quinolineethanol from a mixture of stereoisomer^ forms by using f llbRV4-hvdroxydinaphtho[2,l-d:r.2'- firi,3,21dioxaphosphepin 4-oxide; The solid obtained under step C (30.45 g; 50 mmol; leq.) was suspended in acetone (193.3 g) at a temperature of 20 to 30 0C. This suspension was seeded with (alphaS, betaR)-6- EPO <DP n="23"/>bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-l-naphthalenyl-beta-phenyl-3- quinolineethanol * (1 lbR)-4-hydroxydinaphtho[2, 1 -d: 1 ' ,2 '-f] [ 1 ,3 ,2]dioxaphosphepin 4-oxide salt (9 mg; 0.016 mmol) obtained from previous preparation processes. (l lbR)-4-hydroxydinaphtho[2,l-d:l',2'-fl[l,3,2]dioxaphosphepin 4-oxide (17.60 g; 50 mmol; leq.) was dissolved in dimethylsulfoxide (38.7 g) at 40 to 500C and this solution was added via a filter to the above suspension in acetone within a time frame of 5 to 15 minutes. Then, the reaction mixture was seeded again with (alphaS, betaR) 6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-(l-naphthyl)-beta-phenyl-3- quinolineethanol * (HbR)-4-hydroxydinaphtho[2,l-d:r,2'-fJ[l,3,2]dioxaphosphepin 4-oxide salt (9 mg; 0.016 mmol) obtained from previous preparation processes.The resulting suspension was stirred for 60 minutes (45 to 75 minutes), followed by heating to reflux. The suspension was stirred for 60 minutes (45 to 75 minutes) under reflux, followed by cooling to 25 0C (20 to 30 0C) in 30 to 60 minutes and stirring for 1 to 2 hours at 20 to 30 0C. The resulting solid was filtered off and washed twice with acetone (62.5g for each wash step). The resulting residue (59 g) was suspended in acetone (185.4 g) and the suspension was heated to reflux and stirred under reflux for 2 hours (1.5 to 2.5 hours) followed by cooling to 25 0C (20 to 30 0C) in 30 to 45 minutes and stirring for 45 to 75 minutes. The resulting solid was filtered off and washed with acetone (47 g) followed by washing with toluene (55 g). The obtained solid (54.96 g) was suspended in toluene (40.3 g) and treated (1.4 eq.) with a 10 % potassium carbonate solution (4.23 g K2CO3 in 38.02 g of purified water). The mixture was heated to 80-85 0C and the aqueous layer was separated.To the organic layer, a potassium carbonate solution (0.4 eq.) (1.23 g OfK2CO3 in 11.07 g of purified water) was added. After stirring for 5 to 15 minutes, the aqueous layer was separated and the organic layer was washed with purified water (11.8 g) at 80 to 85 0C.The organic layer was concentrated at 55 0C (50 to 60 0C) under vacuum.The residue was treated with ethanol (69 g) at a temperature > 45 to 500C followed by cooling within 0.5 to 1.5 hours to 0 to 50C and stirring for 0.5 to 1 hour at this temperature. The resulting solid was filtered off, washed twice with ethanol (18 g for each wash step) and dried in vacuo at 70 0C (65 to 75 0C). Yield : 39 % by weight (or 78% by weight calculated on the desired enantiomer) of (alphaS, betaR)-6-bromo-alpha-[2- (dimethylamino)ethyl]-2-methoxy-alpha-l-naphthalenyl-beta-phenyl-3-quinolineethanol (HPLC purity : > 99.6 %; enantiomeric excess > 99.8 %, m.p. 182-1840C). EPO <DP n="24"/>Purity was determined by HPLC using a YMC-Pack ODS-AQ (150 x 4.6 mm, 3 mum) column using as Mobile phase : Mobile phase A : water/trifluoroacetic acid (1000 ml/lml); Mobile phase B ; acetonitrile/trifluoroacetic acid (1000 ml/0.8 ml); eluent gradient starting with 75 % of A and 25 % of B?IO % of A and 90 % of B. Enantiomeric excess was determined by HPLC using a Cyclobond I RSP (250 x 4.6 mm) column using as mobile phase : MeOH/Water/ Ammonium acetate (60 ml/40 ml/0.154 g) adjusted to pH 7 with acetic acid. The obtained product (19.0 g) was suspended in toluene (10.96 g) and heated to 90 0C. The mixture was filtered in the heat and the filter was washed with toluene (1.5 g). The solution was cooled to 70 0C and ethanol (22.16 g) was added dropwise. During the addition of ethanol, the product started to crystallize (optionally a few mg of (alphaS, betaR) 6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-(l-naphthyl)-beta-phenyl-3- quinolineethanol may be added). A further ethanol (32.31 g) was added dropwise at 65 0C and the suspension was cooled to 00C and stirred for 1 hour. The residue was filtered off and washed with ethanol in 2 parts (52 g). The resulting product was dried (40 to 70 0C), yielding 17.07 g of (alphaS, betaR)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2- methoxy-alpha- 1 -naphthalenyl-beta-phenyl-3-quinolineethanol.
