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[ CAS No. 161715-24-8 ] {[proInfo.proName]}

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Chemical Structure| 161715-24-8
Chemical Structure| 161715-24-8
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Product Details of [ 161715-24-8 ]

CAS No. :161715-24-8 MDL No. :MFCD17215369
Formula : C22H31N3O6S2 Boiling Point : -
Linear Structure Formula :- InChI Key :SNUDIPVBUUXCDG-QHSBEEBCSA-N
M.W : 497.63 Pubchem ID :9892071
Synonyms :
L084;TBPM-PI;TBM-PI;SPR994;ME1211
Chemical Name :(4R,5S,6S)-(Pivaloyloxy)methyl 3-((1-(4,5-dihydrothiazol-2-yl)azetidin-3-yl)thio)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate

Calculated chemistry of [ 161715-24-8 ]

Physicochemical Properties

Num. heavy atoms : 33
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.73
Num. rotatable bonds : 10
Num. H-bond acceptors : 7.0
Num. H-bond donors : 1.0
Molar Refractivity : 138.42
TPSA : 159.34 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -7.72 cm/s

Lipophilicity

Log Po/w (iLOGP) : 4.21
Log Po/w (XLOGP3) : 2.27
Log Po/w (WLOGP) : 0.52
Log Po/w (MLOGP) : 2.27
Log Po/w (SILICOS-IT) : 2.17
Consensus Log Po/w : 2.29

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 1.0
Egan : 1.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.7
Solubility : 0.1 mg/ml ; 0.000202 mol/l
Class : Soluble
Log S (Ali) : -5.25
Solubility : 0.00278 mg/ml ; 0.00000559 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -2.13
Solubility : 3.68 mg/ml ; 0.0074 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 5.92

Safety of [ 161715-24-8 ]

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 [ 161715-24-8 ]

* 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 [ 161715-24-8 ]

[ 161715-24-8 ] Synthesis Path-Downstream   1~27

  • 1
  • [ 161715-21-5 ]
  • [ 18997-19-8 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
89.7% Stage #1: Tebipenem With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 25℃; for 1h; Stage #2: Chloromethyl pivalate In water at 25℃; for 0.166667h; 1 Example 1 18mg of tebipenem, 162mL of N,N-dimethylformamide, 6.54g of potassium carbonate, and 0.45g of tetrabutylammonium bromide were reacted at 25°C for 60 minutes.At this temperature, 8.93 g of chloromethyl pivalate was added dropwise. After the reaction was completed, 320 ml of water was added and stirred for 10 minutes. Ethyl acetate (160 ml) was added for extraction.The aqueous phase is extracted once with 160 ml of ethyl acetate, combined with ethyl acetate, washed with water, and separated.The ethyl acetate phase was washed with 640 ml of water, the ethyl acetate phase was added with 60 g of anhydrous sodium sulfate, activated carbon was dried and decolorized, and the filtrate was concentrated. Diisopropyl ether (162 mL) was added dropwise at 25° C., and the mixture was crystallized, filtered, and dried to obtain 17.64 g of a white solid.The purity by HPLC was 99.87%, and the yield was 89.7%.
78% With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 45℃; for 4h;
61% Stage #1: Chloromethyl pivalate With potassium iodide In N,N-dimethyl-formamide at 60℃; for 3h; Stage #2: Tebipenem With triethylbenzylammonium iodide; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 8h; 6 preparation of tebipenem (V) Chloromethyl pivalate(3.01g) and KI (3.32g) dissolved in DMF (30ml) and allowed to react for 3h at 60°C. cool down the temperature to 0°C, then (4R,5S,6S)-3-((1-(4,5-dihydro-2-thiazolinyl) -3-Azetidinyl) thio)-6-((R)-1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] heptan-2-enyl-2-carboxylic acid (IV)(3.84g) , and Benzyltriethylammonium lodide (3.19g) was added and allowed to react for 8h at the same temperature. Then raised the temperature to 5°C and in the reaction system added ethyl acetate (50ml) and water (40ml) . then adjusted pH to 4.0 by adding 1. 0mol/L Citric acid aqueous solution and separate the liquid. The aqueous phase pH adjusted to 7.6 by slowly adding KHCO3, then the resulting solution extracted with ethyl acetate(160ml) and separated. The organic phase washed with saturated NaCl aqueous solution (160ml) , dried over Na2SO4 and filtrated. The filtrate was concentrated under reduced pressure to give a white solid which was dissolved in ethyl acetate (12 ml). Then Cooled to crystallize at ° C, solid filtered and dried in vacuo to give 3.04 g of the white crystal of tebipenem in 61% yield.
1.05 kg Stage #1: Tebipenem With N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 1h; Large scale; Stage #2: Chloromethyl pivalate In N,N-dimethyl-formamide at 45℃; for 5h; Large scale; 1 Example 1 Preparation of crude tebipenem To a 5 L reaction flask, 1.0 kg of tibeprom tetrahydrate, 3 L of dimethylformamide (DMF),0.7 kg ofN,N-diisopropylethylamine (DIPEA), and benzyltriethyl chloride were added. ammonium (TBAB) 500g, 60min the reaction at 25 , this temperature followed bydropwise chloromethyl pivalate Stuttgart 500g of the dropwise reaction was warmed to 45 5h, after the completion of the reaction, cooled to room temperature, water was added 3L stirstirred after 10min, ethyl acetate was added to extract 3L, 3L and the remaining aqueous phase was extracted once with ethyl acetate, followed by ethyl acetate combinedester phase with 1N citric acid solution adjusted to pH 4.0 ± 0.1, followed by liquid separation, the points The aqueous phase after the liquid was extracted threetimeswith ethyl acetate 3 L, the organic phase was discarded, the aqueous phase was adjusted to pH 7.5 ± 0.1 with a saturated aqueous solution of potassium carbonate, and then extractedthree timeswith 3 L of ethyl acetate, and the organic phase was combined. The organic sodium phase was washed three times with a saturated sodium chloride solution, and the organic phase was collected, dried over anhydrous sodium sulfate andfiltered, and the filtrate was concentrated to dryness to give 1.05 kg of white solid as the compound of formula (I). The crude product had an HPLC purity of 98.5%.

