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Inhibitors/Agonists
Metabolic Enzyme
CETP
Anacetrapib
Inhibitors/Agonists
Metabolic Enzyme
CETP

[ CAS No. 875446-37-0 ] {[proInfo.proName]}

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Chemical Structure| 875446-37-0
Chemical Structure| 875446-37-0
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Quality Control of [ 875446-37-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 875446-37-0 ]

SDS Specification
Alternatived Products of [ 875446-37-0 ]

Product Details of [ 875446-37-0 ]

CAS No. :875446-37-0 MDL No. :MFCD16294903
Formula : C30H25F10NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 637.51 Pubchem ID :-
Synonyms :
MK-0859
Chemical Name :(4S,5R)-5-(3,5-Bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one

Calculated chemistry of [ 875446-37-0 ]

Physicochemical Properties

Num. heavy atoms : 44
Num. arom. heavy atoms : 18
Fraction Csp3 : 0.37
Num. rotatable bonds : 9
Num. H-bond acceptors : 13.0
Num. H-bond donors : 0.0
Molar Refractivity : 142.97
TPSA : 38.77 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -3.92 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.72
Log Po/w (XLOGP3) : 8.83
Log Po/w (WLOGP) : 12.78
Log Po/w (MLOGP) : 6.98
Log Po/w (SILICOS-IT) : 9.45
Consensus Log Po/w : 8.55

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 0.0
Egan : 1.0
Muegge : 3.0
Bioavailability Score : 0.17

Water Solubility

Log S (ESOL) : -9.06
Solubility : 0.00000055 mg/ml ; 0.0000000009 mol/l
Class : Poorly soluble
Log S (Ali) : -9.53
Solubility : 0.000000189 mg/ml ; 0.0000000003 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -11.09
Solubility : 0.0000000051 mg/ml ; 0.0 mol/l
Class : Insoluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 4.82

Safety of [ 875446-37-0 ]

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

Application In Synthesis of [ 875446-37-0 ]

* 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 [ 875446-37-0 ]