  • 4
  • [ 843663-66-1 ]
  • [ 110-17-8 ]
  • [ 845533-86-0 ]
YieldReaction ConditionsOperation in experiment
82% In isopropyl alcohol; at 20 - 70℃; for 18h;Heating / reflux; A. Synthesis of the fumarate salt of alphaS, betaR)-6-bromo-alpha-[2-fdimethylamino)ethyll- 2-methoxy-alpha- 1-naphthalenyl- beta-phenyl-3-q uinolineethanol; 1Og (0.018 mol) of (alphaS, betaR)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-l- naphthalenyl-beta-phenyl-3-quinolineethanol and 2.13 g (0.018 mol) of fumaric acid were suspended in 185 ml isopropanol. Dicalite (0.25g) and charcoal (0.25g) were added to the suspension. The mixture was refluxed for an hour, the reaction mixture was cooled to 700C and filtered in the heat. The filter cake was washed with 10ml isopropanol.The mother liquor was slowly cooled to 500C and stirred for 1 hour at this temperature.The reaction mixture was further cooled to room temperature and stirred for 16 hours. The crystals were filtered off and washed with 20 ml isopropanol. The wet cake was dried at 500C during 16 hours.Yield: 1O g of (alpha S, beta R)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy- alpha-l-naphthalenyl-beta-phenyl-3-quinolineethanol (2E)-2-butenedioate (1 :1) (white solid) (82%).
In isopropyl alcohol; at 70 - 80℃; for 1h; Bedaquiline free base (1.19 g), fumaric acid (0.25 g), isopropanol (21 ml) were added into a 100 ml single- necked flask, heated to 70-80 C. until the solution is clear, stirred with heat-preservation for 1 h. Solids were precipitated when the solution was cooled to 50-70 C., the temperature was decreased to 5 C. and the solution was stirred for 1 h, filtered, the filter cake was washed with 10 ml isopropanol, dried at 60 C., -0.1 MPa to obtain end-product <strong>[843663-66-1]bedaquiline</strong> fumarate (1.20 g, yield=84%), and it is used as crude material for each example.
  • 5
  • [ 843663-66-1 ]
  • [ 3132-99-8 ]
  • [ 1032266-07-1 ]
YieldReaction ConditionsOperation in experiment
37% Example A4 a. Preparation of intermediate 7Intermediate 7 (dia A) ftBuLi (1.6M in hexanes, 14.1 ml, 0.0225 mol) was added dropwise at -700C under nitrogen flow to a solution of compound 14 of WO2004/011436 (5.0 g, 9.0 mmol) inTHF (5 0 ml). The mixture was stirred for 2 hours at -700C then dry ice was added.The resulting mixture was stirred lhour at -700C then water was added. The precipitate was filtered off, washed with water, CH3OH then CH3CH2OH and dried under vacuum. Yield: 0.8 g of intermediate 7 (17 %). A second fraction was obtained from the filtrate. Yield: 1.3 g of intermediate 7 (28%).
  • 6
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  • 19
  • [ 73568-35-1 ]
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  • 20
  • [ 654655-69-3 ]
  • [ 10320-49-7 ]
  • [ 843663-66-1 ]
  • [ 654655-80-8 ]
  • 21
  • [ 941-98-0 ]
  • [ 843663-66-1 ]
  • [ 654655-80-8 ]
  • 22
  • rac-(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol [ No CAS ]
  • [ 843663-66-1 ]
  • [ 654655-80-8 ]
YieldReaction ConditionsOperation in experiment
0.35 g Diastereomer 5A (1.0g) was suspended in acetone and the solution of (R)-(-)-BNP ACID (1eq) in DMSO was added. The suspension was stirred and refluxed for 1h, then cooled to room temperature and stirred for another 1h. The suspended solid was filtered and washed by acetone, then recrystallized by ethanol and water. After filtration, the solid was suspended in the solution of toluene and 10% K2CO3 (aq), and the mixture was stirred at 80C for half an hour. The aqueous phase was extracted with toluene, and the organic layers was washed with brine and dried over Na2SO4 . After filtration and evaporation under reduced pressure, the residue was stirred in ethanol under 0C. White solid which precipitates was separated with filtration, and air dried to give 0.35g of bedaquiline, m.p. 170-175C.
