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[ CAS No. 1454846-35-5 ] {[proInfo.proName]}

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Chemical Structure| 1454846-35-5
Chemical Structure| 1454846-35-5
Structure of 1454846-35-5 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1454846-35-5 ]

CAS No. :1454846-35-5 MDL No. :
Formula : C21H19FN6O2 Boiling Point : -
Linear Structure Formula :- InChI Key :IIXWYSCJSQVBQM-LLVKDONJSA-N
M.W : 406.41 Pubchem ID :71731823
Synonyms :
PF-06463922;PF-6463922

Calculated chemistry of [ 1454846-35-5 ]

Physicochemical Properties

Num. heavy atoms : 30
Num. arom. heavy atoms : 17
Fraction Csp3 : 0.24
Num. rotatable bonds : 0
Num. H-bond acceptors : 6.0
Num. H-bond donors : 1.0
Molar Refractivity : 111.44
TPSA : 110.06 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -7.69 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.48
Log Po/w (XLOGP3) : 1.53
Log Po/w (WLOGP) : 2.37
Log Po/w (MLOGP) : 1.19
Log Po/w (SILICOS-IT) : 1.88
Consensus Log Po/w : 1.89

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.74
Solubility : 0.0734 mg/ml ; 0.000181 mol/l
Class : Soluble
Log S (Ali) : -3.45
Solubility : 0.144 mg/ml ; 0.000355 mol/l
Class : Soluble
Log S (SILICOS-IT) : -5.72
Solubility : 0.000771 mg/ml ; 0.0000019 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 4.7

Safety of [ 1454846-35-5 ]

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

Application In Synthesis of [ 1454846-35-5 ]

* 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 [ 1454846-35-5 ]

[ 1454846-35-5 ] Synthesis Path-Downstream   1~19

  • 1
  • [ 1454850-15-7 ]
  • [ 1454846-35-5 ]
YieldReaction ConditionsOperation in experiment
29% With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 1h; Preparation of (10 ?)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro- 2H-8,4-(metheno)pyrazolo[4,3- 7][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (Example 2). Step 4: A solution of compound 342 (400 mg, assumed 0.91 mmol) as the HCI salt and DIPEA (1.17 g, 9.1 mmol) in DMF (5.0 mL) and THF (0.5 mL) was added drop-wise to a solution of HATU (482 mg, 1.27 mmol) in DMF (10.0 mL) at 0 °C over 30 minutes. After complete addition, the mixture was stirred at 0 °C for a further 30 mins. Water (70 mL) was added and the mixture was extracted into EtOAc (2 x 60 mL). The combined organics were washed with saturated aqueous NaHC03 (2 x 100 mL), brine (100 mL), dried over Na2S04, and evaporated. The residue was purified by column chromatography over silica gel, which was eluted with 70% EtOAc/cyclohexane giving 205mg of a pale yellow residue (semi-solid). The solids were dissolved in MTBE (7 mL) and cyclohexane (20 mL) was added slowly with good stirring to precipitate the product. After stirring for 30 minutes, the mixture was filtered, and Example 2 was collected as a white solid (1 10 mg, 29% yield). TLC (Rf = 0.40, 70% EtOAc in cyclohexane). 1H NMR (400 MHz, CDCI3) δ 7.83 (d, 1 H, J = 2.0 Hz), 7.30 (dd, 1 H, J = 9.6, 2.4 Hz), 7.21 (dd, 1 H, J = 8.4, 5.6 Hz), 6.99 (dt, 1 H, J = 8.0, 2.8 Hz), 6.86 (d, 1 H, J = 1 .2 Hz), 5.75 - 5.71 (m, 1 H), 4.84 (s, 2 H), 4.45 (d, 1 H, J = 14.4 Hz), 4.35 (d , 1 H, J = 14.4 Hz), 4.07 (s, 3 H), 3.13 (s, 3 H), 1 .79 (d, 3 H, J = 6.4Hz). LCMS ES m/z 407 [M+H]+.
29% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 1h;
29% With N-ethyl-N,N-diisopropylamine; HATU In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 1h; 1A.4 Step 4: A solution of compound 24 (400 mg, assumed 0.91 mmol) as the HCI salt and DIPEA (diisopropylethylamine) (1 .17 g, 9.1 mmol) in DMF (dimethylformamide) (5.0 mL) and THF (0.5 mL) was added drop-wise to a solution of HATU (2-(1 H-7-azabenzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyl uronium hexafluorophosphate methanaminium) (482 mg, 1 .27 mmol) in DMF (10.0 mL) at 0 °C over 30 minutes. After complete addition, the mixture was stirred at 0 °C for a further 30 mins. Water (70 mL) was added and the mixture was extracted into EtOAc (2 x 60 mL). The combined organics were washed with saturated aqueous NaHC03 (2 x 100 mL), brine (100 mL), dried over Na2S04, and evaporated. The residue was purified by column chromatography over silica gel, which was eluted with 70% EtOAc/cyclohexane giving 205 mg of a pale yellow residue (semi-solid). The solids were dissolved in MTBE (7 mL) and cyclohexane (20 mL) was added slowly with good stirring to precipitate the product. After stirring for 30 minutes, the mixture was filtered, and Example 1A was collected as an amorphous white solid (1 10 mg, 29% yield). TLC (Rf = 0.40, 70% EtOAc in cyclohexane). 1H NMR (400 MHz, CDCI3) δ 7.83 (d, 1 H, J = 2.0 Hz), 7.30 (dd, 1 H, J = 9.6, 2.4 Hz), 7.21 (dd, 1 H, J = 8.4, 5.6 Hz), 6.99 (dt, 1 H, J = 8.0, 2.8 Hz), 6.86 (d, 1 H, J = 1 .2 Hz), 5.75 - 5.71 (m, 1 H), 4.84 (s, 2 H), 4.45 (d, 1 H, J = 14.4 Hz), 4.35 (d ,1 H, J = 14.4 Hz), 4.07 (s, 3 H), 3.13 (s, 3 H), 1 .79 (d, 3 H, J = 6.4Hz). LCMS ES m/z 407 [M+H]+.
29% Stage #1: 2-{(1R)-1-[(2-amino-5-{5-cyano-1-methyl-3-[(methylamino)-methyl]-1H-pyrazol-4-yl}pyridin-3-yl)oxy]ethyl}-4-fluorobenzoic acid hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere;