[ 875446-37-0 ] Synthesis Path-Downstream   1~45

  • 1
  • [ 875446-35-8 ]
  • [ 875446-29-0 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; benzene; at 100℃; for 14h;Heating / reflux; A stirred mixture of (45,57?)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-l,3-oxazolidin-2-one (4.29 g; 7.19 mmol), <strong>[875446-29-0](4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid</strong>(Example 78) (4.57 g; 21.57 mmol), te£ra&w(triphenylphosphine)palladium (0) (1.0 g; 0.86 mmol), andsodium carbonate (6.35 g) in C6H6/EtOH/H2O (120 mL/17 mL/51 mL) was heated at reflux (100C)under N2 for 14 h. The reaction was partitioned between EtOAc (200 mL) and H2O (100 mL). Theaqueous phase was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed withbrine (100 mL), dried (MgSO4), filtered and concentrated in vacua. The residue was purified by silica-gel flash chromatography (0-25% EtOAc/hexanes gradient) to afford (4S,5fl)-5-[3,5-bis(trifluoromethyl)phenyl] -3-{ [4' -fluoro-5' isopropyl-2' -methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-l,3-oxazolidin-2-one as a yellow solid. To remove the yellow impurity, 2.7 g weredissolved in 165 mL EtOH and 275 mg decolorizing charcoal was added (activated carbon, Darco, G-60,100 mesh powder, Aldrich). The mixture was stirred at room temperature for 40 min, filtered, andconcentrated in vacua. Trituration with ca. 25 mL hexanes afforded 2.46 g of the title compound as awhite solid. 1H NMR indicated trace impurities which were removed by silica gel flash chromatography(0-15% EtOAc/hexanes gradient). Residual solvent was removed by lyophilization from acetonitrile.LCMS = 638.3 (M+l)+. .H NMR (benzene-d6, 500 MHz, 1:1 mixture of atropisomers): 8 7.82 (s, 0.5H), 7.60 (s, 0.5 H), 7.57 (s, 1 H), 7.33 (d, J = 8 Hz, 1H), 7.27 (d, J = 9.9 Hz, 2 H), 7.02-6.98 (m, 1 H),6.89 (d, J = 8.5 Hz, 0.5 H), 6.82 (d, J = 8.5 Hz, 0.5 H), 6.45 (d, J= 12.1 Hz, 0.5 H), 6.35 (d, J= 11.9 Hz,0.5 H), 4.94 (d, J = 16.0 Hz, 0.5 H), 4.87 (d, J = 15.8 Hz, 0.5 H), 4.54 (d, J = 8.0 Hz, 0.5 H), 4.50 (d, J =7.8 Hz, 0.5 H), 3.74-3.66 (m, 1 H), 3.23-3.15 (m, 1 H), 3.12 (s, 1.5 H), 2.99 (s, 1.5 H), 2.97-2.92 (m, 0.5H), 2.89-2.84 (m, 0.5 H), 1.21-1.09 (m, 6 H), -0.27 (d, J = 6.7 Hz, 1.5 H), -0.40 (d, J = 6.7 Hz, 1.5 H).
With potassium carbonate;palladium diacetate; In water; acetone; for 1h;Heating / reflux; A mixture of (4S,57?)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-l,3-oxazolidin~2-one (50 mg; 0.084 mmol), <strong>[875446-29-0](4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid</strong>(EXAMPLE 78, 22 mg; 0.105 mmol), palladium acetate (6 mg; 0.0103 mmol), and potassium carbonate(29 mg; 0.257 mmol) in 5:1 acetone/water (6 mL) was heated at reflux for 1 h. Acetone was removed invacua and the residue was diluted with H2O (10 mL) and extracted with CH2C12 (3 x 10 mL). Thecombined extracts were washed with brine (10 mL), dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford(45,5JR)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[4'-fluoro-5'isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-l,3-oxazolidin-2-one as a clear glass.
Reference： [1]Patent: WO2006/14357,2006,A1 .Location in patent: Page/Page column 80
[2]Patent: WO2006/14357,2006,A1 .Location in patent: Page/Page column 80-81
  • 2
  • [ 875446-37-0 ]
  • [ 875550-05-3 ]
YieldReaction ConditionsOperation in experiment
60% Stage #1: anacetrapib With boron tribromide In dichloromethane at 15 - 16℃; for 1h; Stage #2: With water In dichloromethane 2 Example 2 Synthesis of (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-(d3-methoxy)-4-(trifluoromethyl)biphenyl-2-yl)methyl)-4-methyloxazolidin-2-one (Compound 101). The synthesis of (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-(d3-methoxy)-4-(trifluoromethyl)biphenyl-2-yl)methyl)-4-methyloxazolidin-2-one (Compound 101) was carried out as outlined in Scheme 8 below. Synthesis of (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-hydroxy-4-(trifluoromethyl)biphenyl-2-yl)methyl)-4-methyl-1,3-oxazolidin- 2-one (55). A solution of 4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl)methyl)-4-methyl-1,3-oxazolidin-2-one (54) [prepared by methods described in WO2007/005572] (1.4 g) in DCM (5 mL) was treated with BBr3 (0.9 mL) at 15-16° C. and the reaction mixture stirred for 1 hr. The mixture was quenched with ice and diluted with EtOAc (150 mL). The mixture was washed with water, sat'd NaHCO3 solution, and brine, dried (Na2SO4), filtered and the solvent concentrated under reduced pressure. The crude product was purified by chromatography on silica gel to give 1.01 g (60%) of 55. 1H NMR (CDCl3) δ: 7.85 (s, 1H), 7.75-7.62 (m, 4H), 7.42 (m, 1H), 6.96 (dd, 1H), 7.69 (dd, 1H), 5.64 (d, 0.5H), 5.39 (d, 0.5H), 4.92-4.80 (m, 1H), 4.18 (d, 0.5H), 3.99 (d, 0.5H), 3.85 (m, 0.5H), 3.75 (m, 0.5H), 3.19 (m, 1H), 1.17-1.25 (m, 6H), 0.57 (d, 1.5H), 0.45 (d, 1.5H).
Reference： [1]Current Patent Assignee: CONCERT PHARMACEUTICALS INC - US2008/242711, 2008, A1 Location in patent: Page/Page column 15-16
  • 3
  • [ 875446-37-0 ]
  • [ 1220703-07-0 ]
YieldReaction ConditionsOperation in experiment
With water; potassium hydroxide In isopropyl alcohol at 75℃; Sealed tube; 6 INTERMEDIATE 6(R2S)- 1 -f 3,5-Bisftrifluoromethvnphenyl]-2-f ( r4'-fluoro-5'~isopropyI-2'-methoχy-4- (trifluoromethyl)biphenyl-2-yl1 methyl } amino)ρropan- 1 -ol; Potassium hydroxide (368.3 mg, 6.56 mmol) was added to a stirred solution of (4S,5R)-5-[3 ,5-bis(trifluoromethyl)phenyl]-3- { [41-fluoro-5'-isopropyl-2'-methoxy-4- (trifuoromethyl)biphenyI-2-yl]methyl}-4-methyl-l,3-oxazolidin-2-one (0.87 g, 1.36 mmol) in i- PrOH (44.7 mL) and water (9.0 mL) and the mixture was heated at 75 0C in a sealed tube overnight. The reaction was cooled to room temperature and concentrated in vacuo to remove most of the z'-PrOH. Brine (25 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford (UJ25)-l-[3,5-bis(trifluoromethyl)phenyl]-2-([4'-fluoro-5'-isopropyl-2'-methoxy-4- (trifluoromethyl)biphenyl-2-yl] methyl }amino)propan-l-ol, as a colorless solid. R/ = 0.49 (20% EtOAc/hexanes). LCMS calc. = 612.2; found = 611.8 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.76-7.69 (m, 4 H); 7.60 (d, J- 7.8 Hz, 1 H); 7.33 (dd, J- 4.0, 7.9 Hz, 1 H); 7.00 (d, J= 8.5 Hz5 I H); 6.71 (dd, J= 5.9, 1 1.9 Hz3 I H); 4.74 (br d, J- 16.0 Hz, 1 H); 3.85-3.70 (m5 6 H); 3.26-3.18 (m, 1 H); 2.81-2.78 (m, 1 H); 1.28-1.20 (m, 7 H); 0.62 (d, J= 6.5 Hz, 3 H).
Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2010/39474, 2010, A1 Location in patent: Page/Page column 11
  • 4
  • C34H29F10NO8(2-)*2Na(1+) [ No CAS ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
In water-d2 at 37℃; for 3.75h; Sodium phosphate buffer; 48 EXAMPLE 48Cyclization Reactions; The kinetics of the cyclization reactions of the compounds described herein could be followed by the procedure illustrated below for the compound of EXAMPLE 35.The sodium salt of EXAMPLE 35 (20 mg, 0.025 mmol) was dissolved (sonicated to ensure dissolution) in 100 mM sodium phosphate buffer in D2O (pH 7.52, 2.2 mL) and heated at 37 0C in an oil bath. 50 μL aliquots were removed periodically. An aliquot was taken at 3 minutes, then every 15 minutes until 135 minutes from the start, then every 30 minutes until 225 minutes from the start. Each aliquot was diluted with MeCN-d3 (150 μL), and a 1H NMR spectrum was acquired (128 scans at 25 0C, with acquisition starting 3 minutes after the aliquot was taken from the reaction). The tl/2 was determined by examining the spectra to find the point in time where the ratio of starting material (SM) and product was 1 :1, based on 2 independent resolved signals in the aromatic region. The t1/2 was found to be 75-90 min. Liquid chromatography - mass spectrometry (LCMS) of the reaction mixture showed the oxazolidinone III to be the main product. A small amount of SM remained along with a compound having a minor NMR peak that may be attributed to the corresponding carbamate. A small amount (ca. 1%) of the monoethyl ester byproduct was also present as a contaminant from the BOC deprotection step.Table 4 below provides half-life data for some of the compounds described above. The methods for determining the half-lives were approximately the same as described above, with variations in procedure depending on such variables as solubility and reaction rates. The cyclizations using the compounds of EXAMPLES 37, 38, and 47 were carried out in a mixed solvent (D2O/l,4-dioxane-ds = 1 :3) rather than a single solvent (D2O).
Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2010/39474, 2010, A1 Location in patent: Page/Page column 43
  • 5
  • (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one [ No CAS ]
  • 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl [ No CAS ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
88% Stage #1: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one With sodium hexamethyldisilazane In N,N-dimethyl-formamide at -15℃; for 1.5h; Stage #2: 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl In N,N-dimethyl-formamide at -15 - 12℃; AIkylation of Oxazolidinone 11 with 7; Oxazolidinone 11 is alkylated with 7 to yield the desired product, (45,5R)-S-[S5S- bis(trifluoromethyl)phenyl]-3 - { [4 ' -fluoro-5 ' -isopropyl-2 ' -methoxy-4-(trifluoromethyl)biphenyl-2- yl]methyl}-4-methyl-l,3-oxazolidin-2-one (12): EPO DMF, NaHMDS Heptane crystallization12The chiral intermediate (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-l,3- oxazolidin-2-one (11) which was made above is dissolved in DMF (2.8 kg in 32.7 L) and cooled to -15° C. 2.0 M NaHMDS (3.92 L, 1.05eq) was then added over 1.5 hr, followed by addition of the biaryl chloride 7 (2.8kg) in DMF. The mixture was warmed to +12°C and was aged until complete conversion took place. Then 5N HCl (3.4L) was added, followed by 16L of 10%IPAC/Heptane and 34L of water, keeping the temperature between 100C and 200C throughout. The layers were cut and the organic layer was washed twice with 14L of 1:1 DMF:water followed by two 14L water washes. The organic layer was assayed for yield and was then filtered through 2.4 kg of silica gel to remove the excess oxazolidinone to <0.5%. The silica was washed with 5% IPAC/Heptane. The combined organic solutions were distilled to remove IPAC to <1%. The warm heptane solution was then transferred slowly into a 200C heptane solution containing 10 wt% seed. The seed crystals were obtained initially from earlier batches of the same reaction. The slurry was then cooled to -200C and filtered. The filter cake was washed with cold heptane and was then dried, yielding 4.4 kg (88%) of the desired product 12.
Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2007/5572, 2007, A1 Location in patent: Page/Page column 11-12
  • 6
  • 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl [ No CAS ]
  • [ 875444-08-9 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
92% With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 17h; Step 7. (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyI)-3-((4'-fluoro-5,-isopropyl-2*-methoxy-4- (trifluo Oxazolidinone IotaPi (9.58 g, 30.6 mmol), biaryl chloride Pi (10.83 g, 30.0 mmol), tetrabutylammonium iodide (0.02 molar equivalents, based on the amount of biaryl chloride), K2CO3 (2 equivalents), and DMF (12 mL) were charged to a 100 mL flask, and the resulting slurry was stirred at 60 C for 17 hours. Then n-heptane and water were added at the same temperature. The aqueous layer was removed, and the organic layer was washed with water. The product was crystallized by cooling the organic mixture. Isolated crystals were washed with heptane and dried to afford 17.60 g of the titled compound (27.6 mmol, 92 %).
88% The chiral intermediate <strong>[875444-08-9](4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one</strong> (compound of formula XV; cf. also compound 11 in Scheme 3) (28.0 g) prepared by the procedure of WO 2007/005572 is dissolved in DMF (300 mL) and cooled to -15C. 2 M NaHMDS (39.2 mL, 1.05 eq) was then added over 1 h, followed by addition of the blaryl chloride 7 (Scheme 3) (28.0 g) in DMF (50 mL), maintaining the internal temperature below-10 C. The mixture was warmed to + 12 C and was aged until complete conversion took place. Then 5M HCl (35 mL) was added, followed by 160 mL of 10% IPAC/Heptanes and 340 mL of water, keeping the temperature between 10C and 20C throughout. The layers were cut and the organic layer was washed twice with 150 mL of 1/1 DMF/water followed by two 140 mL water washes. The organic layer was then removed under reduced pressure and the resulting residue was purified by flash chromatography (EtOAclhexanes) to remove the excess oxazolidinone 11 (Scheme 3). The obtained colorless oil was then dissolved in refluxing heptanes (200 mL) and the solution was slowly cooled to -20 C. The resulting slurry was then stirred at -20 C for 2 hours and filtered. The filter cake was washed with cold heptanes and was then dried, yielding 44.0 g (88%) of the desired product of compound of formula XV" (anacetrapib) as an amorphous material. An impurity of compound of formula XVII" (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((5'-ethyl-4'-fluoro-2'-methoxy-4-(triftuoromethyl) biphenyl-2-yl)methyl-4-methyloxazolidin-2-one (DMAP) is present in the thus obtained anacetrapib in an amount of about 3 % by weight relative to the total amount of anacetrapib product. DMAP originates from 2'-(chloromethyl)-5-ethyl-4-fluoro-2-mothoxy-4'-trifluoromethyl)biphenyl (EBFCI) representing an impurity which forms in the preparation path of 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl under the above described conditions.
88% The chiral intermediate <strong>[875444-08-9](4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one</strong> (compound 11 in Scheme 3, prepared by procedure of WO 2007/005572) (28.0 g) is dissolved in DMF (300 mL) and cooled to - 15C. 2 M NaHMDS (39.2 mL, 1.05 eq) was then added over 1 h, followed by addition of the biaryl chloride 7 (Scheme 3) (28.0 g) in DMF (50 mL), maintaining the internal temperature below -10 C. The mixture was warmed to + 12 C and was aged until complete conversion took place. Then 5M HCl (35 mL) was added, followed by 160 mL of 10% IPAC/Heptanes and 340 mL of water, keeping the temperature between 10C and 20C throughout. The layers were cut and the organic layer was washed twice with 150 mL of 1/1 DMF/water followed by two 140 mL waterwashes. The organic layer was then removed under reduced pressure and the resulting residue was purified by flash chromatography (EtOAc/hexanes) to remove the excess oxazolidinone 11 (Scheme 3). The obtained colorless oil was then dissolved in refluxing heptanes (200 mL) and the solution was slowly cooled to -20 C. The resulting slurry was then stirred at -20 C for 2 hours and filtered. The filter cake was washed with cold heptanes and was then dried, yielding 44.0 g (88%) of the desired product of Formula IX (anacetrapib) as an amorphous material. The impurity (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((5'-ethyl-4'-fluoro-2'-methoxy-4-(trifluoromethyl) biphenyl-2-yl)methyl)-4-methyloxazolidin-2-one (DMAP) (?3%), which is formed from 2'-(chloromethyl)-5-ethyl-4-fluoro-2-methoxy-4'-(trifluoromethyl)biphenyl (EBFCI) present in the starting material under the conditions described in Step 7, was detected in the product.
88% With sodium hexamethyldisilazane; In N,N-dimethyl-formamide; at -15 - 12℃; The chiral intermediate <strong>[875444-08-9](4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one</strong> (compound 11 in Scheme 3, prepared by procedure of WO 2007/005572) (28.0 g) is dissolved in DMF (300 mL) and cooled to - 15C. 2 M NaHMDS (39.2 mL, 1 .05 eq) was then added over 1 h, followed by addition of the biaryl chloride 7 (Scheme 3 ) (28.0 g) in DMF (50 mL), maintaining the internal temperature below -10 C. The mixture was warmed to + 12 C and was aged until complete conversion took place. Then 5M HCI (35 mL) was added, followed by 160 mL of 10% IPAC/Heptanes and 340 mL of water, keeping the temperature between 10C and 20C throughout. The layers were cut and the organic layer was washed twice with 150 mL of 1/1 DMF/water followed by two 140 mL water washes. The organic layerwas then removed under reduced pressure and the resulting residue was purified by flash chromatography (EtOAc/hexanes) to remove the excess oxazolidinone 11 (Scheme 3). The obtained colorless oil was then dissolved in refluxing heptanes (200 mL) and the solution was slowly cooled to -20 C. The resulting slurry was then stirred at -20 C for 2 hours and filtered. The filter cake was washed with cold heptanes and was then dried, yielding 44.0 g (88%) of the desired product of Formula IX (anacetrapib) as an amorphous material. The impurity (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((5l-ethyl-4l-fluoro-2'-methoxy-4-(trifluoromethyl) biphenyl-2-yl)methyl)-4-methyloxazolidin-2-one (DMAP) (-3%), which is formed from 2'-(chloromethyl)-5-ethyl-4- fluoro-2-methoxy-4'-(trifluoromethyl)biphenyl (EBFCI) present in the starting material under the conditions described in Step 7, was detected in the product.
The chiral intermediate (4S,5R)-5-[3 ,5-Bis(trifluoromethyl)rhohenyl]-4-methyl-l ,3- oxazolidin-2-one (11) which was made above is dissolved in DMF (2.8 kg in 32.7 L) and cooled to -15 C. 2.0 M NaHMDS (3.92 L, 1.05eq) was then added over 1.5 hr, followed by addition of the biaryl chloride 7 (2.8kg) in DMF. The mixture was warmed to +12C and was aged until complete conversion took place. Then 5N HCl (3.4L) was added, followed by 16L of 10%IPAC/Heptane and 34L of water, keeping the temperature between 100C and 200C throughout. The layers were cut and the organic layer was washed twice with 14L of 1:1 DMF:water followed by two 14L water washes. The organic layer was assayed for yield and was then filtered through 2.4 kg of silica gel to remove the excess oxazolidinone to <0.5%. The silica was washed with 5% IPAC/Heptane. The combined organic solutions were distilled to remove IPAC to <1%. The warm heptane solution was then transferred slowly into a 200C heptane solution containing 10 wt% seed. The slurry was then cooled to -200C and filtered. The filter cake was washed with cold heptane and was then dried, yielding the desired product 12.
Step 7: Synthesis of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[[2-(4-fluoro-2-methoxy-5-propan-2- ylphenyl)-5-(trifluoromethyl)phenyl]methyl]-4-methyl- 1, 3-oxazolidin-2-one (anacetrapib); The chiral intermediate <strong>[875444-08-9](4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methyloxazolidin-2-one</strong> (compound of formula XV; cf. also compound 11 in Scheme 3) (28.0 g) prepared by the procedure of WO 2007/005572 is dissolved in DMF (300 mL) and cooled to -15C. 2 M NaHMDS (39.2 mL, 1 .05 eq) was then added over 1 h, followed by addition of the biaryl chloride 7 (Scheme 3 ) (28.0 g) in DMF (50 mL), maintaining the internal temperature below - 10 C. The mixture was warmed to + 12 C and was aged until complete conversion took place. Then 5M HCI (35 mL) was added, followed by 160 mL of 10% IPAC/Heptanes and 340 mL of water, keeping the temperature between 10C and 20C throughout. The layers were cut and the organic layer was washed twice with 150 mL of 1/1 DMF/water followed by two 140 mL water washes. The organic layer was then removed under reduced pressure and the resulting residue was purified by flash chromatography (EtOAc/hexanes) to remove the excess oxazolidinone 11 (Scheme 3). The obtained colorless oil was then dissolved in refluxing heptanes (200 mL) and the solution was slowly cooled to -20 C. The resulting slurry was then stirred at -20 C for 2 hours and filtered. The filter cake was washed with cold heptanes and was then dried, yielding 44.0 g (88%) of the desired product of compound of formula XV" (anacetrapib) as an amorphous material. An impurity of compound of formula XVII" (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((5,-ethyl-4,-fluoro-2'- methoxy-4-(trifluoromethyl) biphenyl-2-yl)methyl)-4-methyloxazolidin-2-one (DMAP) is present in the thus obtained anacetrapib in an amount of about 3 % by weight relative to the total amount of anacetrapib product. DMAP originates from 2'-(chloromethyl)-5-ethyl-4-fluoro-2-methoxy-4'-(trifluoromethyl)biphenyl (EBFCI) representing an impurity which forms in the preparation path of 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy- 4'-(trifluoromethyl)biphenyl under the above described conditions.
17.6 g With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 17h; Oxazolidinone III (9.58 g, 30.6 mmol), biaryl chloride II (10.83 g, 30.0 mmol), tetrabutylammonium iodide (0.02 molar equivalents, based on the amount of biaryl chloride), K2CO3 (2 equivalents), and DMF (12 mL) were charged to a 100 mL flask, and the resulting slurry was stirred at 60 C. for 17 hours. Then n-heptane and water were added at the same temperature. The aqueous layer was removed, and the organic layer was washed with water. The product was crystallized by cooling the organic mixture. Isolated crystals were washed with heptane and dried to afford 17.60 g of the titled compound (27.6 mmol, 92%).