  • 23
  • [ 106-40-1 ]
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  • 24
  • [ 316146-27-7 ]
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  • [ 654655-80-8 ]
  • 25
  • [ 654655-68-2 ]
  • [ 843663-66-1 ]
  • [ 654655-80-8 ]
  • 26
  • [ 843663-66-1 ]
  • (1R,2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol sulphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% With sulfuric acid; In isopropyl alcohol; (1 R,2S)- 1 -(6-Bromo-2-methoxy-3 -quinolyl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl-butan- 2-ol in the amount of 100 mg (0.18 mmol) was suspended in 14 ml of isopropyl alcohol. 18.4 mg (0.18 mmol) of sulphuric acid (96%) was added to this suspension. The resulting solution was slowly concentrated by partial evaporation of the solvent (about 7 ml) at the room temperature. The separated crystalline product was removed by filtration and dried at 30 to 40C. Yield 39 mg (33%). Melting point 188 C (DSC). XRPD: Fig. 6
  • 27
  • [ 843663-66-1 ]
  • (1R,2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol phosphate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% With phosphoric acid; In tetrahydrofuran; (1 R,2S)- 1 -(6-Bromo-2-methoxy-3 -qwnolyl)-4-dimemylamino-2-(l -naphthyl)- 1 -phenyl-butan- 2-ol in the amount of 100 mg (0.18 mmol) was dissolved in 20 ml of tetrahydrofuxan. 20.8 mg (0.18 mmol) of phosphoric acid (85%) was added to this solution. A white solid substance was separated during slow evaporation of the solvent at the room temperature. Yield 40 mg (33%). Melting point 159C (DSC). XRPD: Fig. 18.
  • 28
  • [ 843663-66-1 ]
  • [ 87-69-4 ]
  • (1R,2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol tartrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% In acetonitrile; ( 1 R,2S)- 1 - (6-Bromo-2-methoxy-3 -quinolyl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl-butan- 2-ol in the amount of 100 mg (0.18 mmol) was suspended in 4 ml of acetonitrile. 27 mg (0.18 mmol) of tartaric acid was added to this suspension. A white solid substance was separated during slow evaporation of the solvent at the room temperature. Yield 43 mg (34%). Melting point 103C (DSC). XRPD: Fig. 10
  • 29
  • [ 843663-66-1 ]
  • [ 77-92-9 ]
  • (1R,2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol citrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% In isopropyl alcohol; ( 1 R ,25)- 1 - (6-Bromo-2-methoxy-3 -quinolyl)-4-dimethylamino-2-( 1 -naphthyl)- 1 -phenyl-butan- 2-ol in the amount of 100 mg (0.18 mmol) was suspended in 8 ml of isopropyl alcohol. 34.6 mg (0.18 mmol) of citric acid was added to this suspension. A white solid substance was separated during slow evaporation of the solvent at the room temperature. Yield 50 mg (37%). Melting point 102C (DSC). XRPD: Fig. 14.
  • 30
  • [ 843663-66-1 ]
  • [ 77-92-9 ]
  • (1R,2S)-1-(6-bromo-2-methoxy-3-quinolyl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol citrate [ No CAS ]
YieldReaction ConditionsOperation in experiment
96.6% In isopropyl alcohol; at 50 - 80℃; for 1h; (1R,2S)-1-(6-Bromo-2-methoxy-3 -quinolyl)-4-dimethylamino-2-(1 -naphthyl)- 1 -phenyl- butan-2-ol in the quantity of 3.995 mg (7.2· 10"4 mol) was suspended in 85 ml of isopropyl alcohol. 1.3685 mg (7. -10"4 mol) of citric acid was added to this suspension. This suspension was heated up to 80C (slightly turbid solution). Being continuously stirred, this solution was left to slowly cool down to 50C and left to be stirred at this temperature for 1 hour. Being continuously stirred, the obtained suspension was left to slowly cool down to the room temperature and filtered. The solid fraction was dried in a vacuum drier at the pressure of 20 kPa and temperature of 50C for 16 hours. Yield 5.180 mg (96.6%). Melting point 174C (DSC). XRPD: Fig. 1.