  • 2
  • [ 179337-62-3 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: 88 percent / potassium thioacetate / dimethylformamide / 5.5 h / 100 °C 2.1: KOH / propan-2-ol; methanol / 0.17 h / 5 °C 2.2: 87 percent / HCl / propan-2-ol; methanol / 15 h / 5 °C 3.1: 94 percent / diisopropyl ethylamine; MeCN / 2 h / -20 °C 4.1: 82 percent / sodium hydrogen carbonate / Pd-C / butan-1-ol; H2O / 1.5 h / 20 °C / 3000.24 Torr 5.1: 78 percent / benzyltriethylammonium chloride; diisopropylethylamine / dimethylformamide / 4 h / 45 °C
  • 3
  • [ 161715-27-1 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: 93 percent / DMAP; Et3N / tetrahydrofuran / 0.5 h / 5 °C 2.1: 88 percent / potassium thioacetate / dimethylformamide / 5.5 h / 100 °C 3.1: KOH / propan-2-ol; methanol / 0.17 h / 5 °C 3.2: 87 percent / HCl / propan-2-ol; methanol / 15 h / 5 °C 4.1: 94 percent / diisopropyl ethylamine; MeCN / 2 h / -20 °C 5.1: 82 percent / sodium hydrogen carbonate / Pd-C / butan-1-ol; H2O / 1.5 h / 20 °C / 3000.24 Torr 6.1: 78 percent / benzyltriethylammonium chloride; diisopropylethylamine / dimethylformamide / 4 h / 45 °C
  • 4
  • [ 161715-28-2 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: KOH / propan-2-ol; methanol / 0.17 h / 5 °C 1.2: 87 percent / HCl / propan-2-ol; methanol / 15 h / 5 °C 2.1: 94 percent / diisopropyl ethylamine; MeCN / 2 h / -20 °C 3.1: 82 percent / sodium hydrogen carbonate / Pd-C / butan-1-ol; H2O / 1.5 h / 20 °C / 3000.24 Torr 4.1: 78 percent / benzyltriethylammonium chloride; diisopropylethylamine / dimethylformamide / 4 h / 45 °C
  • 5
  • [ 161715-20-4 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 82 percent / sodium hydrogen carbonate / Pd-C / butan-1-ol; H2O / 1.5 h / 20 °C / 3000.24 Torr 2: 78 percent / benzyltriethylammonium chloride; diisopropylethylamine / dimethylformamide / 4 h / 45 °C
Multi-step reaction with 3 steps 1.1: 0.5% Pd/C; sodium hydrogencarbonate; hydrogen / butan-1-ol; water / 3 h / 25 - 30 °C / 7500.75 Torr 2.1: N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 35 °C 2.2: 7 - 8 °C 3.1: sodium hydrogencarbonate / water; ethyl acetate / 2.5 h
  • 6
  • [ 179337-57-6 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 94 percent / diisopropyl ethylamine; MeCN / 2 h / -20 °C 2: 82 percent / sodium hydrogen carbonate / Pd-C / butan-1-ol; H2O / 1.5 h / 20 °C / 3000.24 Torr 3: 78 percent / benzyltriethylammonium chloride; diisopropylethylamine / dimethylformamide / 4 h / 45 °C
Multi-step reaction with 3 steps 1.1: acetonitrile / 0.17 h / 20 °C 1.2: 10 h / -20 °C 2.1: hydrogen; sodium hydrogencarbonate; palladium 10% on activated carbon / butan-1-ol; water / 7 h / 20 °C / 3000.3 - 3750.38 Torr 3.1: potassium iodide / N,N-dimethyl-formamide / 3 h / 60 °C 3.2: 8 h / 0 °C
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 3.5 h / -20 °C 2.1: 0.5% Pd/C; sodium hydrogencarbonate; hydrogen / butan-1-ol; water / 3 h / 25 - 30 °C / 7500.75 Torr 3.1: N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 35 °C 3.2: 7 - 8 °C 4.1: sodium hydrogencarbonate / water; ethyl acetate / 2.5 h
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile 2.1: hydrogen; water; palladium on activated charcoal / butan-1-ol 3.1: N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 25 °C / Large scale 3.2: 5 h / 45 °C / Large scale

