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[ CAS No. 159989-65-8 ] {[proInfo.proName]}

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Chemical Structure| 159989-65-8
Chemical Structure| 159989-65-8
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Product Details of [ 159989-65-8 ]

CAS No. :159989-65-8 MDL No. :MFCD00931436
Formula : C33H49N3O7S2 Boiling Point : -
Linear Structure Formula :- InChI Key :NQHXCOAXSHGTIA-SKXNDZRYSA-N
M.W : 663.89 Pubchem ID :64142
Synonyms :
AG 1343 Mesylate;Nelfinavir (mesylate);Nelfin;AG-1343
Chemical Name :(3S,4aS,8aS)-N-(tert-Butyl)-2-((2R,3R)-2-hydroxy-3-(3-hydroxy-2-methylbenzamido)-4-(phenylthio)butyl)decahydroisoquinoline-3-carboxamide methanesulfonate

Calculated chemistry of [ 159989-65-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 45
Num. arom. heavy atoms : 12
Fraction Csp3 : 0.58
Num. rotatable bonds : 12
Num. H-bond acceptors : 8.0
Num. H-bond donors : 5.0
Molar Refractivity : 183.63
TPSA : 189.95 ?2

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) : -8.57 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.59
Log Po/w (XLOGP3) : 2.5
Log Po/w (WLOGP) : 4.95
Log Po/w (MLOGP) : 2.52
Log Po/w (SILICOS-IT) : 4.56
Consensus Log Po/w : 3.63

Druglikeness

Lipinski : 1.0
Ghose : None
Veber : 2.0
Egan : 1.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -4.94
Solubility : 0.00769 mg/ml ; 0.0000116 mol/l
Class : Moderately soluble
Log S (Ali) : -6.13
Solubility : 0.000487 mg/ml ; 0.000000734 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -7.26
Solubility : 0.0000364 mg/ml ; 0.0000000548 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 5.99

Safety of [ 159989-65-8 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H317-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 159989-65-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 159989-65-8 ]