  • 31
  • [ 654655-69-3 ]
  • [ 10320-49-7 ]
  • [ 843663-66-1 ]
  • (R,S)-bedaquiline [ No CAS ]
  • C32H31BrN2O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With n-butyllithium; (S)-N-benzylprolinol; lithium diisopropyl amide; In tetrahydrofuran; hexane; n-heptane; ethylbenzene; at -78 - -72℃; for 3h;Inert atmosphere; 45 ml of THF and 15.4 g (80.5 mmol, 1.10 eq) of N-benzyl-L-Prolinol were added in a dry 500 mL four-necked glass reaction flask under a nitrogen atmosphere, and the reaction flask was placed in a cold trap -72~-78C. then 2.5 M (80.5 mmol) of n-butyllithium in N-hexane solution 32ml(80.5mmol) was added, followed by the addition of 2.0 M LDA (mixed solvent of heptane- ethylbenzene - tetrahydrofuran) 44.0 ml (88.0 mmol) , and THF 21 ml. A solution of 6-bromo-3-benzyl-2-methoxy quinoline 24.0 g (73.2 mmol, 1.0 eq) was dissolved in THF (30 ml) , then slowly added dropwise to the above four necked flask. After the completion of the drop within 70 min, during the feeding process maintain internal temperature to -72 ~ - 78 C, and after completion of addition , continue to stir the reaction for 3 h. A solution of 17.4 g (76.9 mmol) of a solution of 3-N, N-dimethylamino-1-naphthyl-1-propanone and 50 ml of THF in was slowly added dropwise and dubbed in solution,during addition process maintain internal temperature to -72 ~ -78 C, and after completion of addition , continue the reaction for 3 h. HPLC test results of reaction materials: Enantiomer A / A '= 82: 18 (ee: 64%); diastereomer (A + A') AB + B ') = 4.8. The ratio of two pairs of diastereomers (A + A ') / (B + B') was 4: 1 in the absence of a chiral inducer. In the above reaction solution slowly add saturated ammonium chloride solution 30 mL, keep stirring slowly until temperature reaches to room temperature, then Placed for 12 h for precipitation filtration carried out , washed filter cake with ethyl acetate 25 mL and most of the filter cake is diastereomer (B,B'). The organic layer was separated from the filtrate and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. In the residue added 120 mL of ethanol, then heated to 80 C and stirred for 2 h. After heating, the mixture was allowed to cool to room temperature and stirring was continued for 2 h. suction filtration carried out , washed filter cake with 25ml ethanol. then dried under vacuum at room temperature to give bedaquiline (1R,2S) crude product: whitish solid, 10.4 g, HPLC test results: A / A '= 95: 5 (ee: 90%), containing 2.3% by weight of (B + B'). The above (1R, 2S) - bedaquiline crude 9.8g, isopropyl alcohol 250ml,were heated to dissolve, then cooled to 0 C for crystallization. Filtration was carried out , washed with a small amount of cold isopropanol, and vacuum drying to obtain white crystals :(1R, 2S) - bedaquiline 6.40 g, yield 15.6 wt%(based on 6-bromo-3-benzyl-2-methoxyquinoline), optical purity ee: 99.2%, chemical purity 99.6% (excluding B and B ').