  • 2
  • [ 1454846-35-5 ]
  • [ 64-19-7 ]
  • [ 1924207-18-0 ]
YieldReaction ConditionsOperation in experiment
87.8% at 20℃; for 3h; Large scale; 4.4 Step 4: Acetic acid (1 .0 kg, 16.6 mol) was added to the organic layer containing compound 27. The reaction mixture was concentrated and then held for at least 3 h with stirring at RT. The resulted slurry was filtered. The filter cake was washed with ethyl acetate (2 L) and dried under vacuum to give 3.20 kg (87.8% yield) of Example 4 acetic acid solvate (Form 3). The spectroscopic data of this material was identical to that of an authentic sample of the crystalline acetic acid Form 3 of (10R)-7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro- 2/-/-8,4-(metheno)pyrazolo[4,3- ?][2,5,1 1 ]-benzoxadiazacyclo-tetradecine-3-carbonitrile prepared according to Example 3.
  • 3
  • [ 1643141-20-1 ]
  • [ 1454846-35-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: triethylamine / 2-methyltetrahydrofuran / 0.5 h / 35 °C / Inert atmosphere; Large scale 1.2: 2 h / 20 - 25 °C / Large scale 2.1: catacxium A; palladium diacetate; potassium acetate / water; tert-Amyl alcohol / Inert atmosphere; Reflux; Large scale 3.1: water; hydrogenchloride / ethyl acetate / 25 °C / Inert atmosphere; Large scale
  • 4
  • [ 1643141-23-4 ]
  • [ 1454846-35-5 ]
YieldReaction ConditionsOperation in experiment
82% With hydrogenchloride In methanol; water at 60℃; for 3h; 2 Alternative Preparation of Form 7 of (10 ?')-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo- 10,15,16,17-tetrahvdro-2/-/-8,4-(metheno')pyrazolo[4,3- ?l[2,5,1 l lbenzoxadiazacvclotetra-decine- 3-carbonitrile (lorlatinib') Free Base Into a 100 mL Easymax reactor equipped with an overhead stirrer, was added the bis- Boc protected macrocycle 1_ (prepared as described in International Patent Publication No. WO 2014/207606 at Example 4) (7g, 10 mmol) and methanol (28 mL; 4 mL/g of PF-06668559). The slurry was heated to 60°C and treated with 6N hydrochloric acid (9 mL, 54 mmol) and held for 3 hours. Once reaction was determined complete, the mixture was cooled to 40°C and treated with 1 N sodium hydroxide (39mL, 39 mmol) to partially neutralize the mixture. The mixture was treated with 2-methyltetrahydrofuran (53 mL), followed by neutralization to pH 7 with 1 N sodium hydroxide (13.5 mL, 13.5 mmol). The mixture was treated with sodium chloride (10.1 g, 173 mmol) and warmed to 60°C. The bottom aqueous layer was removed using a separatory funnel. The organic phase was washed with water (50 mL) at 60°C. The water wash was removed by separatory funnel. The organic layer was speck free filtered into a clean 125 mL reactor fitted with overhead agitator and distillation head. Additional 2- methyltetrahydrofuran (70mL) was added to the organic mixture and the mixture was concentrated by atmospheric distillation to a volume of approximately 30 mL. The solution was treated with 2-methyltetrahydrofuran (12 mL) and adjusted to 60°C. The solution was treated