Reference： [1]Patent: WO2013/66768,2013,A1 .Location in patent: Page/Page column 11
[2]Patent: EP2468736,2012,A1 .Location in patent: Page/Page column 37
[3]Patent: EP2468735,2012,A1 .Location in patent: Page/Page column 31
[4]Patent: WO2013/91696,2013,A1 .Location in patent: Page/Page column 36-37
[5]Angewandte Chemie - International Edition,2013,vol. 52,p. 6196 - 6201
    Angew. Chem.,2013,vol. 125,p. 6316 - 6321
[6]Patent: WO2007/92642,2007,A2 .Location in patent: Page/Page column 24
[7]Patent: WO2012/85133,2012,A1 .Location in patent: Page/Page column 40-41
[8]Patent: US2014/303380,2014,A1 .Location in patent: Paragraph 0050
YieldReaction ConditionsOperation in experiment
In ethanol; water at 19 - 25℃; for 24h; 1 12.9 mg of amorphous anacetrapib was weighed into a small 4 ml glass vial and dissolved in 50 microliters (µl) of ethanol : water 95 : 5 (v/v) and 200 µl of ethanol were added. To this solution 100 µl of water was added and a slightly turbid suspension was obtained. This suspension was stirred at room temperature at about 19 °C to 25 °C for about one day. Thereafter, the vial was stored in a refrigerator at 5 +/- 2 °C for about five weeks. Light microscopic inspection of the solid formed in the stored vial showed that crystalline material was obtained. Yield is about 10 mg.
  • 8
  • [ 886496-63-5 ]
  • [ 875444-08-9 ]
  • [ 875446-37-0 ]
Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 199 - 203
  • 9
  • [ 875446-29-0 ]
  • [ 1185737-50-1 ]
  • [ 875446-37-0 ]
Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 199 - 203
YieldReaction ConditionsOperation in experiment
<Synthesis of anacetrapib> (4S,5R)-5-(3,5-Bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-methoxy-4-(tri fluoromethyl)-[1,1'-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one (anacetrapib) White solid mp: 60-61°C IR (KBr): v1763, 1332, 1281, 1181, 1133cm-1 1H NMR (C6D6, 1:1 mixture of atropisomers (two isomers can be observed through NMR because rotation of the C-C single bond at the biaryl is suppressed)): δ7.87(s, 0.5H), 7.64(s, 0.5H), 7.60(s, 1H), 7.37(d, J=8.2Hz, 1H), 7.29(d, J=6.9Hz, 2H), 7.05-7.01(m, 1H), 6.93(d, J=8.5Hz, 0.5H), 6.86(d, J=8.4Hz, 0.5H), 6.48(d, J=11.9Hz, 0.5H), 6.39(d, J=11.9Hz, 0.5H), 4.98(d, J=15.8Hz, 0.5H), 4.91(d, J=15.6Hz, 0.5H), 4.60(d, J=7.8Hz, 0.5H), 4.55(d, J=7.6Hz, 0.5H), 3.76(d, J=15.6Hz, 0.5H), 3.72(d, J=15.8Hz, 0.5H), 3.27-3.18(m, 1H), 3.16(s, 1.5H), 3.02(s, 1.5H), 3.00-2.97(m, 0.5H), 2.93-2.89(m, 0.5H), 1.23-1.19(m, 4.5H), 1.13(d, J=6.9Hz, 1.5H), -0.24(d, J=5.0Hz, 1.5H), -0.37(d, J=5.0Hz, 1.5H) 13C NMR (acetone-d6): δ163.1 160.6, 157.3, 156.8, 156.5, 156.4, 156.3, 156.2, 143.1, 142.9, 140.4, 140.2, 137.9, 137.8, 132.9, 132.5, 132.2(q, JC-F=33.5Hz), 130.3(q, JC-F=32.6Hz), 130.1(q, JC-F=32.6Hz), 129.8, 129.8, 129.6, 129.5, 127.8, 127.8, 127.6, 127.5, 127.4, 125.8(q, JC-F=3.8Hz), 125.5(q, JC-F=3.8Hz), 125.2(q, JC-F=271Hz), 125.1(q, JC-F=3.8Hz), 124.6(q, JC-F=2.9Hz), 124.2(q, JC-F=272Hz), 123.0(q, JC-F=3.8Hz), 100.5, 100.3, 100.2, 100.1, 77.6, 77.5, 56.3, 56.2, 54.7, 54.6, 44.9, 43.8, 27.4, 27.3, 23.1, 23.0, 23.0, 22.9, 14.2, 14.1 ESI-MS m/z 660 [M+Na]+ HRMS (ESI-TOF) calcd. for C30H26F10NO3 m/z 638.1748 [M+H]+, found 638.1744 [α]D27 -8.3 (c 0.65, CHCl3, 99% ee)
  • 11
  • [ 74457-86-6 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 3.1: N-Bromosuccinimide / acetonitrile / 35 °C 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: Inert atmosphere 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 24 h / 35 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -15 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 3.1: N-Bromosuccinimide / acetonitrile / 35 °C 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: Inert atmosphere 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 30 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -15 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 3.1: N-Bromosuccinimide / acetonitrile / 35 °C 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 3.1: N-Bromosuccinimide / acetonitrile / 35 °C 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: sulfuric acid / 12 h / Reflux 4.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 5.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 5.2: 1 h / 15 - 20 °C / pH 2 6.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 8.2: -10 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: sulfuric acid / 12 h / Reflux 4.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 5.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 5.2: 1 h / 15 - 20 °C / pH 2 6.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 8.2: -10 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: sulfuric acid / 12 h / Reflux 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: -35 °C 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 7.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 8.2: -10 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: sulfuric acid / 12 h / Reflux 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: -35 °C 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 7.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 8.2: -10 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: sulfuric acid / 12 h / Reflux 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: -35 °C 5.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 6.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 8.2: -10 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: sulfuric acid / 12 h / Reflux 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: -35 °C 5.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 6.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 8.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: dichloromethane; tetrahydrofuran / 0 °C / Inert atmosphere 1.2: 20 °C 2.1: hydrogen / palladium on activated carbon / methanol / 50 °C / 2250.23 Torr / Inert atmosphere 2.2: 40 °C 3.1: n-butyllithium / toluene; hexane / -80 - -55 °C / Inert atmosphere 3.3: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 5.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 °C
Multi-step reaction with 7 steps 1.1: dichloromethane; tetrahydrofuran / 0 °C / Inert atmosphere 1.2: 20 °C 2.1: hydrogen / palladium 10% on activated carbon / ethanol / 40 °C / 775.74 Torr 3.1: N-Bromosuccinimide / acetonitrile / 35 °C 4.1: n-butyllithium / toluene; hexane / -80 - -55 °C / Inert atmosphere 4.3: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 6.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 °C
Multi-step reaction with 7 steps 1.1: dichloromethane; tetrahydrofuran / 0 °C / Inert atmosphere 1.2: 20 °C 2.1: hydrogen / palladium 10% on activated carbon / ethanol / 40 °C / 775.74 Torr 3.1: N-Bromosuccinimide / acetonitrile / 35 °C 4.1: n-butyllithium / toluene; hexane / -80 - -55 °C / Inert atmosphere 4.3: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 6.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 0.67 h / 20 - 35 °C / Inert atmosphere 1.2: 5 - 25 °C 2.1: trifluoroacetic acid; diphenyl sulfide; hydrogen; 5%-palladium/activated carbon / Isopropyl acetate / 12 h / 60 °C / 3345.86 Torr / Inert atmosphere 3.1: hydrogen bromide; dihydrogen peroxide / Isopropyl acetate; water / 3.67 h / 25 - 30 °C / Darkness 4.1: TurboGrignard; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 4.2: 1 h / -20 °C 4.3: -20 - 20 °C 5.1: tricyclohexylphosphine tetrafluoroborate; bis(η3-allyl-μ-chloropalladium(II)); potassium carbonate / water; acetonitrile / 70 °C / Inert atmosphere 6.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 15 °C 7.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C
Multi-step reaction with 6 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: hydrogen; hydrogenchloride; palladium 10% on activated carbon / water; ethanol / 1 h / 40 °C / 775.74 Torr 3.1: N-Bromosuccinimide / acetonitrile / 35 °C 4.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 4.2: 12 h / 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: hydrogen; hydrogenchloride; palladium 10% on activated carbon / water; ethanol / 1 h / 40 °C / 775.74 Torr 3.1: N-Bromosuccinimide / acetonitrile / 35 °C 4.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 4.2: 12 h / 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 4.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 4.2: 12 h / 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 4.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 4.2: 12 h / 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 4.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 4.2: 12 h / 20 °C 5.1: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 6.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 4.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 5.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 5.2: 12 h / 20 °C 6.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 4.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 5.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 5.2: 12 h / 20 °C 6.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: tetrahydrofuran / 1 h / -15 - 0 °C 2: N-Bromosuccinimide / acetonitrile / 60 °C 3: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: tetrahydrofuran / 1 h / -15 - 0 °C 2: hydrogen; hydrogenchloride; palladium 10% on activated carbon / water; ethanol / 1 h / 40 °C / 775.74 Torr 3: N-Bromosuccinimide / acetonitrile / 35 °C 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1: tetrahydrofuran / 1 h / -15 - 0 °C 2: N-Bromosuccinimide / acetonitrile / 60 °C 3: sulfuric acid / water / 12 h / Dean-Stark; Reflux 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 6: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1: tetrahydrofuran / 1 h / -15 - 0 °C 2: N-Bromosuccinimide / acetonitrile / 60 °C 3: sulfuric acid / water / 12 h / Dean-Stark; Reflux 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 7: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1: tetrahydrofuran / 1 h / -15 - 0 °C 2: N-Bromosuccinimide / acetonitrile / 60 °C 3: sulfuric acid / water / 12 h / Dean-Stark; Reflux 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 7: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1: tetrahydrofuran / 1 h / -15 - 0 °C 2: N-Bromosuccinimide / acetonitrile / 60 °C 3: sulfuric acid / water / 12 h / Dean-Stark; Reflux 4: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 5: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 6: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 4.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 5.2: 13 h / 0 - 20 °C 6.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: hydrogen; hydrogenchloride; palladium 10% on activated carbon / water; ethanol / 1 h / 40 °C / 775.74 Torr 3.1: N-Bromosuccinimide / acetonitrile / 35 °C 4.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 5.2: 13 h / 0 - 20 °C 6.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: tetrahydrofuran / 1 h / -15 - 0 °C 2: N-Bromosuccinimide / acetonitrile / 60 °C 3: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: tetrahydrofuran / 1 h / -15 - 0 °C 2: hydrogen; hydrogenchloride; palladium 10% on activated carbon / water; ethanol / 1 h / 40 °C / 775.74 Torr 3: N-Bromosuccinimide / acetonitrile / 35 °C 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 4.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 5.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 6.2: 13 h / 0 - 20 °C 7.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1: tetrahydrofuran / 1 h / -15 - 0 °C 2: N-Bromosuccinimide / acetonitrile / 60 °C 3: sulfuric acid / water / 12 h / Dean-Stark; Reflux 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 6: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 7: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1: tetrahydrofuran / 1 h / -15 - 0 °C 2: N-Bromosuccinimide / acetonitrile / 60 °C 3: sulfuric acid / water / 12 h / Dean-Stark; Reflux 4: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 5: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 6: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 7: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 0.5 h / 20 - 35 °C / Inert atmosphere 2.1: diphenyl sulfide; 5%-palladium/activated carbon; hydrogen; trifluoroacetic acid / Isopropyl acetate / 12 h / 60 °C / 3345.86 Torr / Inert atmosphere 3.1: dihydrogen peroxide; hydrogen bromide / water / 3.67 h / 25 - 30 °C / Darkness 4.1: N,N,N,N,-tetramethylethylenediamine; TurboGrignard / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 4.2: 1 h / -20 °C 5.1: potassium carbonate; bis(η3-allyl-μ-chloropalladium(II)); C18H33P*BF4(1+)*H(1+) / acetonitrile / 70 °C / Inert atmosphere 6.1: thionyl chloride; N,N-dimethyl-formamide / 10 - 15 °C 7.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 0.5 h / 20 - 35 °C / Inert atmosphere 2.1: diphenyl sulfide; 5%-palladium/activated carbon; hydrogen; trifluoroacetic acid / Isopropyl acetate / 12 h / 60 °C / 3345.86 Torr / Inert atmosphere 3.1: dihydrogen peroxide; hydrogen bromide / water / 3.67 h / 25 - 30 °C / Darkness 4.1: N,N,N,N,-tetramethylethylenediamine; TurboGrignard / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 4.2: 1 h / -20 °C 5.1: nickel dibromide; P(p-CH3OC6H4)3; potassium phosphate / toluene / 15 h / 80 °C / Inert atmosphere 5.2: 20 °C / Inert atmosphere 6.1: thionyl chloride; N,N-dimethyl-formamide / 10 - 15 °C 7.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2468736, 2012, A1
[2]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2468736, 2012, A1
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[5]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[6]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[7]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[8]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[9]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[10]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[11]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[12]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[13]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2012/85133, 2012, A1
[14]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2012/85133, 2012, A1
[15]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2012/85133, 2012, A1
[16]Current Patent Assignee: MERCK & CO INC - WO2013/66768, 2013, A1
[17]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[18]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[19]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[20]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[21]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[22]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[23]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[24]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[25]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[26]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[27]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[28]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[29]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[30]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[31]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[32]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[33]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[34]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[35]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[36]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[37]Current Patent Assignee: MERCK & CO INC - US2014/303380, 2014, A1
[38]Current Patent Assignee: MERCK & CO INC - US2014/303380, 2014, A1
  • 12
  • [ 96826-25-4 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 2.1: N-Bromosuccinimide / acetonitrile / 35 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 24 h / 35 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -15 - 12 °C
Multi-step reaction with 6 steps 1.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 2.1: N-Bromosuccinimide / acetonitrile / 35 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 30 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -15 - 12 °C
Multi-step reaction with 6 steps 1.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 2.1: N-Bromosuccinimide / acetonitrile / 35 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 2.1: N-Bromosuccinimide / acetonitrile / 35 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: -35 °C 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: -35 °C 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: -35 °C 4.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: -35 °C 4.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: hydrogen / palladium 10% on activated carbon / ethanol / 40 °C / 775.74 Torr 2.1: N-Bromosuccinimide / acetonitrile / 35 °C 3.1: n-butyllithium / toluene; hexane / -80 - -55 °C / Inert atmosphere 3.3: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 5.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 °C
Multi-step reaction with 6 steps 1.1: trifluoroacetic acid; diphenyl sulfide; hydrogen; 5%-palladium/activated carbon / Isopropyl acetate / 12 h / 60 °C / 3345.86 Torr / Inert atmosphere 2.1: hydrogen bromide; dihydrogen peroxide / Isopropyl acetate; water / 3.67 h / 25 - 30 °C / Darkness 3.1: TurboGrignard; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 3.2: 1 h / -20 °C 3.3: -20 - 20 °C 4.1: tricyclohexylphosphine tetrafluoroborate; bis(η3-allyl-μ-chloropalladium(II)); potassium carbonate / water; acetonitrile / 70 °C / Inert atmosphere 5.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 15 °C 6.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 3.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 3.2: 12 h / 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 3.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 3.2: 12 h / 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1.1: hydrogen; hydrogenchloride; palladium 10% on activated carbon / water; ethanol / 1 h / 40 °C / 775.74 Torr 2.1: N-Bromosuccinimide / acetonitrile / 35 °C 3.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 3.2: 12 h / 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1.1: hydrogen; hydrogenchloride; palladium 10% on activated carbon / water; ethanol / 1 h / 40 °C / 775.74 Torr 2.1: N-Bromosuccinimide / acetonitrile / 35 °C 3.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 3.2: 12 h / 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 3.2: 12 h / 20 °C 4.1: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 4.2: 12 h / 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 4.2: 12 h / 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: N-Bromosuccinimide / acetonitrile / 60 °C 2: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: hydrogen; hydrogenchloride; palladium 10% on activated carbon / water; ethanol / 1 h / 40 °C / 775.74 Torr 2: N-Bromosuccinimide / acetonitrile / 35 °C 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: N-Bromosuccinimide / acetonitrile / 60 °C 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: N-Bromosuccinimide / acetonitrile / 60 °C 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: N-Bromosuccinimide / acetonitrile / 60 °C 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: N-Bromosuccinimide / acetonitrile / 60 °C 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 3.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 4.2: 13 h / 0 - 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: hydrogen; hydrogenchloride; palladium 10% on activated carbon / water; ethanol / 1 h / 40 °C / 775.74 Torr 2.1: N-Bromosuccinimide / acetonitrile / 35 °C 3.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 4.2: 13 h / 0 - 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: N-Bromosuccinimide / acetonitrile / 60 °C 2: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: hydrogen; hydrogenchloride; palladium 10% on activated carbon / water; ethanol / 1 h / 40 °C / 775.74 Torr 2: N-Bromosuccinimide / acetonitrile / 35 °C 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1.1: N-Bromosuccinimide / acetonitrile / 60 °C 2.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 5.2: 13 h / 0 - 20 °C 6.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: N-Bromosuccinimide / acetonitrile / 60 °C 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: N-Bromosuccinimide / acetonitrile / 60 °C 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: diphenyl sulfide; 5%-palladium/activated carbon; hydrogen; trifluoroacetic acid / Isopropyl acetate / 12 h / 60 °C / 3345.86 Torr / Inert atmosphere 2.1: dihydrogen peroxide; hydrogen bromide / water / 3.67 h / 25 - 30 °C / Darkness 3.1: N,N,N,N,-tetramethylethylenediamine; TurboGrignard / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 3.2: 1 h / -20 °C 4.1: potassium carbonate; bis(η3-allyl-μ-chloropalladium(II)); C18H33P*BF4(1+)*H(1+) / acetonitrile / 70 °C / Inert atmosphere 5.1: thionyl chloride; N,N-dimethyl-formamide / 10 - 15 °C 6.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C
Multi-step reaction with 6 steps 1.1: diphenyl sulfide; 5%-palladium/activated carbon; hydrogen; trifluoroacetic acid / Isopropyl acetate / 12 h / 60 °C / 3345.86 Torr / Inert atmosphere 2.1: dihydrogen peroxide; hydrogen bromide / water / 3.67 h / 25 - 30 °C / Darkness 3.1: N,N,N,N,-tetramethylethylenediamine; TurboGrignard / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 3.2: 1 h / -20 °C 4.1: nickel dibromide; P(p-CH3OC6H4)3; potassium phosphate / toluene / 15 h / 80 °C / Inert atmosphere 4.2: 20 °C / Inert atmosphere 5.1: thionyl chloride; N,N-dimethyl-formamide / 10 - 15 °C 6.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2468736, 2012, A1
[2]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2468736, 2012, A1
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[5]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[6]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[7]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[8]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[9]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[10]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[11]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[12]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[13]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2012/85133, 2012, A1
[14]Current Patent Assignee: MERCK & CO INC - WO2013/66768, 2013, A1
[15]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[16]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[17]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[18]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[19]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[20]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[21]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[22]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[23]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[24]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[25]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[26]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[27]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[28]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[29]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[30]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[31]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[32]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[33]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[34]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[35]Current Patent Assignee: MERCK & CO INC - US2014/303380, 2014, A1
[36]Current Patent Assignee: MERCK & CO INC - US2014/303380, 2014, A1
  • 13
  • [ 875446-29-0 ]
  • [ 875446-37-0 ]
Reference： [1]Patent: EP2468736,2012,A1
[2]Patent: EP2468736,2012,A1
[3]Patent: EP2468735,2012,A1
[4]Patent: EP2468735,2012,A1
[5]Patent: WO2012/85133,2012,A1
[6]Patent: WO2013/66768,2013,A1
[7]Patent: WO2013/91696,2013,A1
[8]Patent: WO2013/91696,2013,A1
[9]Patent: WO2014/111953,2014,A1
[10]Patent: US2014/303380,2014,A1
[11]Patent: US2014/303380,2014,A1
[12]Patent: CN106032362,2016,A
  • 14
  • 2-(2-fluoro-4-methoxyphenyl)isopropane [ No CAS ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / acetonitrile / 35 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: Inert atmosphere 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 24 h / 35 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -15 - 12 °C
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / acetonitrile / 35 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: Inert atmosphere 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 30 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -15 - 12 °C
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / acetonitrile / 35 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / acetonitrile / 35 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / acetonitrile / 35 °C 2.1: n-butyllithium / toluene; hexane / -80 - -55 °C / Inert atmosphere 2.3: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 4.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 °C
Multi-step reaction with 5 steps 1.1: hydrogen bromide; dihydrogen peroxide / Isopropyl acetate; water / 3.67 h / 25 - 30 °C / Darkness 2.1: TurboGrignard; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 2.2: 1 h / -20 °C 2.3: -20 - 20 °C 3.1: tricyclohexylphosphine tetrafluoroborate; bis(η3-allyl-μ-chloropalladium(II)); potassium carbonate / water; acetonitrile / 70 °C / Inert atmosphere 4.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 15 °C 5.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C
Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide / acetonitrile / 35 °C 2.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 2.2: 12 h / 20 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide / acetonitrile / 35 °C 2.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 2.2: 12 h / 20 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1: N-Bromosuccinimide / acetonitrile / 35 °C 2: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 3: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / acetonitrile / 35 °C 2.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 3.2: 13 h / 0 - 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1: N-Bromosuccinimide / acetonitrile / 35 °C 2: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 3: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 4: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1.1: dihydrogen peroxide; hydrogen bromide / water / 3.67 h / 25 - 30 °C / Darkness 2.1: N,N,N,N,-tetramethylethylenediamine; TurboGrignard / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 2.2: 1 h / -20 °C 3.1: potassium carbonate; bis(η3-allyl-μ-chloropalladium(II)); C18H33P*BF4(1+)*H(1+) / acetonitrile / 70 °C / Inert atmosphere 4.1: thionyl chloride; N,N-dimethyl-formamide / 10 - 15 °C 5.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C
Multi-step reaction with 5 steps 1.1: dihydrogen peroxide; hydrogen bromide / water / 3.67 h / 25 - 30 °C / Darkness 2.1: N,N,N,N,-tetramethylethylenediamine; TurboGrignard / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 2.2: 1 h / -20 °C 3.1: nickel dibromide; P(p-CH3OC6H4)3; potassium phosphate / toluene / 15 h / 80 °C / Inert atmosphere 3.2: 20 °C / Inert atmosphere 4.1: thionyl chloride; N,N-dimethyl-formamide / 10 - 15 °C 5.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2468736, 2012, A1
[2]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2468736, 2012, A1
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[5]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2012/85133, 2012, A1
[6]Current Patent Assignee: MERCK & CO INC - WO2013/66768, 2013, A1
[7]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[8]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[9]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[10]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[11]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[12]Current Patent Assignee: MERCK & CO INC - US2014/303380, 2014, A1
[13]Current Patent Assignee: MERCK & CO INC - US2014/303380, 2014, A1
  • 15
  • [ 944317-92-4 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: Inert atmosphere 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 24 h / 35 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -15 - 12 °C
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: Inert atmosphere 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 30 - 45 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -15 - 12 °C
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: 1 h / 15 - 20 °C / pH 2 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 - 12 °C
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: 1 h / 15 - 20 °C / pH 2 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 - 12 °C
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene; hexane / -80 - -55 °C / Inert atmosphere 1.3: 1 h / 15 - 20 °C / pH 2 2.1: potassium carbonate / dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 3.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 °C
Multi-step reaction with 4 steps 1.1: TurboGrignard; N,N,N,N,-tetramethylethylenediamine / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 1.2: 1 h / -20 °C 1.3: -20 - 20 °C 2.1: tricyclohexylphosphine tetrafluoroborate; bis(η3-allyl-μ-chloropalladium(II)); potassium carbonate / water; acetonitrile / 70 °C / Inert atmosphere 3.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 15 °C 4.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C
Multi-step reaction with 3 steps 1.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 1.2: 12 h / 20 °C 2.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 3.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 3 steps 1.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 1.2: 12 h / 20 °C 2.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 3.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 4 steps 1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 2: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 4 steps 1.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 2.2: 13 h / 0 - 20 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 4 steps 1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 2: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 3: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 4 steps 1.1: N,N,N,N,-tetramethylethylenediamine; TurboGrignard / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 1.2: 1 h / -20 °C 2.1: nickel dibromide; P(p-CH3OC6H4)3; potassium phosphate / toluene / 15 h / 80 °C / Inert atmosphere 2.2: 20 °C / Inert atmosphere 3.1: thionyl chloride; N,N-dimethyl-formamide / 10 - 15 °C 4.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C
Multi-step reaction with 4 steps 1.1: N,N,N,N,-tetramethylethylenediamine; TurboGrignard / tetrahydrofuran / 3 h / 40 °C / Inert atmosphere 1.2: 1 h / -20 °C 2.1: potassium carbonate; bis(η3-allyl-μ-chloropalladium(II)); C18H33P*BF4(1+)*H(1+) / acetonitrile / 70 °C / Inert atmosphere 3.1: thionyl chloride; N,N-dimethyl-formamide / 10 - 15 °C 4.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2468736, 2012, A1
[2]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2468736, 2012, A1
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[5]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2012/85133, 2012, A1
[6]Current Patent Assignee: MERCK & CO INC - WO2013/66768, 2013, A1
[7]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[8]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[9]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[10]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[11]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[12]Current Patent Assignee: MERCK & CO INC - US2014/303380, 2014, A1
[13]Current Patent Assignee: MERCK & CO INC - US2014/303380, 2014, A1
  • 16
  • [ 875548-97-3 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 2.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 2.2: -15 - 12 °C
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 2.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 2.2: -10 - 12 °C
Multi-step reaction with 2 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 2.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 2.2: -10 °C
Multi-step reaction with 4 steps 1: Dess-Martin periodane / dichloromethane / 2 h / 20 °C 2: isopropyl alcohol / 2 h / 35 - 40 °C 3: sodium tetrahydroborate / methanol / 2 h / 20 °C 4: tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 70 - 75 °C
Multi-step reaction with 2 steps 1: thionyl chloride; N,N-dimethyl-formamide / 10 - 15 °C 2: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C

Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - EP2468736, 2012, A1
[2]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[3]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2012/85133, 2012, A1
[4]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2014/111953, 2014, A1
[5]Current Patent Assignee: MERCK & CO INC - US2014/303380, 2014, A1
  • 17
  • [ 348-57-2 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 3.1: tetrahydrofuran / 1 h / -15 - 0 °C 4.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 5.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 5.2: 1 h / 15 - 20 °C / pH 2 6.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 8.2: -10 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 3.1: tetrahydrofuran / 1 h / -15 - 0 °C 4.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 5.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 5.2: 1 h / 15 - 20 °C / pH 2 6.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 8.2: -10 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 3.1: tetrahydrofuran / 1 h / -15 - 0 °C 4.1: sulfuric acid / 12 h / Reflux 5.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 6.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 6.2: 1 h / 15 - 20 °C / pH 2 7.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 8.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 9.2: -10 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 3.1: tetrahydrofuran / 1 h / -15 - 0 °C 4.1: sulfuric acid / 12 h / Reflux 5.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 6.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 6.2: 1 h / 15 - 20 °C / pH 2 7.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 8.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 9.2: -10 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 3.1: tetrahydrofuran / 1 h / -15 - 0 °C 4.1: sulfuric acid / 12 h / Reflux 5.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 5.2: -35 °C 6.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 8.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 9.2: -10 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 3.1: tetrahydrofuran / 1 h / -15 - 0 °C 4.1: sulfuric acid / 12 h / Reflux 5.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 5.2: -35 °C 6.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 8.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 9.2: -10 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 3.1: tetrahydrofuran / 1 h / -15 - 0 °C 4.1: sulfuric acid / 12 h / Reflux 5.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 5.2: -35 °C 6.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 7.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 8.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 9.2: -10 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 3.1: tetrahydrofuran / 1 h / -15 - 0 °C 4.1: sulfuric acid / 12 h / Reflux 5.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 5.2: -35 °C 6.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 7.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 8.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 9.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 5.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 5.2: 12 h / 20 °C 6.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 5.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 5.2: 12 h / 20 °C 6.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 5.1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 6.1: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 5.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 5.2: 12 h / 20 °C 6.1: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 7.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 5.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 6.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 6.2: 12 h / 20 °C 7.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 5.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 6.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 6.2: 12 h / 20 °C 7.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 5.1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 6.1: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 7.1: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 8.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 5.1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 6.1: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 8.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 5.1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 6.1: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 8.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 5.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 6.1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 7.1: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 8.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 5.1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 6.1: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 7.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 5.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 6.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 6.2: 13 h / 0 - 20 °C 7.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 5.1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 6.1: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 7.1: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 8.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 5.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 6.1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 7.1: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 8.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / -10 - 2 °C 2.2: 1 h / 0 - 5 °C 3.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 4.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 5.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 6.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 7.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 7.2: 13 h / 0 - 20 °C 8.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C

Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[2]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[5]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[6]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[7]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[8]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[9]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[10]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[11]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[12]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[13]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[14]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[15]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[16]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[17]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[18]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[19]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[20]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[21]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[22]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[23]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
  • 18
  • [ 450-88-4 ]
  • [ 875446-37-0 ]
Reference： [1]Patent: EP2468735,2012,A1
[2]Patent: EP2468735,2012,A1
[3]Patent: EP2468735,2012,A1
[4]Patent: EP2468735,2012,A1
[5]Patent: EP2468735,2012,A1
[6]Patent: EP2468735,2012,A1
[7]Patent: EP2468735,2012,A1
[8]Patent: EP2468735,2012,A1
[9]Patent: WO2013/91696,2013,A1
[10]Patent: WO2013/91696,2013,A1
[11]Patent: WO2013/91696,2013,A1
[12]Patent: WO2013/91696,2013,A1
[13]Patent: WO2013/91696,2013,A1
[14]Patent: WO2013/91696,2013,A1
[15]Patent: WO2013/91696,2013,A1
[16]Patent: WO2013/91696,2013,A1
[17]Patent: WO2013/91696,2013,A1
[18]Patent: WO2013/91696,2013,A1
[19]Patent: WO2013/91696,2013,A1
[20]Patent: WO2013/91696,2013,A1
[21]Patent: WO2013/91696,2013,A1
[22]Patent: WO2013/91696,2013,A1
[23]Patent: WO2013/91696,2013,A1
  • 19
  • [ 914221-54-8 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: -35 °C 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: -35 °C 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: -35 °C 4.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: -35 °C 4.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C
Multi-step reaction with 5 steps 1.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 3.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 3.2: 12 h / 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 3.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 3.2: 12 h / 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 3.2: 12 h / 20 °C 4.1: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 4.2: 12 h / 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 4.2: 12 h / 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 3.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 4.2: 13 h / 0 - 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1.1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 5.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 5.2: 13 h / 0 - 20 °C 6.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 7 steps 1: tetrahydrofuran; dichloromethane / 2 h / -10 - 0 °C / Inert atmosphere 2: sulfuric acid / water / 12 h / Dean-Stark; Reflux 3: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 5: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 6: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 7: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C

Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[2]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[5]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[6]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[7]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[8]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[9]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[10]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[11]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[12]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[13]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[14]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[15]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[16]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[17]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[18]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[19]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[20]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[21]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[22]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[23]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
  • 20
  • [ 1383814-85-4 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 2.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 3.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 3.2: -10 - 12 °C
Multi-step reaction with 3 steps 1: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 2: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 3: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[2]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
  • 21
  • [ 958029-46-4 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: sulfuric acid / 12 h / Reflux 2.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: sulfuric acid / 12 h / Reflux 2.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: sulfuric acid / 12 h / Reflux 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: -35 °C 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: sulfuric acid / 12 h / Reflux 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: -35 °C 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: sulfuric acid / 12 h / Reflux 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: -35 °C 3.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 6 steps 1.1: sulfuric acid / 12 h / Reflux 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: -35 °C 3.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C
Multi-step reaction with 4 steps 1.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 2.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 2.2: 12 h / 20 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 4 steps 1.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 2.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 2.2: 12 h / 20 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 2.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 2.2: 12 h / 20 °C 3.1: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 2.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 3.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 3.2: 12 h / 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 2.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 3.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 3.2: 12 h / 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 2: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 3: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 2: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 3: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 2: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 3: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 2: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 3: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 2: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1.1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 2.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 3.2: 13 h / 0 - 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1: 1,1,3,3-Tetramethyldisiloxane; trifluoroacetic acid / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C / Inert atmosphere 2: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 3: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 4: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1.1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 2.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 3.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 4.2: 13 h / 0 - 20 °C 5.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 2: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 3: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 6 steps 1: sulfuric acid / water / 12 h / Dean-Stark; Reflux 2: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 3: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 4: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 5: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 6: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C

Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[2]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[5]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[6]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[7]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[8]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[9]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[10]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[11]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[12]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[13]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[14]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[15]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[16]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[17]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[18]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[19]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[20]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[21]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[22]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[23]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
  • 22
  • [ 1383814-82-1 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C
Multi-step reaction with 5 steps 1.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C
Multi-step reaction with 5 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: -35 °C 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C
Multi-step reaction with 5 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: -35 °C 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C
Multi-step reaction with 5 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: -35 °C 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C
Multi-step reaction with 5 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: -35 °C 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C
Multi-step reaction with 4 steps 1.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 2.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 2.2: 12 h / 20 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 4 steps 1.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 2.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 2.2: 12 h / 20 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 4 steps 1.1: Triisopropyl borate; n-butyllithium / hexane; tetrahydrofuran; toluene / 1 h / -80 - -10 °C / Inert atmosphere 1.2: 12 h / 20 °C 2.1: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 3.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 2: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 3: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 2: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 3: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 2: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 4: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 2: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 4: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1.1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 2.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 3.2: 13 h / 0 - 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1: hydrogen; hydrogen bromide; 5%-palladium/activated carbon / methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 2: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 3: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 4: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 5 steps 1: n-butyllithium / hexane; tetrahydrofuran; toluene / 0.5 h / -80 - -35 °C / Inert atmosphere 2: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 3: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 4: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C

Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[2]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[5]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[6]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[7]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[8]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[9]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[10]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[11]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[12]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[13]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[14]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[15]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[16]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
  • 23
  • [ 1383814-83-2 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 - 12 °C
Multi-step reaction with 4 steps 1.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 - 12 °C
Multi-step reaction with 4 steps 1.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 - 12 °C
Multi-step reaction with 4 steps 1.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 - 12 °C
Multi-step reaction with 4 steps 1: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 2: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 4 steps 1: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 2: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 3: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 4 steps 1: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 2: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 3: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Multi-step reaction with 4 steps 1: hydrogen; 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 2: potassium carbonate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 3: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C

Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[2]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[3]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[4]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2468735, 2012, A1
[5]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[6]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[7]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
[8]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
  • 24
  • [ 875446-55-2 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: hydrogen / palladium on activated carbon / methanol / 50 °C / 2250.23 Torr / Inert atmosphere 1.2: 40 °C 2.1: n-butyllithium / toluene; hexane / -80 - -55 °C / Inert atmosphere 2.3: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 4.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 °C
Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2012/85133, 2012, A1
  • 25
  • [ 1383676-72-9 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: toluene; tetrahydrofuran / 5 - 10 °C 1.3: 15 - 20 °C / pH 2 2.1: potassium carbonate / dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 3.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 °C
Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2012/85133, 2012, A1
  • 26
  • C9H11I2NO [ No CAS ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 2.1: copper(l) chloride; potassium <i>tert</i>-butylate; 1,10-Phenanthroline / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 2.2: 18 h / 50 °C / Inert atmosphere 3.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / -20 °C / Inert atmosphere 3.2: 18 h / 20 °C
Reference： [1]Ogawa, Takanori; Kumagai, Naoya; Shibasaki, Masakatsu [Angewandte Chemie - International Edition, 2013, vol. 52, # 24, p. 6196 - 6201][Angew. Chem., 2013, vol. 125, # 24, p. 6316 - 6321]
  • 27
  • (4S,5R)-5-(3,5-diiodophenyl)-4-methyloxazolidin-2-one [ No CAS ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: copper(l) chloride; potassium <i>tert</i>-butylate; 1,10-Phenanthroline / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 1.2: 18 h / 50 °C / Inert atmosphere 2.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / -20 °C / Inert atmosphere 2.2: 18 h / 20 °C
Reference： [1]Ogawa, Takanori; Kumagai, Naoya; Shibasaki, Masakatsu [Angewandte Chemie - International Edition, 2013, vol. 52, # 24, p. 6196 - 6201][Angew. Chem., 2013, vol. 125, # 24, p. 6316 - 6321]
  • 28
  • (1R,2S)-1-(3,5-diiodophenyl)-2-nitropropan-1-ol [ No CAS ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: hydrogenchloride; zinc / 1 h / 0 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 3.1: copper(l) chloride; potassium <i>tert</i>-butylate; 1,10-Phenanthroline / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 3.2: 18 h / 50 °C / Inert atmosphere 4.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / -20 °C / Inert atmosphere 4.2: 18 h / 20 °C
Reference： [1]Ogawa, Takanori; Kumagai, Naoya; Shibasaki, Masakatsu [Angewandte Chemie - International Edition, 2013, vol. 52, # 24, p. 6196 - 6201][Angew. Chem., 2013, vol. 125, # 24, p. 6316 - 6321]
  • 29
  • [ 17352-25-9 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: / tetrahydrofuran / 20 h / -60 - 20 °C / Inert atmosphere 2.1: hydrogenchloride; zinc / 1 h / 0 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 4.1: copper(l) chloride; potassium <i>tert</i>-butylate; 1,10-Phenanthroline / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 4.2: 18 h / 50 °C / Inert atmosphere 5.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / -20 °C / Inert atmosphere 5.2: 18 h / 20 °C
Multi-step reaction with 5 steps 1.1: / tetrahydrofuran / 64 h / -60 °C 2.1: hydrogenchloride; zinc / 1 h / 0 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 4.1: copper(l) chloride; potassium <i>tert</i>-butylate; 1,10-Phenanthroline / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 4.2: 18 h / 50 °C / Inert atmosphere 5.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / -20 °C / Inert atmosphere 5.2: 18 h / 20 °C
Reference： [1]Ogawa, Takanori; Kumagai, Naoya; Shibasaki, Masakatsu [Angewandte Chemie - International Edition, 2013, vol. 52, # 24, p. 6196 - 6201][Angew. Chem., 2013, vol. 125, # 24, p. 6316 - 6321]
[2]Ogawa, Takanori; Kumagai, Naoya; Shibasaki, Masakatsu [Angewandte Chemie - International Edition, 2013, vol. 52, # 24, p. 6196 - 6201][Angew. Chem., 2013, vol. 125, # 24, p. 6316 - 6321]
  • 30
  • [ 851513-74-1 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 2.2: 13 h / 0 - 20 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
  • 31
  • [ 368-77-4 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: calcium chloride / 5,5-dimethyl-1,3-cyclohexadiene / 24 h / 125 °C / Inert atmosphere 2.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 3.2: 13 h / 0 - 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
  • 32
  • [ 958029-47-5 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 1.2: 13 h / 0 - 20 °C 2.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 3.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C
Reference： [1]Current Patent Assignee: NOVARTIS AG; Sandoz (in: Novartis) - WO2013/91696, 2013, A1
  • 33
  • [ 702641-05-2 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: bis-triphenylphosphine-palladium(II) chloride; potassium carbonate / ethanol; water / 10 h / Reflux 2: Dess-Martin periodane / dichloromethane / 2 h / 20 °C 3: isopropyl alcohol / 2 h / 35 - 40 °C 4: sodium tetrahydroborate / methanol / 2 h / 20 °C 5: tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 70 - 75 °C
Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2014/111953, 2014, A1
  • 34
  • [ 875551-32-9 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: isopropyl alcohol / 2 h / 35 - 40 °C 2: sodium tetrahydroborate / methanol / 2 h / 20 °C 3: tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 70 - 75 °C
Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2014/111953, 2014, A1
  • 35
  • [ 871917-79-2 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: Dimethylphenylsilane; trifluoroacetic acid / 5 h / 0 - 5 °C 2: palladium on carbon; hydrogen / methanol / 3 h / 20 °C / 3750.38 Torr / Autoclave 3: isopropyl alcohol / 2 h / 35 - 40 °C 4: sodium tetrahydroborate / methanol / 2 h / 20 °C 5: tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 70 - 75 °C
Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2014/111953, 2014, A1
  • 36
  • [ 1152029-16-7 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: isopropyl alcohol / 2 h / 35 - 40 °C 2: sodium tetrahydroborate / methanol / 2 h / 20 °C 3: tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 70 - 75 °C
Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2014/111953, 2014, A1
  • 37
  • [ 1220703-07-0 ]
  • [ 530-62-1 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
4.5g In tetrahydrofuran; N,N-dimethyl-formamide at 70 - 75℃; for 2h; 11 Example 11: Preparation of 5(R)- [3,5-Bis(trifluoromethyl)phenylj -3- [4’-fluoro-S’-isopropyl-2 ‘-methoxy-4-(trifluoromethyl)biphenyl-2-ylmethylj -4(S)-methyloxazolidin-2-one (Anacetrapib, Formula I) In a clean round bottom flask, 10gm of (1R, 2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-[({2-[4- fluoro-2-methoxy-5 -Qropan-2-yl)phenylj-5-(trifluoromethy1)phenyl } methyl)amino]propan- 1 -ol (formula II, obtained as in Example 10), 50m1 of tetrahydrofuran ,6.63gm of 1,1-carbonylimidazole (CDI) and 25m1 of dimethyl formamide was added at about room temperature. The reaction mixture was heated to about 70-75°C and stirred for about 2 hours. The reaction mass was concentrated under vacuum to form an oily mass. The oily mass was dissolved in ethyl acetate and washed with water. The organic layer was dried over sodium sulphate and concentrated under vacuum to form an oily mass. The oily mass was purified by columnchromatography using hexane: ethyl acetate (95:5) to yield 4.5gm of titled compound as a white solid. Melting point range: 70-73°C; HPLC Purity: 99.74%; Chiral Purity: 99.9%; Surface Area in (m2/g): 1.18; Particle size: d (0.1) 12.989 tm, d (0.5) 62.241 rim, d (0.9) 200.380 rim.IR:3840.85, 3736.11, 3444.19, 2969.51, 2876.62, 1763.00, l621.58, 1590.83, 1514.39, 1497.01, 1466.56, 1447.94, 1398.77, 1331.48, 1280.77, 1234.31, 1181.19, 1132.26, 1081.14, 1028.16,973.06, 952.86, 902.53, 844.68 cm1.
Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2014/111953, 2014, A1 Location in patent: Page/Page column 26; 27
  • 38
  • [ 877384-16-2 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: palladium on carbon; hydrogen / methanol / 3 h / 20 °C / 3750.38 Torr / Autoclave 2: isopropyl alcohol / 2 h / 35 - 40 °C 3: sodium tetrahydroborate / methanol / 2 h / 20 °C 4: tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 70 - 75 °C
Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2014/111953, 2014, A1
  • 39
  • [ 875444-08-9 ]
  • [ 875548-97-3 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
72% Take 100ml round mouth flask, add intermediate V and methylene chloride, cool to below 5 , stirring slowly dropping thionyl chloride.The resulting reaction mixture was incubated at 15-20 & lt; 0 & gt; C for 2-3 hours and the TLC monitoring reaction was complete.The mixture was stirred with water for 10 minutes, and the layers were allowed to stand apart. The aqueous layer was removed and compound VI was added to a 100 ml round bottom flask followed by tetrabutylammonium iodide, K2CO3, And the mixture was stirred at 60 C for 16-18 hours. TLC was used to monitor the reaction. After completion of the reaction, n-heptane and water were added under heat.The aqueous layer was discarded and the organic layer was washed with water (3 times) and concentrated to give a yellow liquid, which was added with ethanol: water (1: 20 by volume) and allowed to stand to give a white powder. The final product Compound).Yield 72%.
Reference： [1]Patent: CN106032362,2016,A .Location in patent: Paragraph 0045-0048
  • 40
  • [ 121-50-6 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / acetonitrile / 80 °C / Inert atmosphere 2.1: tert.-butylnitrite; potassium hydroxide; water / acetonitrile / 0 °C 3.1: thionyl chloride / dichloromethane / 5 - 20 °C 3.2: 60 °C
Reference： [1]Current Patent Assignee: HUNAN QIANJIN XIANGJIANG PHARM - CN106032362, 2016, A
  • 41
  • [ 1383676-71-8 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / diethyl ether / 6 h / 20 °C / Cooling with ice 2: isopropyl alcohol / 20 h / Reflux 3: dichloromethane / 2 h / 20 °C / Inert atmosphere 4: potassium hydroxide / tetrahydrofuran; methanol / 20 °C / Inert atmosphere
Reference： [1]Current Patent Assignee: HUNAN DEMEI INFORMATION TECH - CN106496154, 2017, A
  • 42
  • [ 1383814-88-7 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: isopropyl alcohol / 20 h / Reflux 2: dichloromethane / 2 h / 20 °C / Inert atmosphere 3: potassium hydroxide / tetrahydrofuran; methanol / 20 °C / Inert atmosphere
Reference： [1]Current Patent Assignee: HUNAN DEMEI INFORMATION TECH - CN106496154, 2017, A
  • 43
  • C37H33F10NO4 [ No CAS ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
89% With potassium hydroxide In tetrahydrofuran; methanol at 20℃; Inert atmosphere; 2 Synthesis of Compound 6 KOH (0.232 mmol) in MeOH (10 mL) was added dropwise to a solution of compound 5 (134.3 mg, 0.232 mmol) in dry THF (10 mL) at room temperature under nitrogen. After stirring at room temperature for 1 hour, the reaction was quenched with saturated sodium carbonate (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were dried, concentrated in vacuo and the residue was purified by column chromatography (V (ethyl acetate) / V (hexanes) = 1/9 -> 1/4) and concentrated until most of the solvent was distilled off (Late blister bumping), adding n-heptane to remove the residual solvent; adding n-pentane (8 mL) to the residue, warming up to 40-50 deg.C to dissolve, slowly dropping to -10 deg.c and stirring overnight. The filter cake was dried under reduced pressure at 40 ° C for 21 h to give anacetrapib (102 mg, 89%).
Reference： [1]Current Patent Assignee: HUNAN DEMEI INFORMATION TECH - CN106496154, 2017, A Location in patent: Paragraph 0041; 0053; 0054
  • 44
  • [ 875444-08-9 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 25 °C / Inert atmosphere 1.2: 25 °C / Inert atmosphere 2.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / water; ethanol; toluene / 2 h / Inert atmosphere; Reflux
Reference： [1]Vachal, Petr; Duffy, Joseph L.; Campeau, Louis-Charles; Amin, Rupesh P.; Mitra, Kaushik; Murphy, Beth Ann; Shao, Pengcheng P.; Sinclair, Peter J.; Ye, Feng; Katipally, Revathi; Lu, Zhijian; Ondeyka, Debra; Chen, Yi-Heng; Zhao, Kake; Sun, Wanying; Tyagarajan, Sriram; Bao, Jianming; Wang, Sheng-Ping; Cote, Josee; Lipardi, Concetta; Metzger, Daniel; Leung, Dennis; Hartmann, Georgy; Wollenberg, Gordon K.; Liu, Jian; Tan, Lushi; Xu, Yingju; Chen, Qinghao; Liu, Guiquan; Blaustein, Robert O.; Johns, Douglas G. [Journal of Medicinal Chemistry, 2021, vol. 64, # 18, p. 13215 - 13258]
  • 45
  • [ 702641-06-3 ]
  • [ 875446-37-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 - 25 °C / Inert atmosphere 1.2: 25 °C / Inert atmosphere 2.1: tetrakis(triphenylphosphine) palladium(0); sodium carbonate / water; ethanol; toluene / 2 h / Inert atmosphere; Reflux
Reference： [1]Vachal, Petr; Duffy, Joseph L.; Campeau, Louis-Charles; Amin, Rupesh P.; Mitra, Kaushik; Murphy, Beth Ann; Shao, Pengcheng P.; Sinclair, Peter J.; Ye, Feng; Katipally, Revathi; Lu, Zhijian; Ondeyka, Debra; Chen, Yi-Heng; Zhao, Kake; Sun, Wanying; Tyagarajan, Sriram; Bao, Jianming; Wang, Sheng-Ping; Cote, Josee; Lipardi, Concetta; Metzger, Daniel; Leung, Dennis; Hartmann, Georgy; Wollenberg, Gordon K.; Liu, Jian; Tan, Lushi; Xu, Yingju; Chen, Qinghao; Liu, Guiquan; Blaustein, Robert O.; Johns, Douglas G. [Journal of Medicinal Chemistry, 2021, vol. 64, # 18, p. 13215 - 13258]
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