[ 159989-65-8 ] Synthesis Path-Downstream   1~7

YieldReaction ConditionsOperation in experiment
93% The product of example (1) (10 g) was dissolved in methanol (30 ml) and treated with carbon (1 g) for 15 min at 25-3O0C. The carbon was removed by filtration through hyflo and washed with methanol (10 ml). Concentrated the combined filtrate at 45-50C under reduced pressure (200-20 mm Hg) till no solvent distills out, which leaves a foamy residue. Continued to heat the residue to 50-550C under reduced pressure (10-20 mm Hg) further 1 h. Cooled the residue to 25- 300C, added methyl t-butyl ether (50 ml) and stirred for 15 min. Filtered the product and washed with methyl t-butyl ether (10 ml). After drying 12 h at 80- 85C under reduced pressure (10-20 mm Hg) yield is 9.3 g (93%).Total solvents present in product are < 0.1% w/w (By GC) and product is amorphous by XRD.
92% The product of example (1) (10 g) was dissolved in absolute alcohol (40 ml) and treated with carbon (1 g) for 15 min at 25-300C. The carbon was removed by filtration through hyflo and washed with 10 ml of absolute alcohol. The combined filtrate was concentrated at 45-500C under reduced pressure (200-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-550C under reduced pressure (10-20 mm Hg) for 1 h, cooled to 25-300C, added methyl t-butyl ether (50 ml) and stirred for 15 min at 25-300C. The resulting free flowing product was filtered and washed with methyl t-butyl ether (10 ml). The product was dried at 70-750C for 12 h under reduced pressure (10-20 mm Hg) to obtain 9.2 g (92%), of title compound.
92% The product of example (1) (10 g) was dissolved in methanol (40 ml) and treated with carbon (1 g) for 15 min at 25-300C. The carbon was removed by filtration through hyflo and washed with 10 ml of methanol. The combined filtrate was concentrated at 45-50 under reduced pressure (200-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 5O-55C under reduced pressure (10-20 mm Hg) for 1 h, added 50 ml of heptanes and stirred for 10 min at 25-3O0C. The resulting free flowing product was filtered and <n="11"/>washed with heptanes (2 x 10 ml). The product was dried at 70-75C for 12 h under reduce pressure (10-20 mrn Hg) to obtain 9.2 g (92%).
91% The product of example (1) (10 g) was dissolved in absolute alcohol (40 ml) and treated with carbon (1 g) for 15 min at 25-300C. The carbon was removed by filtration through hyflo and washed with 10 ml of absolute alcohol. The combined filtrate was concentrated at 45-500C under reduced pressure (200-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-550C under reduced pressure (10-20 mm Hg) for 1 h, cooled to 25-300C, added cyclohexane (50 ml) and stirred for 15 min at 25-300C. The resulting free flowing product was filtered and washed with cyclohexane (10 ml). <n="10"/>The product was dried at 70-750C for 12 h under reduced pressure (10-20 mm Hg) to obtain 9.1 g (91%), of title compound.
91.5% The product of example (1) (10 g) was dissolved in methanol (40 ml) and treated with carbon (1 g) for 15 min at 25-30C. The carbon was removed by filtration through hyflo and washed with 10 ml of methanol. The combined filtrate was concentrated at 45-50 0C under reduced pressure (200-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-55C under reduced pressure (10-20 mm Hg) for 1 h, added 50 ml of hexanes and stirred for 10 min at 25-3O0C. The resulting free flowing product was filtered and washed with hexanes (2 x 10 ml). The product was dried at 70-75C for 12 h under reduce pressure (10-20 mm Hg) to obtain 9.15 g (91.5%).
88% The product of example (1) (10 g) was dissolved in methanol (30 ml) and treated with carbon (1 g) for 15 min at 25-30C. The carbon was removed by filtration through hyflo and washed with 10 ml of methanol. The combined filtrate was concentrated at 40-45C under reduced pressure (150-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-550C under reduced pressure (10-20 mm Hg) for 1 h, cooled to 25-300C, added cyclohexane (50 ml) and stirred for 15 min at 25-300C. The resulting free flowing product was filtered and washed with cyclohexane (10 ml). The product was dried at 70-750C for 4 h under reduced pressure (10-20 mm Hg) to obtain 8.8 g (88%), of amorphous nelfinavir mesylate. Purity: > 99.5% (HPLC) Assay: > 99% (HPLC) Total Solvents: < 0.2% w/w (GC); and product is amorphous by XRD.; Nelfinavir mesylate (10 g, obtained by known methods) was dissolved in methanol (30 ml) and treated with carbon (1 g) for 15 min at 25-30C. The carbon was removed by filtration through hyflo and washed with 10 ml of methanol. The combined filtrate was concentrated at 40-45C under reduced pressure (150-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-550C under reduced pressure (10-20 mm Hg) for 1 h, cooled to 25-300C, added 50 ml of cyclohexane and stirred for 15 min at 25-300C. The resulting slurry product was filtered and washed with cyclohexane (10 ml). The product was dried at 70-750C for 4 h under reduce pressure (10-20 mm Hg) to obtain 9.0 g (90%) of the title compound.Total residual solvents are < 0.1% w/w (By GC) and the product was amorphous by XRD.