with n-heptane (10.5 mL), followed by seeding with Form 7 of lorlatinib free base (45 mg, 0.1 1 mmol). After aging the slurry for 1 hour, n heptane (73.5 mL) was added over 2 hours at 60°C. The resultant slurry was held for 1 hour at 60°C followed by cooling to 20°C over 1 hour and granulated for 16 hours. The slurry was filtered, and the product cake was washed with n heptane (12 mL). The solids were dried in the oven at 60°C for 12 hours to give Form 7 of PF-0463922 free base (8.24 mmol, 3.36 g) as a white solid in 82% yield with >98% purity.
With hydrogenchloride; water In ethyl acetate at 25℃; Inert atmosphere; Large scale; 4.3 Step 3: To a reactor under N2 was added compound 26 (4.74 kg, 7.82 mol) and ethyl acetate (54 L). Hydrochloric acid 37% (5.19 L, 63.2 mol) was charged slowly while keeping the internal temperature below 25°C. The reaction mixture was stirred for 24 - 48 h until the reaction was complete. Ethyl acetate (54L) and water (54 L) were added. The reaction mixture was then treated with triethylamine until pH 8 - 9 was reached. The aqueous layer was removed and then the organic layer was washed water (2 x 54 L). The organic layer was concentrated under reduced pressure to approx. 54 L to give compound 27 (unisolated).
In tetrahydrofuran at 225℃; for 0.166667h; Flow reactor;
676 mg With hydrogenchloride In water; ethyl acetate at 28℃; for 17h; 2; 28 Example 2: Preparation of Lorlatinib Form Z (10R)-(7-di -tert-butyloxy carbonyl amino)- l2-fluoro-2, 10, 16-trimethyl- 15-oxo- l0,l5,l6,l7-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h]-[2,5,l l]benzoxadiazacyclotetradecine-3-carbonitrile (3.68 grams, 6.07 mmol, prepared according to Example 7) was dissolved in ethyl acetate (18.4 mL) and 37% HC1 was added dropwise while keeping the internal temperature below 28°C. The reaction mixture was stirred for 17 hours to complete Boc-deprotection. To the reaction mixture, water (40 ml) was added and layers were separated at pH <1. Then, to the aqueous layer, fresh ethyl acetate (40 mL) was added and pH was adjusted to pH 9.2 using saturated solution of Na2C03. Layers were separated and organic layer was dried at anhydrous Na2S04 and evaporated to dryness. The evaporated residue containing 0.8 grams of Lorlatinib was dissolved in methanol (1.6 mL), then water (1.6 mL) was added and reaction suspension was warmed to reflux temperature and stirred for 1 hour. The obtained solution was then cooled at room temperature for 2-3 hours and oiling out was occurred. The mixture was then warmed again to reflux temperature for about half an hour and left cool down slowly to room temperature overnight. Oiling out was occurred again and the mixture was stirred for one day at room temperature and crystallization was occurred. The resulting suspension was filtered off and dried at room conditions (open Petri dish at about 20-25 °C and 30-40 % relative humidity) yielding 676 mg of crystalline Lorlatinib form Z (water content by KF 9.4 %).