  • 32
  • [ 843663-66-1 ]
  • (1R,2S)-4-(dimethylamino)-1-(2-methoxyquinolin-3-yl)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With palladium 10% on activated carbon; hydrogen; triethylamine; In tetrahydrofuran; at 30℃; under 760.051 Torr; for 4h; 3.0 g (5.4 mmol) of <strong>[843663-66-1]bedaquiline</strong> monomer, 45 ml of tetrahydrofuran and 3.0 ml (21.6 mmol) of triethylamine were added successively into a 100 ml three-necked flask, and the solid was completely dissolved. The solution was colorless and transparent. Then followed by the addition od 0.44 g of 10% palladium on carbon (Xi'an Kai Li, 65.5% water) and the reaction was subjected to hydrogenation reaction at 30 C under normal pressure for 4 hours. The reaction was stopped, the nitrogen was purged for 10 minutes, after that suction filtered was carried out , then washed with 15 ml of tetrahydrofuran and palladium on carbon was recovered to give a pale yellow clear filtrate. Concentrate under reduced pressure to give a yellow oily liquid. Add 30 ml of ethyl acetate and 30 ml of purified water and Oil dissolved. The solution was transferred to a separatory funnel, shaken, allowed to stand, separated the liquid to separate out the aqueous phase. The organic phase was washed once with 20 ml of purified water, once with 20 ml of saturated brine, then dried over anhydrous sodium sulphate, subjected to filtration, washed with 5 ml of ethyl acetate and concentrated under reduced pressure to give a yellow solid. Purification by column chromatography (200-300 mesh silica gel with the eluent as a petroleum ether-ethyl acetate (V: V = 8: 1, 1% by volume triethylamine)) and obtained 2.3 g of an off- white (ash gray color) powder with a yield of 90%
  • 33
  • 3-dimethylamino-1-(naphthalene-1-yl)-prop-2-en-1-one [ No CAS ]
  • [ 843663-66-1 ]
  • 34
  • [ 941-98-0 ]
  • [ 843663-66-1 ]
  • 35
  • [ 654655-80-8 ]
  • [ 843663-66-1 ]
YieldReaction ConditionsOperation in experiment
39% With (R)-1,1'-binaphthyl-2,2'-phosphoric acid; In dimethyl sulfoxide; acetone; at 20℃; for 3h;Reflux; The first step: salt,Split. Compound 10 (91.3 g, 0.15 mol) was suspended in 240 ml of acetone at room temperature,Add a resolving agent(R) - (-) - binaphthol phosphate(52.8 g, 0.15 mol) in DMSO (35 ml).After the addition was completed, the solution became clear, the reaction solution was stirred at room temperature for 1h and then heated to reflux for 1h,Then slowly cooled to room temperature, filtered after stirring for 2h and the resulting white solid was washed twice with acetone.The resulting solid was suction filtered with 220ml acetone reflux beating 2h, then slowly cooled to room temperature and filtered,The resulting solid was washed once with 50 ml of acetone and dried to give 165.0 g of a white lumpy solid.The second step: free. The white solid obtained in the first step was suspended in 150 ml of toluene and then 40 ml of a 10% potassium carbonate solution was added. The mixture was then heated to reflux, cooled to room temperature, and then separated. The organic phase was separated and washed with 50 ml of water at 80 C twice The separated toluene layer was concentrated to dryness under reduced pressure directly at 56 C without drying. The evaporated white solid was refluxed with 150 ml of ethanol for 1 h and then slowly cooled to 0 C and stirred at low temperature for 1 h. The mixture was filtered, the filter cake was washed with 50 ml of ethanol and then dried in vacuo at 70 C to give 35.6 g of white solid with a yield of 39 %, HPLC purity 99.6%, ee value 99.8%
39% 1st step: salt formation, split. Compound 10 (91.3 g, 0.15 mol) was suspended in 240 ml of acetone at room temperature, and 35 ml of a solution of resolving agent (R)-(-)-1,1?-binaphthyl-2,2?-diyl hydrogenphosphate (52.8 g, 0.15 mol) in DMSO was added dropwise. After the completion of the dropwise addition, the solution became clear. The reaction mixture was stirred at room temperature for 1 hour, then warmed to reflux for 1 hour, then slowly cooled to room temperature, stirred for 2 h and then filtered, and the obtained white solid was washed twice with acetone. The solid obtained by suction filtration was refluxed with 220 ml of acetone for 2 h, then slowly cooled to room temperature and then filtered with suction. The obtained solid was washed once with 50 ml of acetone, and dried to give a white solid.2nd step: free. The white solid obtained in the first step was suspended in 150 ml of toluene, then 40 ml of a 10% potassium carbonate solution was added, and then the mixture was heated to reflux, cooled to room temperature, and then separated, and the organic phase was separated, and then washed twice with water 50 ml at 80 C. The separated toluene layer was concentrated to dryness under reduced pressure at 56 C without drying. The white solid which was evaporated to dryness was refluxed with 150 ml of ethanol for 1 hour, then slowly cooled to 0 C, and stirred at low temperature for 1 hour, filtered, and the filter cake was washed with 50 ml of ethanol, and then dried under vacuum at 70 C to give a white solid 35.6 g, yield 39 %, HPLC purity 99.6%, ee value 99.8%.