  • 7
  • [ 682747-73-5 ]
  • [ 179337-57-6 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In acetonitrile at -10℃; for 3h; 2 Example 2: Production of pivaloyloxymethyl (1R, 5S, 6S)-2-[1-(1,3-thiazolin-2-yl)azet idin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate [] In 1 ml of acetonitrile, was dissolved 0.32 g of an oily residue containing (4R, 5R, 6S) -6-[(1R) -1-hydroxyethyl]-3-diphenylphosphorylox y-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxyl ic acid pivaloyloxymethyl ester synthesized and purified in the same manner as in Reference Example 3. To the resulting solution, was added 0.07 g (0.33 mmol) of a compound represented by formula (18): [] and was dropwise added 0.09 g (0.70 mmol) of diisopropylethylamine at -10°C, followed by stirring the mixture for 3 hours at the same temperature. After the completion of the reaction, 20 ml of ethyl acetate and 20 ml of water was added to the reaction mixture. To the resulting solution, was added aqueous citric acid solution to extract the target compound into the water phase. It was extracted again into the ethyl acetate phase by adding 20 ml of ethyl acetate and potassium bicarbonate. The resulting solution was dried over sodium sulfate, and then the solvent was removed by evaporation from the solution. The production of the title compound was confirmed by NMR analysis.
With N-ethyl-N,N-diisopropylamine In acetonitrile at -10℃; for 3h; 1 (Reference Example 1) Production of pivaloyloxymethyl (1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)azetidin-3-yl]thio-6-[(1R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate; [] A solution was prepared by dissolving 0.32 g of an oily residue containing (4R,5R,6S),-6-[(1R)-1-hydroxyethyl]-3-diphenylphosphoryloxy-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid pivaloyloxymethyl ester, which was synthesized as in Example 5 and purified, in 1 ml of acetonitrile, and 0.07 g (0.33 mmol) of a compound represented by formula (18): [] was added thereto. Subsequently, 0.09 g (0.70 mmol) of diisopropylethylamine was added dropwise thereto at -10°C, and stirring was performed at the same temperature for 3 hours. After the reaction was completed, 20 ml of ethyl acetate and 20 ml of water were added to the reaction solution, and extraction into an aqueous layer was carried out by adding aqueous citric acid, and then extraction into an ethyl acetate layer was carried out by adding 20 ml of ethyl acetate and potassium bicarbonate. The extraction solution was dried over sodium sulfate, and then the solvent was removed by distillation. NMR analysis confirmed the formation of the target compound. NMR δ (CDCl3) : 1.23 (9H, s), 1.23 (3H, d, J = 7.1), 1.34 (3H, d, J = 6.4 Hz), 3.13 - 3.21 (1H, m), 3.23 (1H, dd, J = 2.7, 6.8 Hz), 3.37 (2H, t, J = 7.6 Hz), 3.94 - 4.03 (4H, m), 4.10 - 4.26 (3H, m), 4.36 - 4.42 (2H, m), 5.84 (1H, d, J = 5.5 Hz), 5.97 (1H, d, J = 5.5 Hz)