  • 5
  • [ 1454846-35-5 ]
  • [ 75-36-5 ]
  • [ 1883490-44-5 ]
YieldReaction ConditionsOperation in experiment
15 mg Stage #1: (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile With pyridine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: acetyl chloride In tetrahydrofuran at 0℃; for 4h; 1 Example 1: The synthesis of(1 OR)-7-acetamido- 1 2-fluoro-2, 10,1 6-trimethyl- 15 -oxo- 10,15,16,1 7-tetrahydro-2H-8, 4-(metheno)pyrazolo [4,3-h] [2,5,11] -benzoxadiazacyclotetradecine-3 -carbonitrile (Compound 10). Example 1: The synthesis of(1 OR)-7-acetamido- 1 2-fluoro-2, 10,1 6-trimethyl- 15 -oxo- 10,15,16,1 7-tetrahydro-2H-8, 4-(metheno)pyrazolo [4,3-h] [2,5,11] -benzoxadiazacyclotetradecine-3 -carbonitrile (Compound 10). 100461 To a solution of(1 OR)-7 -amino-i 2-fluoro-2, 10,1 6-trimethyl- 1 5-oxo- 10,15,16,1 7-tetrahydro-2H-8,4-( metheno)pyrazolo [4,3-h] [2,5,11 ]-benzoxadiazacyclotetradecine-3 -carbonitrile (50 mg) in THF (2 mL) was added pyridine (189.6 mg, 10.0 eq) at 0 °C and stirred for 0.5 h, then acetyl chloride (150.4 mg, 8.0 eq) was added portionwise. The reaction was stirred for 4 hours at 0 °C, and TLC indicated the completion of the reaction. Water (20 mL) was added to the reaction, and the aqueous layer was extracted with EA (2 xiO mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate. The crude product was purified by preparative TLC plate to give white solid (15 mg) as Compound 10. 1H-NMR (400 MHz, CDC13): 8.13 ppm, (d, J= 1.6 Hz, 1H), 8.04 (s, 1H), 7.31 (dd, Jj = 2.8 Hz, J2 9.6 Hz, 1H), 7.25 (m, 1H), 7.06 (m, 2H), 5.79 (m, 1H), 4.13 (s, 3H), 3.16 (s, 3H), 2.59 (s, 3H), 1.83 (d, J 6.0 Hz, 3H). MS mlz 449 [M+i].
15 mg Stage #1: (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile With pyridine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: acetyl chloride In tetrahydrofuran at 0℃; for 4h; 1 The synthesis of (10R)-7-acetamido-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (Compound 10) To a solution of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (50 mg) in THF (2 mL) was added pyridine (189.6 mg, 10.0 eq) at 0° C. and stirred for 0.5 h, then acetyl chloride (150.4 mg, 8.0 eq) was added portionwise. The reaction was stirred for 4 hours at 0° C., and TLC indicated the completion of the reaction. Water (20 mL) was added to the reaction, and the aqueous layer was extracted with EA (2*10 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate. The crude product was purified by preparative TLC plate to give white solid (15 mg) as Compound 10. 1H-NMR (400 MHz, CDCl3): 8.13 ppm, (d, J=1.6 Hz, 1H), 8.04 (s, 1H), 7.31 (dd, J1=2.8 Hz, J2=9.6 Hz, 1H), 7.25 (m, 1H), 7.06 (m, 2H), 5.79 (m, 1H), 4.13 (s, 3H), 3.16 (s, 3H), 2.59 (s, 3H), 1.83 (d, J=6.0 Hz, 3H). MS m/z 449 [M+1].
  • 6
  • (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile [ No CAS ]
  • [ 103321-49-9 ]
  • C38H32FN7O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
30 mg With pyridine In dichloromethane at 20℃; for 16h; 2 Example 2 Example 2: The synthesis of(1 OR)-7-(2-aminoacetyl)amino- 1 2-fluoro-2, 10,1 6-trimethyl- 1 5-oxo- 10,15,16,1 7-tetra hydro-2H-8,4-(metheno)pyrazolo[4,3 -h] [2,5,11 ]-benzoxadiazacyclotetradecine-3 -carb onitrile (Compound 6). j0047J The Fmoc-glycine (763.4 mg, 2.6 mmol, 20.0 eq) was added into 50C12 (16.0 mL) and the mixture was heated to reflux for 2 h. Evaporation in vacuum to give a white solid. The solid was dissolved in DCM (8.0 mL), and a solution of (1 OR)-7-amino- 1 2-fluoro-2, 10,1 6-trimethyl- 1 5-oxo- 10,15,16,1 7-tetrahydro-2H-8,4-( metheno)pyrazolo [4,3-h] [2,5,11 ]-benzoxadiazacyclotetradecine-3 -carbonitrile(Compound A, 50.0 mg, 0.13 mmol, 1.0 eq) in pyridine (16.0 mL) was added in twoportions. The reaction mixture was stirred for 16 hours at RT. Then water (20 mL) was added. The aqueous lay was extracted with DCM (2x10 mL), and the organic layerswere combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by preparative TLC plate to give compound 5 (30 mg).To a solution of Compound 5 (30.0 mg) in DCM (2.0 mL) was added piperidine (0.1 mL) at 0 °C. The reaction was stirred 5 hours at RT and TLC indicated the completion of the reaction. The reaction mixture was concentrated and washed with n-Hexane (2x 5 mL) to give crude product. Then the crude product was purified by flash column chromatography on silica gel (the silica gel was pre-washed with 1% Et3N in DCM) with DCMIMeOH (100:1) to give Compound 6 (12.3 mg). ‘H-NIVIR (400 1VIHz, CDC13): 8.23 ppm. (s, 1H), 7.31 (m, 1H), 7.25 (m, 1H), 7.14 (d, J= 2.0 Hz, 1H), 7.04 (m, 2H), 5.80 (m, 1H), 4.46(m, 2H), 4.12(s, 3H), 3.78(s, 2H), 3.17 (s, 3H), 1.85 (d, J = 6.0 Hz, 3H). MS mlz: 464 [M+1].
