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[ CAS No. 1374639-75-4 ] {[proInfo.proName]}

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Chemical Structure| 1374639-75-4
Chemical Structure| 1374639-75-4
Structure of 1374639-75-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1374639-75-4 ]

CAS No. :1374639-75-4 MDL No. :MFCD28167746
Formula : C27H36N8O5 Boiling Point : -
Linear Structure Formula :- InChI Key :NHANOMFABJQAAH-UHFFFAOYSA-N
M.W : 552.63 Pubchem ID :57334219
Synonyms :
LEE011 succinate;Kisqali
Chemical Name :7-Cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate

Calculated chemistry of [ 1374639-75-4 ]

Physicochemical Properties

Num. heavy atoms : 40
Num. arom. heavy atoms : 15
Fraction Csp3 : 0.48
Num. rotatable bonds : 9
Num. H-bond acceptors : 9.0
Num. H-bond donors : 4.0
Molar Refractivity : 157.38
TPSA : 165.81 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 : Yes
Log Kp (skin permeation) : -10.29 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.63
Log Po/w (XLOGP3) : -0.87
Log Po/w (WLOGP) : 1.97
Log Po/w (MLOGP) : 1.06
Log Po/w (SILICOS-IT) : 1.09
Consensus Log Po/w : 1.38

Druglikeness

Lipinski : 2.0
Ghose : None
Veber : 1.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.11

Water Solubility

Log S (ESOL) : -2.4
Solubility : 2.19 mg/ml ; 0.00397 mol/l
Class : Soluble
Log S (Ali) : -2.13
Solubility : 4.09 mg/ml ; 0.00741 mol/l
Class : Soluble
Log S (SILICOS-IT) : -5.51
Solubility : 0.00169 mg/ml ; 0.00000306 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 4.07

Safety of [ 1374639-75-4 ]

Signal Word:Danger Class:6.1
Precautionary Statements:P273-P301+P310-P305+P351+P338-P314 UN#:2811
Hazard Statements:H301-H315-H319-H372-H400 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 1374639-75-4 ]

* 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 [ 1374639-75-4 ]