With N-ethyl-N,N-diisopropylamine In acetonitrile Tebipenem pivoxil hydrobromide (TBPM-PI-HBr, SPR-994)can be obtained by several main ways: 2) Coupling of malonic acid monobenzyl ester (XVII) withiodomethyl pivalate (XVI) in the presence of DIEA in acetonitrile,followed by debenzylation with H2 over Pd/C in EtOAcgives malonic acid monopivaloyloxymethyl ester (XVIII),which is treated with MgBr2·Et2O or MgCl2 in THF, followedby coupling with azetidine derivative (XIX) [obtained bythe reaction of (3S,4S)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone (XX) with CDIin THF] in the presence of Et3N to yield ketoester (XXI).Azidation of intermediate (XXI) with C12H25-Ph-SO2N3 in thepresence of Et3N in CH2Cl2 provides diazo compound (XXII),which is O-deprotected using HCl in CH2Cl2/MeOH/H2O toproduce alcohol (XXIII). Intramolecular cyclization of compound(XXIII) in the presence of Rh(O-Oct)2 in refluxing CH2Cl2 affords azabicyclo[3.2.0]heptane derivative (XXIV),which is condensed with diphenyl chlorophosphate (XXV)in the presence of DIEA and DMAP in CH2Cl2 to furnishenol phosphate (XXVI). Coupling of phosphate (XXVI) with1-(4,5-dihydro-1,3-thiazol-2-yl)azetidine-3-thiol hydrochloride(XIa) using DIEA in acetonitrile gives tebipenem pivoxil(XXVII) (11), which is finally treated with HBr in MEK, i-PrOH,dioxane or acetone (12). Scheme 2
  • 8
  • [ 692779-24-1 ]
  • [ 179337-57-6 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (4R,5R,6S)-6-[(1R)-1-trimethylsilyloxyethyl]-3-diphenylphosphoryloxy-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid pivaloyloxymethyl ester; 1-(4,5-dihydro-1,3-thiazol-2-yl)-3-mercaptoazetidine hydrochloride With N-ethyl-N,N-diisopropylamine In acetonitrile at 0℃; for 1.9h; Stage #2: With water; citric acid In ethyl acetate Stage #3: With potassium hydrogencarbonate In water; ethyl acetate 1 Example 1: Production of pivaloyloxymethyl(1R,5S,6S)-2-[1-(1,3-thiazolin-2-yl)azet idin-3-yl] thio-6-[(1R)-1-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylate [] In 15 ml of acetonitrile, was dissolved 4.53 g of a yellow oily residue containing (4R,5R,6S)-6-[(1R)-1-trimethylsilyloxyethyl]-3-diphenylph osphoryloxy-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid pivaloyloxymethyl ester synthesized in Reference Example 2. To the resulting solution, was added 1.10 g (5.1 mmol) of a compound represented by formula (18) : [] and was dropwise added 1.8 ml (10.3 mmol) of diisopropylethylamine under cooling with ice, followed by stirring the mixture for 1.9 hours at the same temperature. After the completion of the reaction, the solvent was removed by evaporation from the mixture, followed by adding 40 ml of ethyl acetate and 100 ml of water. The resulting solution was washed with aqueous potassium bicarbonate solution and aqueous sodium bicarbonate solution. To the resulting ethyl acetate solution, was added aqueous citric acid solution to make the solution acidic, thereby extracting the target compound into the water phase. It was extracted again into the ethyl acetate phase by adding 50 ml of ethyl acetate and potassium bicarbonate. The solvent was removed by evaporation from the solution until the weight of the solution is reduced to 12 g. To the resulting solution, was added 25 ml of heptane to precipitate a crystal, which was filtered and washed to obtain 1.87 g of a white crystal containing the title compound. NMRδ (CDCl3): 1.23 (9H, s), 1.23 (3H, d, J = 7.1), 1.34 (3H, d, J = 6. 4 Hz), 3.13-3.21 (1H, m), 3.23 (1H, dd, J=2.7, 6.8 Hz), 3.37 (2H, t, J = 7.6 Hz), 3.94-4.03 (4H, m), 4.10-4.26 (3H, m), 4.36-4.42 (2H, m), 5.84 (1H, d, J = 5.5 Hz), 5.97 (1H, d, J = 5.5 Hz)