  • 7
  • [ 29022-11-5 ]
  • [ 1454846-35-5 ]
  • [ 1883490-50-3 ]
YieldReaction ConditionsOperation in experiment
30 mg Stage #1: N-(fluoren-9-ylmethoxycarbonyl)glycine With thionyl chloride for 2h; Reflux; Stage #2: (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile With pyridine In dichloromethane at 20℃; for 16h; 2 The Fmoc-glycine (763.4 mg, 2.6 mmol, 20.0 eq) was added into SOCl2 (16.0 mL) and the mixture was heated to reflux for 2 h. Evaporation in vacuum to give a white solid. The solid was dissolved in DCM (8.0 mL), and a solution of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (Compound A, 50.0 mg, 0.13 mmol, 1.0 eq) in pyridine (16.0 mL) was added in two portions. The reaction mixture was stirred for 16 hours at RT. Then water (20 mL) was added. The aqueous lay was extracted with DCM (2×10 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by preparative TLC plate to give compound 5 (30 mg). To a solution of Compound 5 (30.0 mg) in DCM (2.0 mL) was added piperidine (0.1 mL) at 0° C. The reaction was stirred 5 hours at RT and TLC indicated the completion of the reaction. The reaction mixture was concentrated and washed with n-Hexane (2×5 mL) to give crude product. Then the crude product was purified by flash column chromatography on silica gel (the silica gel was pre-washed with 1% Et3N in DCM) with DCM/ MeOH (100:1) to give Compound 6 (12.3 mg). 1H-NMR (400 MHz, CDCl3): 8.23 ppm. (s, 1H), 7.31 (m, 1H), 7.25 (m, 1H), 7.14 (d, J=2.0 Hz, 1H), 7.04 (m, 2H), 5.80 (m, 1H), 4.46(m, 2H), 4.12(s, 3H), 3.78(s, 2H), 3.17 (s, 3H), 1.85 (d, J=6.0 Hz, 3H). MS m/z: 464 [M+1].
  • 8
  • [ 1454846-35-5 ]
  • [ 110-16-7 ]
  • [ 2135926-03-1 ]
YieldReaction ConditionsOperation in experiment
92.7% In water; ethyl acetate at 60℃; for 18h; 1 Preparation of ( 10 )-7-amino-12-fluoro-2, 10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro- 2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacvclotetradecine-3-carbonitrile (PF-06463922) maleate hydrate (Form 2) A 500-mL glass jar containing a magnetic stir bar was charged with maleic acid (1.20 equiv., 3.12 g), EtOAc (10.0 mL/g, 90.0 mL) and water (4 equiv., 1.60 mL). The contents were stirred at room temp for several minutes. The clear maleic acid solution was charged to an EasyMax dosing pump. A 100-mL EasyMax reactor equipped with an overhead agitator, temperature probe and a dosing pump, was charged with lorlatinib free base (9.00 g, 1.00 equiv.) and EtOAc (5.0 ml_/g, 45.0 mL) and the suspension was heated to 70 °C (Tj). , The reactor was charged with an additional 10 mL of EtOAc (10.0 mL, 1.1 1 ml_/g), to bring the total EtOAc volume to 55.0 mL (6.11 mL/g). Upon visual confirmation that no solids remained and a clear solution was persistent at 70 °C, the maleic acid solution was dosed over 90 min (1 mL /min). After 45.0 mL had been dosed, the jacket temperature was decreased to 60 °C and the dosing continued. The reactor was held at 60° (Tj) for 18 h then cooled to 10 °C over 33 min (1.5 K/min). The solids were isolated by filtration through a 65-mL, medium-porosity, sintered- glass funnel lined with Whatman paper. The mother liquor was returned to the reactor and stirred at 450 rpm to remove the solids that were adhered to the reactor. After several minutes the slurry in the reactor was emptied onto the filter cake. After the mother liquor was pulled from the filter cake, the vacuum was disconnected and fresh, anhydrous EtOAc (15.0 mL) was poured onto the filter cake. The filter cake was agitated manually using a spatula, then the vacuum was reconnected and the EtOAc rinse was pulled away. The product cake was covered with a clean crystallizing dish and dried by pulling air through the filter for 3 days (11.1 g, 92.7% yield).
  • 9
  • [ 2306101-64-2 ]
  • [ 1454846-35-5 ]
YieldReaction ConditionsOperation in experiment
96% With hydrogenchloride In methanol; water at 20℃; for 2h; 1.4 Add 50g of methanol to a 100mL four-necked reaction flask, then add 2g (0.004mol) of compound 6, dropwise add 0.8g (0.008mol) of hydrochloric acid solution, stir for 2h at room temperature, remove the -BOC group, concentrate under reduced pressure, and finally get Loratinib was 1.56g, the yield was 96%.
With hydrogenchloride 1.5 Synthesis of lorlatinib General procedure: 1g of intermediate (22) and (22R) mix well with HCl, remove the protecting group - Boc, and finally obtain intermediate 23 and lolatinib, yielding 0.83 g of product in a yield of 95.3% (mass data is the same as the next lorlatinib synthesis).