[ 1374639-75-4 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 1003-03-8 ]
  • [ 1374639-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine / ethyl acetate / 7 h / 18 - 40 °C / Inert atmosphere 2.1: tetrabutyl ammonium fluoride / bis-triphenylphosphine-palladium(II) chloride / water; tetrahydrofuran / 2 h / 25 - 67 °C / Inert atmosphere 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.67 h / 25 - 60 °C / Inert atmosphere 4.1: sodium cyanide / N,N-dimethyl-formamide; tetrahydrofuran / 4.25 h / 17 - 23 °C / Inert atmosphere 5.1: caesium carbonate / palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 4-methyl-2-pentanone / 3.25 h / 37 - 103 °C / Inert atmosphere 6.1: hydrogenchloride; water / toluene / 1.08 h / 9 - 28 °C / Inert atmosphere 6.2: Si-thiol functionalized silica gel / 6 h / 30 - 53 °C / pH 2.9 - 3.5 7.1: isopropyl alcohol / 27 - 83 °C / Inert atmosphere
  • 2
  • [ 110-15-6 ]
  • [ 1211441-98-3 ]
  • 7-cyclopentyl-N,N-dimethyl-2-[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate [ No CAS ]
YieldReaction ConditionsOperation in experiment
94.9% In isopropyl alcohol; at 27 - 83℃;Inert atmosphere; A nitrogen-flushed, 1 L, 4-neck, round bottom flask is charged with 11.16 g (0.0945 mol, 1.05 eq.) of succinic acid (A5), and 245 g (312 mL) of 2-propanol. The suspension is stirred and warmed to 65±3 C. to obtain a clear solution. The solution is filtered while warmed through glass-fiber filter paper. The filtrate is held at 30±3 C. for addition to A4. A nitrogen-flushed 2 L, 4-neck, round bottom flask is charged with 39.11 g (0.09 mol, 1.0 eq) of 7-cyclopentyl-N,N-dimethyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (A4) and 1115 g (1420 mL) of 2-propanol. The resulting suspension is stirred and heated to 80±3 C. to obtain a hazy yellow solution. The solution is cooled to 70±3 C. and filtered through a 25 g pad of Celite. The warm, filtered A4 solution is transferred to a nitrogen-flushed, 3 L, Argonaut reactor system and re-heated to 80±3 C. The succinic acid/2-propanol solution is added over 1 h maintaining 80±3 C. throughout the addition. The batch is seeded after 80% of the succinic acid solution has been added. The sample is stirred at 80±3 C. for 1 h after the addition is completed and cooled to 20±3 C. over 1 h, held 30 minutes and the solids are filtered. The filter cake is washed with 78 g (100 mL) of 2-propanol. The solids are dried at 60 C. for at least 16 h or until the LOD is 1% to afford 47.16 g (94.9%, corrected) of Compound A6 as a yellow, crystalline solid, mp 202-203 C.
78.7% In water; acetone; at 0 - 50℃;Flow reactor; Inert atmosphere; In a glove box under inert atmosphere (nitrogen), a solution of succinic acid (0.8 g) in water (9.6 mL) was prepared at 50 C (solution A). Ribociclib base (2.8 g) was charged in a 100 mL reactor. Solution A was added to Ribociclib base. The mixture was further diluted with water (10 mL), then succinic acid (0.72 g) was added to the mixture affording complete dissolution. Water was then distilled under vacuum to a residual volume of 10 mL at 50 C. Acetone (56 mL) was added at 50 C and precipitation was observed after addition of about 30 mL of acetone. The suspension was then cooled down to 0 C in 1 h and kept under stirring at 0 C for 30 min. The solid was isolated by filtration and washed with acetone (10 mL). Ribociclib succinate was dried under vacuum at 50 C for 18 h (2.8 g, 78.7% yield, 99.04%) purity).
  • 3
  • [ 571188-59-5 ]
  • [ 1374639-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: caesium carbonate / palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 4-methyl-2-pentanone / 3.25 h / 37 - 103 °C / Inert atmosphere 2.1: hydrogenchloride; water / toluene / 1.08 h / 9 - 28 °C / Inert atmosphere 2.2: Si-thiol functionalized silica gel / 6 h / 30 - 53 °C / pH 2.9 - 3.5 3.1: isopropyl alcohol / 27 - 83 °C / Inert atmosphere
  • 4
  • [ 571189-16-7 ]
  • [ 1374639-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: hydrogen / palladium 10% on activated carbon / water; methanol / 0.25 h / 19 - 54 °C / 1551.49 - 2327.23 Torr / Inert atmosphere 2.1: caesium carbonate / palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 4-methyl-2-pentanone / 3.25 h / 37 - 103 °C / Inert atmosphere 3.1: hydrogenchloride; water / toluene / 1.08 h / 9 - 28 °C / Inert atmosphere 3.2: Si-thiol functionalized silica gel / 6 h / 30 - 53 °C / pH 2.9 - 3.5 4.1: isopropyl alcohol / 27 - 83 °C / Inert atmosphere
  • 5
  • [ 733039-20-8 ]
  • [ 1374639-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: tetrabutyl ammonium fluoride / bis-triphenylphosphine-palladium(II) chloride / water; tetrahydrofuran / 2 h / 25 - 67 °C / Inert atmosphere 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.67 h / 25 - 60 °C / Inert atmosphere 3.1: sodium cyanide / N,N-dimethyl-formamide; tetrahydrofuran / 4.25 h / 17 - 23 °C / Inert atmosphere 4.1: caesium carbonate / palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 4-methyl-2-pentanone / 3.25 h / 37 - 103 °C / Inert atmosphere 5.1: hydrogenchloride; water / toluene / 1.08 h / 9 - 28 °C / Inert atmosphere 5.2: Si-thiol functionalized silica gel / 6 h / 30 - 53 °C / pH 2.9 - 3.5 6.1: isopropyl alcohol / 27 - 83 °C / Inert atmosphere
  • 6
  • [ 1211443-61-6 ]
  • 7-cyclopentyl-N,N-dimethyl-2-[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate [ No CAS ]
  • 7
  • [ 1374639-76-5 ]
  • [ 1374639-75-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1.67 h / 25 - 60 °C / Inert atmosphere 2.1: sodium cyanide / N,N-dimethyl-formamide; tetrahydrofuran / 4.25 h / 17 - 23 °C / Inert atmosphere 3.1: caesium carbonate / palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / 4-methyl-2-pentanone / 3.25 h / 37 - 103 °C / Inert atmosphere 4.1: hydrogenchloride; water / toluene / 1.08 h / 9 - 28 °C / Inert atmosphere 4.2: Si-thiol functionalized silica gel / 6 h / 30 - 53 °C / pH 2.9 - 3.5 5.1: isopropyl alcohol / 27 - 83 °C / Inert atmosphere