  • 2
  • [ 75-75-2 ]
  • [ 159989-64-7 ]
  • [ 159989-65-8 ]
YieldReaction ConditionsOperation in experiment
98% In acetone; at 20 - 35℃; for 2h;Product distribution / selectivity; Methanesulfonic acid (8.46 g, 88 mmol) was added to a suspension of nelfinavir base (50 g, 88 mmol) in acetone (400 ml) at 25-35C, and stirred to obtain a clear solution. Stirred the reaction mixture for ~2 h at 20-25C, and the precipitated product was collected by filtration and washed with acetone (100 ml). This was dried at 70-75C under reduced pressure till LOD was -8% w/w to yield 57.5 g (98%) of the title compound having the purity > 99.5% (HPLC) and the product is crystalline by XRD.
92% To a suspension of nelfinavir base (10 g, 17.6 m. mol) in methanol (50 ml) added methanesulfonic acid (1.69 g, 1.76 m mol) was added and stirred for 10 min at 25- 30C. The resulting clear solution was treated with carbon (1 g) for 15 min at 25- 300C. The carbon was removed by filtration through hyflo and washed with 10 ml of methanol. The combined filtrate was concentrated at 40-450C under reduced pressure (150-20 mm Hg) till no more solvent distills out, leaving a foamy residue. This was further kept at 50-550C under reduced pressure (10-20 mm Hg) for 1 h, cooled to 25-3O0C, added 50 ml of cyclohexane and stirred for 15 min at 25-3O0C. The resulting free flowing product was filtered and washed with cyclohexane (10 ml). The product was dried at 70-75C for 4 h under reduce pressure (10-20 mm Hg) to obtain 1 1.0 g (92%) of the title compound.Total solvents are < 0.1% w/w (By GC) and the product was amorphous by XRD.
80 - 100% In ethanol;Product distribution / selectivity; Procedure for Spray Drying Nelfinavir Free Base to Obtain Nelfinavir Mesylate; [44.1] Generally, nelfinavir free base can be converted to nelfinavir mesylate using the following novel spray drying procedure. Nelfinavir free base and an organic solvent (such as methanol, ethanol, isopropanol, THF, acetone, or MIBK) are mixed in a suitable vessel, and an equivalent amount of methanesulfonic acid is added. Ethanol is the preferred solvent. The mixture is stirred until nelfinavir mesylate is formed. The resultant slurry or solution is pumped into the spray dryer where the following settings are controlled:The inlet and outlet temperatures, feed rate, and atomizer type can be adjusted to optimize output and particle size distribution. Spray dried nelfinavir mesylate is collected at the spray dryer outlet collection point. Specifically, this conversion was performed as described below. 19.4 kg +/- 5 % Alcohol (USP, 190 proof) and 6.00 kg +/- 1% nelfinavir free base were added to a clean, dry 20-40L stainless steel container . The mixture was stirred until homogenous, then 1.04 kg +/- 1% methanesulfonic acid, 99%, was added. The mixture was stirred until all solids were dissolved. A 0.2mu filter cartridge was connected to the pump inlet, and the alcohol solution was pumped through the filter into the spray dryer set with the following initial settings:The inlet and outlet temperatures, feed rate, and wheel speed can be adjusted to optimize output and particle size distribution. The specific spray dryer used was a Niro Atomizer Portable Spray Dryer, type HT (equipped for inert gas) connected to an active carbon filter for removal of organic solvent residues. After the bulk of the solution had been spray dried, the mixing tank was rinsed into the spray dryer with 1.0 kg +/- 5% Alcohol, USP, 190 proof. The spray dried nelfinavir mesylate was collected in 80-100% theory yield.
77% In ethanol; 4-methyl-2-pentanone; at 0 - 45℃; for 5.83333h; Nelfinavir base (20 g) is suspended in ethanol (30 ml), and methanesulfonic acid (3.4 g) is added at temperature of 28C to 45C over 20 min. The reaction mixture is maintained at 40C to 45C for lhr to get clear solution. The obtained clear solution is cooled to 28C to 30C and methyl isobutyl ketone (58 ml) is added over 30 min, mixed at temperature of 28C to 30C for 2 hrs. The reaction mass is cooled and maintained at 0C to 5C for 2 hr. The precipitated solid is filtered, washed with chilled methyl isobutyl ketone (10 ml) and dried at 90C to 100C under vacuum till becomes constant weight.Out put: 18 g (77 % of the theoretical)