With hydrogenchloride In ethyl acetate at 45 - 50℃; for 2h; 3 Example 3. Preparation of Lorlatinib Form 2 (10R)-(7-di-tert-butyloxycarbonylamino)-12-fluoro-2, 10, 16-trimethyl-l 5-oxo- 10, 15, 16, 17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h]- (0149) [2,5,l l]benzoxadiazacyclotetradecine-3-carbonitrile (6.84 grams, assay 87.6 %, 10.11 mmol) was dissolved in ethyl acetate (49.1 mL) and 37% HC1 (4.27 mL) was added. The reaction mixture was heated at 45-50°C and stirred for 2 hours to complete Boc-deprotection reaction. Into the reaction mixture, water was added (184 mL) and the mixture was cooled to 20-25°C. The layers were separated and the aqueous layer washed with ethyl acetate (30.7 mL). Into aqueous layer, methylene chloride (61.4 mL) was added and the pH was adjusted to pH 9.3 using 10% solution of NaOH. Layers were separated and the aqueous layer extracted additionally with methylene chloride (49.1 mL). The organic layers were combined, washed with water (49.1 mL) and evaporated by vacuum distillation to dryness. Methanol (61.7 mL) was added and the obtained solution was heated to 55°C. Water was added (61.7 mL) drop- wise to the solution during 5 minutes. The obtained solution was then stirred overnight at 50- 55°C. The obtained suspension was cooled at 0-5°C over 2 hours and was further stirred for additional 2 hours at 0-5°C with stirring. The suspension was filtered off and vacuum dried at 45°C for 3 hours to obtain Lorlatinib Form 2 (assay 97.0%, water content by KF 2.20 %).
  • 10
  • [ 1455009-85-4 ]
  • [ 1454846-35-5 ]
YieldReaction ConditionsOperation in experiment
89.4% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 50℃; for 3h; 1-4; 1-6 Example 2 Add 0.1 mol of formula A compound to 200ml DMF, add 0.15 mol of condensing agent TBTU, 50 mmol of alkali accelerator DBU, and slowly stir until the system is uniformly mixed, then heat the system to 50C, keep the temperature for 3 hours, and detect the completion of the reaction by TLC. , Slowly cool the system to room temperature, add 100ml saturated ammonium chloride solution to quench the reaction, continue stirring for 20min, let stand for 5min, add ethyl acetate extraction (100ml X3), collect the organic layer, distill the organic layer under reduced pressure to complete The solvent was removed to obtain a solid crude product, which was washed with 200 ml of n-hexane and dried in vacuum to obtain the target product loratinib with a yield of 89.4% and a purity of 97.4%.
89.4% With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 50℃; for 3h; 1-4; 1-6 Example 2 Add 0.1 mol of formula A compound to 200ml DMF, add 0.15 mol of condensing agent TBTU and 50 mmol of alkali accelerator DBU, slowly stir until the system is uniformly mixed, then heat the system to 50°C, keep the temperature for 3 hours, and check that the reaction is complete by TLC , Slowly cool the system to room temperature, add 100ml saturated ammonium chloride solution to quench the reaction, continue stirring for 20min, let stand for 5min, add ethyl acetate for extraction (100ml×3), collect the organic layer, and distill the organic layer under reduced pressure. The solvent was completely removed to obtain a solid crude product, which was washed with 200 ml of n-hexane and dried under vacuum to obtain the target product lorlatinib with a yield of 89.4% and a purity of 97.4%.
87.6% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate at 65℃; for 5h; Green chemistry; 3.3 S3, a preparation method of lorazinib, comprising the following steps: Compound 5 (42.1 g, 0.1 mol), DIPEA (15.51 g, 0.12 mol) was added to the reactor in that order.Stir,During the stirring process, HATU (114.12g, 0.3mol) was added to the reactor, the temperature was raised to 65 ° C, and the reaction was kept for 5 hours. After the reaction was completed, 500 mL of water was added to quench the reaction, and then 500 mL of ethyl acetate was added to the reactor. The mixture was extracted and the aqueous layer was separated. The aqueous layer was re-extracted with ethyl acetate (500 mL). The ethyl acetate layer was combined, ethyl acetate was concentrated, and the concentrate was separated by column chromatography to obtain lorazinib (35.56 g). 87.6%, the structural characterization and content determination of lorazinib are shown in Figures 1-3.
78.5% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 65℃; for 5h;