  • 8
  • [ 1374639-77-6 ]
  • 7-cyclopentyl-N,N-dimethyl-2-[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate [ No CAS ]
  • 9
  • [ 110-15-6 ]
  • [ 1211441-98-3 ]
  • 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide succinate salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
97.1% In tetrahydrofuran; at 25 - 70℃; Tetrahydrofuran (120 mL) and Ribociclib (3.0g, 0.0069 moles) were charged into 250 mL 4 neck round bottomed flask at 30±5C and stirred for 5-10 min. to get cream colored suspension. Reaction mass was heated to 65-70C and stirred for 15 min to get clear solution. The solution of succinic acid (0.85g, 0.0072moles) in tetrahydrofuran (60 mL) was added to the above reaction mass dropwise through addition funnel at 65-70C. After addition of succinic acid solution, pale yellow coloured suspension was formed in the reaction mass and was stirred for lh. Then the reaction mass was cooled to 25-35C and stirred for lh. Product was filtered off under suction. Product was dried in vacuum oven at 65-70C to afford title compound as cream coloured solid. Weight of the product: 3.7g (97.1% by theory) as cream coloured solid. Purity by HPLC > 99.0%. (0115) The obtained crystalline compound is characterized by PXRD as illustrated in figure- 1.
95% In isopropyl alcohol; at 85℃; for 0.5h; dd 100g of Rebizzini (Formula 4), 1200g of isopropanol to a 2L three-necked flask, heat to 85 C, while 28.53gSuccinic acid was added to 240 g of isopropanol and dissolved by heating. Then, a succinic acid/isopropanol mixed solution was added dropwise to a 2 L three-necked flask.After the addition is completed, a large amount of solid is precipitated, stirred for 30 minutes, naturally cooled to room temperature, stirred for 2 to 3 hours, filtered, and used less.The mixture was washed with cold isopropanol and dried under reduced pressure at 60 C for 24 hours. Resino succinate (Formula 5) dry product 120g, yield 95.0%, byThe purity by HPLC (area normalization method) was 99.91%, the maximum single impurity was 0.06%, and the palladium residue was 0.2 ppm.
90% In methanol; dichloromethane; at 20 - 30℃; Method-1 Ribociclib (2 g) and succinic acid (600 mg) were added in the solution of dichloromethane (30 mL) and methanol (10 mL) at 20-30C. Reaction mixture was stirred for 5 0-60 mm followed by addition of diisopropyl ether (20 mL) at the same temperature. The reaction mixture was stirred for 4-5 hrs. The solid soformed, was collected by filtration and dried to give Ribociclib succinate form-N (2.3g).Yield: 90%; HPLC Purity: 99.76%
In methanol; acetonitrile; at 50℃; for 48h; 10141] 30.7 mg of the non-hydrate form (prepared according to patent CN103201275A) was added into 2.2 mL of acetonitrile/methanol (v/v=10/1), then stirred at 50 C. for 48 hours, until solids precipitate out.The XRPD data of the mono-succinate Form Iproduced in this example is listed in Table 4 and the XRPDpattern was displayed in FIG. 5.The ?H NMR spectrum of the mono-succinateForm I produced in this example is displayed in FIG. 6. ?HNMR data is shown as following: ?H NMR (400 MHz, DM50) oe 9.33 (s, 1H), 8.76(s, 1H), 8.16 (d, J=9.1 Hz, 1H), 8.00 (d, J=2.9 Hz, 1H), 7.45(dd, J9.1, 3.0 Hz, 1H), 6.60 (s, 1H), 4.79-4.68 (m, 1H),3.16-3.00 (m, 14H), 2.34 (s, 4H), 1.98 (s, 4H), 1.64 (d, J=5.5Hz, 2H). ?H NMR results show that Form I is a monosuccinate of compound I.DSC curve of mono-succinate Form I was displayed in FIG. 7. Form I is an anhydrate, the DSC data showed an endothermic peak at 197 C. (onset temperature).TGA curve of mono-succinate Form I was displayed in FIG. 8. The TGA data showed 2.0% weight loss up to 178 C
435 mg In isopropyl alcohol; at 25 - 75℃; for 16h; Ribociclib free base (500 mg) was added to iso-propanol (30 mL) and stirred at 75C for 25 minutes to obtain a reaction mixture. Iso-propanol (2.5 mL) with succinic acid (150 mg) was added to the reaction mixture and stirring was continued at 75C for 4 hours. Iso-propanol (10 mL) was again added to the reaction mixture and the mixture was stirred at ambient temperature for 12 hours to obtain a solid. The solid obtained wascollected by filtration and then dried at 50C under vacuum for 10 hours to obtain the titlecompound. Yield: 435 mg
1.2 g In water; at 25 - 55℃; Succinic acid (0.285 g, 0.0024mol) was charged into a reaction flask containing water (5.0 rnL) at 25-30C. Reaction mass was heated to 50-55C. Charged Ribociclib base (1.0 g, 0.0023mol) at 50-55C and stirred for 2hours minutes at 50-55C. Reaction mass filtered through 0.22 micron filter and washed with water (2.0 mL). Concentrated the reaction mass under vacuum at 65-70C with Heptane, isolated the product. Dried the material under vacuum at 55-60C for 12- 15 hours.Yield: 1.2 g.
In 1,4-dioxane; at 25 - 30℃; for 4h; To a suspension of ribociclib base (1.0 g) in l,4-dioxane (30ml) was added succinic acid (0.28g ) at 25-30C. The reaction mixture was stirred at 25-30C for 4 hr. The solids were isolated by filtration and dried at 50C under vacuum, resulted the title compound (T l5g) and identified by XRD as Form-C2, as presented in figure 1.
In isopropyl alcohol; Weigh 5.0mg succinic acid in 1.0mL isopropanol, weigh 20.0mg of compound (I) suspended in 1.0mL isopropanol,A solution of succinic acid in isopropanol was added dropwise, filtered, and the filter cake was dried in vacuum at 40 C to obtain a solid.

  • 10
  • [ 1374639-78-7 ]
  • 7-cyclopentyl-N,N-dimethyl-2-[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide succinate [ No CAS ]
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[ 1374639-75-4 ]

Chemical Structure| 1211441-98-3

A288696[ 1211441-98-3 ]

7-Cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Reason: Free-salt