76 - 92% In tetrahydrofuran; for 2h;Product distribution / selectivity; Procedure for Precipitation of Nelfinavir Free Base to Obtain Nelfinavir Mesylate; Alternatively, nelfinavir free base can be converted to nelfinavir mesylate using the following novel precipitation procedure. Nelfinavir free base is slurried or dissolved in a suitable solvent (such as THF, methanol, or ethanol). THF is the preferred solvent. A molar equivalent amount of methanesulfonic acid is added, and the mixture is stirred until all solids dissolve. The solution is added to several volumes of an antisolvent (such as methyl t-butyl ether, diethyl ether, hexanes, or heptanes) that is rapidly stirring. Diethyl ether is the preferred antisolvent. After stirring, the mixture is filtered and washed with antisolvent. The solid is dried in a vacuum oven to yield nelfinavir mesylate. Specifically, this conversion was performed as described below. Nelfinavir free base (10.2 kg, 18.0 mol) and 24 L of tetrahydrofuran were added to a 100L reactor. Methanesulfonic acid (1.8 kg, 18.48 mol) also was added to the reactor. The reactor was stirred until all solids dissolved, and then the solution was filtered into a 100 gallon polypropylene tank containing 306 L methyl t-butyl ether or diethyl ether that was rapidly stirring. After stirring for 2 hours, the 100 gallon tank contents were filtered, washed with 17 L of methyl t-butyl ether or diethyl ether, and pulled as dry as possible. The solid was transferred to a rotocone drier and dried in a vacuum oven at 60-65C (at least 26 in. Hg or higher vacuum) for 12-72 hours or until the methyl t-butyl ether or diethyl ether content of the dried solid was below 1%. If necessary, the drier contents could be milled in a Fitzmill grinder to accelerate drying. Typical yields of nelfinavir mesylate range from 9 to 11 kg. (76% - 92% theory). In this application, Applicants have described certain theories and reaction mechanisms in an effort to explain how and why this invention works in the manner in which it works. These theories and mechanisms are set forth for informational purposes only. Applicants are not to be bound by any particular chemical, physical, or mechanical theory of operation. While the invention has been described in terms of various preferred embodiments using specific examples, those skilled in the art will recognize that various changes and modifications can be made without departing from the spirit and scope of the invention, as defined in the appended claims.
69% In ethanol; acetone; at 25 - 35℃; for 1.16667h;Product distribution / selectivity; To a suspension of nelfinavir base (1O g, 17.6 m mol) in ethanol (25 ml) added methanesulfonic acid (1.69 g, 17.6 m mol) and stirred for 10 min at 25-35C. To the resulting clear solution added acetone (125 ml) and stirred for 1 h at 25-300C, where upon product precipitated out, which was collected by filtration, washed with acetone (25 ml) and dried at 75-80C under reduced pressure to yield 8.1 g (69%) of the title compound.
68.4% In tetrahydrofuran; 2-Pentanone; at 0 - 45℃; for 5h; Nelfinavir base (25 g) is suspended in THF (75 ml) , and methanesulfonic acid (4.25 g) is added at temperature of 26C to 40C over 30 min. The reaction mixture is maintained at 40C to 45C for lhr to get clear solution. The obtained clear solution is cooled to 28C to 32C and 2-pentanone (145 ml) is added over 30 min, mixed at temperature of 28C to 32C for 1 hrs. The reaction mass is cooled and maintained at 0C to 5C for 2 hr. The precipitated solid is filtered, washed with chilled 2-pentanone (12.5 ml) and dried at 90C to 100C under vacuum till becomes constant weight.Out put: 20 g (68.4 % of the theoretical)
68.6% In tetrahydrofuran; butanone; at 0 - 45℃; for 5.83333h; Nelfinavir base (25 g) is suspended in THF (75 ml), and methanesulfonic acid (4.25 g) is added at temperature below 45C over 30 min. The reaction mixture is maintained at 40C to 45C for lhr to get clear solution. The obtained clear solution is cooled to 28C to 30C and methyl ethyl ketone (145 ml) is added over 20min, mixed at temperature of 25C to 30C for 2 hrs. The reaction mass is cooled and maintained at 0C to 5C for 2 hrs. The precipitated solid is filtered, washed with chilled methyl ethyl ketone (12.5 ml) and dried at 90C to 100C under vacuum till becomes constant weight.Out put: 20 g (68.6 % of the theoretical)
57% In methanol; acetone; at 0 - 45℃; for 6h; Nelfinavir base (15 g) is suspended in methanol (22.5 ml), and methanesulfonic acid (2.55 g) is added at temperature below 45C over 30 min. The reaction mixture is maintained at 40C to 45C for lhr to get clear solution. The obtained clear solution is cooled to a temperature of 25C to 30C, acetone (87 ml) is added over 30 min and mixed for 2hrs at 25C to 30C. The reaction mass is cooled to 0C to 5C and maintained for 2 hrs. The precipitated solid is filtered, washed with chilled acetone (7.5 ml) and dried at 90C to 100C under vacuum till becomes constant weight.Out put: 10 g (57 % of the theoretical)