  • 11
  • [ 2375584-68-0 ]
  • [ 1454846-35-5 ]
YieldReaction ConditionsOperation in experiment
87.5% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane at 75℃; for 4h; Inert atmosphere; Green chemistry; 4.2 S2, Preparation of lorazinib: Compound 3 (28.2 g, 0.05 mol), potassium carbonate (13.8 g, 0.1 mol), 1.97 g of Pd(Dppf)2Cl2 was used as a catalyst (the catalyst mass was 7% by mass of the compound 1), and it was added to the reactor, and 300 mL was added. The 1,4-dioxane was used as a solvent to drive the air in the reactor by nitrogen. The reaction system was heated to 75 ° C, and the reaction was kept for 4 h. The reaction was completed by TLC. The reaction mixture was concentrated to dryness. The mixture was stirred and layered, and the organic phase was collected. The aqueous layer was extracted once with ethyl acetate (300 mL), and the organic phase was combined. The organic phase was concentrated and then subjected to column chromatography to give lautarinib (35.52 g), yield 87.5%.
  • 12
  • [ 1454846-35-5 ]
  • [ 2379393-61-8 ]
YieldReaction ConditionsOperation in experiment
With hydrogen bromide In water; butan-1-ol at 90℃; 16 Example 16. Preparation of Lorlatinib Hydrobromide form Hl Lorlatinib (200 mg) was suspended in 2 mL of l-butanol. Suspension was heated to 90°C and stirred until full dissolution was observed. Solution containing 90 mg of 48% w/w water solution of hydrobromic acid in 2 mL of l-butanol was added dropwise to the hot solution of Lorlatinib. Solution was cooled to RT and precipitation occurred. Suspension was stirred at RT for additional 30 minutes. Solids were filtered, washed three times with 2 mL of n-heptane and dried on air. The obtained solid corresponds to Lorlatinib hydrobromide form Hl as analyzed by XRPD and the XRPD pattern is shown in Figure 15.
  • 13
  • [ 2541062-18-2 ]
  • [ 1454846-35-5 ]
YieldReaction ConditionsOperation in experiment
45% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 2h; r Step r: (10R)-7-amino-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H-8,4-(methine (Base bridge)-pyrazolo[4,3-h][2,5,11]benzoxadiazepine tetracycline-3-carbonitrile (Intermediate 18) Intermediate 17 (100mg, 0.217mmol) was dissolved in DMF (10mL), DIPEA (42mg, 0.325mmol) was added,The temperature was lowered to 0°C, HATU (123.5mg, 0.325mmol) was slowly added, and the reaction was carried out at 0°C for 2 hours.The reaction solution was added to water, extracted with ethyl acetate, the organic phase was washed with water, dried, concentrated, and column chromatography was used to obtain 40 mg, yield: 45%.
  • 14
  • [ 50-00-0 ]
  • [ 1454846-35-5 ]
  • [ 2541061-97-4 ]
YieldReaction ConditionsOperation in experiment
74.7% With tetrabutyl ammonium fluoride In dichloromethane; water at 20℃; 1 Example 1: (10R)-7-hydroxymethylamino-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H-8,4 -(Methylene bridge)-pyrazolo[4,3-h][2,5,11]benzoxadiazepine ring-3-carbonitrile (compound 1) Intermediate 18 (100mg, 0.245mmol) was suspended in water (1mL), dichloromethane (1mL), methanol (1mL), aqueous formaldehyde solution (37%, 0.4mL) and tetrabutylammonium fluoride (1M , 0.08mL).Overnight at room temperature, the reaction solution was extracted with dichloromethane, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column to obtain a solid 80 mg with a yield of 74.7%.
  • 15
  • [ 1454846-35-5 ]
  • [ 541-41-3 ]
  • [ 2541061-98-5 ]
YieldReaction ConditionsOperation in experiment
29.7% With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; 2 Example 2: (10R)-7-Ethyl carbamate-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H-8,4 -(Methylene bridge)-pyrazolo[4,3-h][2,5,11]benzoxadiazepine ring-3-carbonitrile (compound 2) Intermediate 18 (100mg, 0.245mmol) was dissolved in THF, DIPEA (38mg, 0.294mmol) was added, ethyl chloroformate (26.5mg, 0.245mmol) was slowly added at 0°C,Then it was stirred overnight at room temperature, the reaction solution was washed with water, extracted with ethyl acetate, the organic phase was dried and spin-dried, and the column was purified to obtain 35 mg, yield: 29.7%.