  • 36
  • [ 654655-69-3 ]
  • [ 2752-87-6 ]
  • [ 843663-66-1 ]
YieldReaction ConditionsOperation in experiment
9.45 g With acetic acid; lithium diisopropyl amide; In tetrahydrofuran; at -80 - -70℃;Inert atmosphere; 23.4 g of lithium diisopropylamide was added to 90 ml of tetrahydrofuran under N 2 gas at 20-25 C,The solution was cooled to -70 to -80 C and 57.4 g of Compound A in tetrahydrofuran was added dropwise.The reaction mixture was stirred at -70 to -80 C.To the reaction mixture, 40 g of a tetrahydrofuran solution of Compound B was added dropwise,The reaction mixture was stirred at -70 to -80 C. To the reaction mixture was added 39 g of acetic acid,The reaction gave 34.97 g of 1- (6-bromo-2-methoxy-3-quinolinyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol.The above product was chromatographed on silica gel to give 9.45 g of bedaquiline and 25.18 g of other isomers.
  • 37
  • [ 843663-66-1 ]
  • [ 3132-99-8 ]
  • [ 1032265-50-1 ]
  • 38
  • [ 843663-66-1 ]
  • [ 73183-34-3 ]
  • C38H43BN2O4 [ No CAS ]
  • 39
  • [ 654655-69-3 ]
  • [ 10320-49-7 ]
  • [ 843663-66-1 ]
  • (R,S)-bedaquiline [ No CAS ]
YieldReaction ConditionsOperation in experiment
3-Benzyl-6-bromo-2-methoxyquinoline (49.2 g, 150 mmol, 1 eq))Dissolved in 80ml anhydrous tetrahydrofuran, under the protection of nitrogen,A tetrahydrofuran solution of lithium diisopropylamide (72.9 g, 180 mmol, 1.2 eq) at about -78 C was slowly added dropwise thereto, and the reaction was stirred for 1-2 hours.Add (3-dimethylamino) -1'-ethylnaphthyl ketone (41 g, 180 mmol, 1.2 eq)Dissolved in 80ml of anhydrous tetrahydrofuran and added it to the previous reaction,Reaction at -78 C for 14-20h under nitrogen protection. Acetic acid (22.5 g, 375 mmol)Dissolved in anhydrous tetrahydrofuran (22.5ml), added to the reaction solution,The reaction solution was heated to 0 C, 200 ml of water was added, filtered, and washed with water.8.5 g of solid enantiomer B was obtained. The organic phase was separated from the filtrate, and the solvent was evaporated from the oil phase.Add 100 ml of ethanol to the residue, cool, filter, and wash with ethanol.Vacuum drying at 50 ,This gave 28.4 g of a mixture of A and B (84.4% A and 4.6% B).
  • 40
  • [ 845533-86-0 ]
  • [ 843663-66-1 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate In dichloromethane 2.1.1. Free base bedaquiline (1). The free base used during synthesis was prepared by extracting a CH2Cl2 solution of the fumarate three times with saturated NaHCO3 solution (Rombouts et al., 2016). The identity and purity of the free base thus afforded from the material supplied by Johnson & Johnson was verified using NMR spectroscopy [m.p. 175-176 °C; literature value 181°C (Zvatora, Dammer, Ridvan etal., 2016)]. 1H NMR (500 MHz, ACN-d3): δ 8.82 (s, 1H), 8.66 (d, J = 8.7 Hz, 1H), 8.03 (s, 1H), 8.02 (d, J = 7.3 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 7.7 Hz, 4H), 7.49 (t, J = 7.7 Hz,1H), 7.30 (m, 3H), 6.87 (m, 3H), 5.88 (s, 1H), 4.20 (s, 3H), 2.52 (d, J = 14.6 Hz, 1H), 2.01 (m, 2H), 1.89 (m, 7H). Single crystals were grown by dissolving bedaquiline (30 mg, 0.054 mmol) in acetone (1 ml) in a 5 ml scintillation vial and the solution was allowed to evaporate slowly to obtain medium-sized plate-shaped crystals of 1.
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[ 843663-66-1 ]

Chemical Structure| 845533-86-0

A648653[ 845533-86-0 ]

(1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol fumarate

Reason: Free-Salt