  • 3
  • [ 67000-01-5 ]
  • [ 159989-64-7 ]
  • [ 159989-65-8 ]
YieldReaction ConditionsOperation in experiment
95% With methanesulfonic acid; In tetrahydrofuran; EXAMPLE 9 Production of Methanesulfonate of Compound [15] (3S,4aS,8aS)-2-[(2R,3R)-2-Hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenylthiobutyl]decahydroisoquinoline-3-carboxylic acid t-butylamide (compound [15], 7.80 g, 13.7 mmol) was suspended in tetrahydrofuran (40 ml) and methanesulfonic acid (0.918 ml, 14.1 mmol) was added, which was stirred until the solid was completely dissolved. The mixture was dropwise added to methyl-t-butyl ether (470 ml) (after rinsing with 5 ml of tetrahydrofuran). Precipitate was produced instantaneously with the dropwise addition. The mixture was stirred at room temperature for 2 hours after the dropwise addition. The precipitate was collected by filtration, washed with methyl-t-butyl ether (27 ml) and dried at 65 C. for one day under reduced pressure to give (3S,4aS,8aS)-2-[(2R,3R)-2-hydroxy-3-(3-hydroxy-2-methylbenzoylamino)-4-phenylthiobutyl]decahydroisoquinoline-3-carboxylic acid t-butylamide methanesulfonate (8.68 g, yield 95%) as a colorless solid. 1 H-NMR (CD3 OD, 300 MHz) delta: 7.93 (brd.s,1H), 7.43 (m,1H), 7.30 (m,2H), 7.22 (m,1H), 7.03 (t,J=5.9 Hz,1H), 6.86 (m,2H), 4.19 (m,1H), 4.08 (m,1H), 3.61 (dd,J=9.7,1.3 Hz,1H), 3.45 (dd,J=10.4,2.6 Hz,1H), 3.38 (dd,J=9.8,2.9 Hz,1H), 3.28 (m,1H), 3.17 (m,1H), 3.05 (dd, J=10.4,7.7 Hz,1H), 2.68 (s,3H), 2.26 (s,3H), 2.2-2.1 (m,12H), 1.30(s,9H)
  • 4
  • [ 42417-31-2 ]
  • [ 159989-65-8 ]
  • C48H73N5O8S [ No CAS ]
  • C64H101N7O12S [ No CAS ]
  • 5
  • [ 159989-65-8 ]
  • AG1346 hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With Thiamine hydrochloride; In propylene glycol;Heating; VIRACEPT (Nelfinavir Mesylate) is a selective, competitive, reversible inhibitor of HIV protease which shows a strong food effect.An HCl salt of nelfinavir was obtained via the following procedure. An equimolar ratio of <strong>[159989-65-8]nelfinavir mesylate</strong> and thiamine HCl in propylene glycol were mixed, heated to dissolution and slowly evaporated (over 2 months). Crystals formed as tiny needles, clear in color.Crystal Data for Nelfinavir HCl: Orthorhombic, P212121, a=10.7998(11) , b=10.9951(11) , c=26.198(3) , alpha=90 degrees, beta=90 degrees, gamma =90 degrees, V=3110.9(5) 3, Z=4.FIGS. 11-13 shows the OH-OH chain, the chloride interaction, and the packing diagram of nelfinavir HCl, respectively.
  • 6
  • (2R,3R)-4-((3S,4aS,8aS)-3-(tertbutylcarbamoyl)octahydroisoquinolin-2(1H)-yl)-3-hydroxy-1-(phenylthio)butan-2-aminium benzoate [ No CAS ]
  • [ 159989-65-8 ]
  • 7
  • [ 201402-97-3 ]
  • [ 159989-65-8 ]
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