  • 16
  • [ CAS Unavailable ]
  • [ 1454846-35-5 ]
  • [ 2541061-99-6 ]
YieldReaction ConditionsOperation in experiment
39.2% With acetic anhydride at 20℃; Cooling with ice; 3 Example 3: (10R)-7-aminocarbaldehyde-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H-8,4- (Methylene bridge)-pyrazolo[4,3-h][2,5,11]benzoxadiazepine tetradecanoyl-3-carbonitrile (compound 3) Under ice bath conditions, intermediate 18 (100 mg, 0.245 mmol) was slowly added to formic acid (113 mg, 2.45 mmol), acetic anhydride (37 mg, 0.367 mmol) was slowly added, and after the addition, stirred at room temperature overnight.The reaction solution was diluted with ethyl acetate, washed with water, dried, concentrated, and column chromatography to obtain a solid 42 mg, yield: 39.2%.
  • 17
  • [ 1454846-35-5 ]
  • [ 229625-50-7 ]
  • [ 2541062-06-8 ]
YieldReaction ConditionsOperation in experiment
13% Stage #1: (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: di-tert-butyl chloromethyl phosphate In N,N-dimethyl-formamide at 20℃; for 2h; 10 Example 10: (10R)-7-aminomethyl di-tert-butyl phosphate-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H -8,4-(Methylene bridge)-pyrazolo[4,3-h][2,5,11]benzoxadiazepine tetradecen-3-carbonitrile (compound 10) Intermediate 18 (100mg, 0.246mmol) was dissolved in 1mL DMF, NaH (10mg, 0.246mmol) was added under ice bath, and after the addition, reacted at 0°C for 0.5h,Then add di-tert-butyl chloromethyl phosphate (67mg, 0.246mmol) in DMF (0.5mL) to the reaction solution and react at room temperature for 2h,The reaction solution was poured into water and extracted with DCM. The organic phase was washed with water, saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column to obtain a solid 20 mg, yield: 13%.
  • 18
  • [ 13057-17-5 ]
  • [ 1454846-35-5 ]
  • [ 2541062-10-4 ]
YieldReaction ConditionsOperation in experiment
28.9% Stage #1: (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: bromethyl methyl ether In N,N-dimethyl-formamide at 20℃; for 2h; 14 Example 14: (10R)-7-methoxymethylamino-12-fluoro-2,10,16-trimethyl-5-oxo-10,15,16,17-tetrahydro-2H-8, 4-(methine bridge)-pyrazolo[4,3-h][2,5,11]benzoxadiazepine ring-3-carbonitrile (compound 14) Intermediate 18 (100mg, 0.246mmol) was dissolved in 1mL DMF, NaH (10mg, 0.246mmol) was added under ice bath, and after the addition, reacted at 0°C for 0.5h,Then add bromomethyl methyl ether (30.7mg, 0.246mmol), react at room temperature for 2h,The reaction solution was poured into water, extracted with DCM, and the organic phase was washed with water and saturated sodium chloride.It was dried with anhydrous sodium sulfate and purified by column to obtain a solid 32 mg. Yield: 28.9%.
  • 19
  • [ 75-00-3 ]
  • [ 1454846-35-5 ]
  • [ 2857872-01-4 ]
YieldReaction ConditionsOperation in experiment
82 % With sodium hydride In dimethyl sulfoxide at 0 - 20℃; 9 Example 1 Preparation of (10R)-7-methoxymethylamino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H.8,4-(metheno)pyrazolo[4,3.h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile General procedure: Compound (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H.8,4-(metheno)pyrazolo[4,3.h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (100mg, 0.246mmol) was dissolved in 20ml of dimethyl sulfoxide, in Cool in an ice bath to 0°C, add sodium hydride and continue stirring for 3 minutes, slowly add chloromethyl methyl ether dropwise, remove the ice bath, return to room temperature, and continue stirring for 4 hours. After adding water to stop the reaction, extract with dichloromethane, dry over anhydrous sodium sulfate, filter and concentrate. The crude product was subjected to column chromatography with ethyl acetate:petroleum ether=1:10 to obtain 82 mg of off-white solid with a yield of 74%.
Same Skeleton Products
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