  • 9
  • [ CAS Unavailable ]
  • [ 198696-59-2 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
96.8% Stage #1: C12H18N4S3 With tributylphosphine In water; acetonitrile at 20 - 35℃; for 0.833333h; Inert atmosphere; Stage #2: C28H32NO9P With N-ethyl-N,N-diisopropylamine In water; acetonitrile at -10 - 35℃; for 4h; Inert atmosphere; 5 Under nitrogen, the compound (IV) (20.8g, 0.06mol) ,tributyl phosphate (24.6g) and water (2.16g) addedinto to 300mL of acetonitrile, stirred at room temperature for 50min, the reaction solution was cooled to -10 , and then adding the compound (III) (57.4 g,0.10 mol), was added dropwise diisopropylethylamine (24.4mL, 0.14mmol), was added dropwise at room temperature after the reaction 4h.Was added 500mL ethyl acetate and water, an acidic aqueous solution adjusted to pH 5.6 200mL, separated, aqueous layer, aqueous layer alkalineneutral pH 7.8, extracted twice with ethyl acetate (600mL * 2), the organic layer was washed with water, saturated brine washed with water, dried over anhydrous magnesium sulfate,filtered, and concentrated.Was added 100mL of ethyl acetate, dissolved by heating, 250mL of n-heptane was added dropwise, slowly cooled to 0 deg.] C, stirred at the same temperaturestirred for 2h, filtered and dried to give the object compound (I) 48.1g, yield 96.8%, purity 98.5% .
  • 10
  • [ CAS Unavailable ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: acetonitrile / 0.17 h / 20 °C 1.2: 10 h / -20 °C 2.1: hydrogen; sodium hydrogencarbonate; palladium 10% on activated carbon / butan-1-ol; water / 7 h / 20 °C / 3000.3 - 3750.38 Torr 3.1: potassium iodide / N,N-dimethyl-formamide / 3 h / 60 °C 3.2: 8 h / 0 °C
  • 11
  • [ 90776-59-3 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 3.5 h / -20 °C 2.1: 0.5% Pd/C; sodium hydrogencarbonate; hydrogen / butan-1-ol; water / 3 h / 25 - 30 °C / 7500.75 Torr 3.1: N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 35 °C 3.2: 7 - 8 °C 4.1: sodium hydrogencarbonate / water; ethyl acetate / 2.5 h
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile 2.1: hydrogen; water; palladium on activated charcoal / butan-1-ol 3.1: N-benzyl-N,N,N-triethylammonium chloride; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 25 °C / Large scale 3.2: 5 h / 45 °C / Large scale
  • 12
  • [ 211558-19-9 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
92.1% With sodium hydrogencarbonate In water; ethyl acetate for 2.5h; 8 A mixture of 94.0 g of intermediate III and 560 ml of a 2 wt% aqueous solution of sodium bicarbonate was obtained in Example 6 After mixing, 370 ml of ethyl acetate was added, stirred for 2.5 hours,After completion of the reaction, the mixture was separated to obtain an aqueous layer and an ethyl acetate layer,The ethyl acetate layer was dried, concentrated, then dissolved in acetone, crystallized from isopropyl ether,The filter cake was dried to obtain 72.5 g of tebipenem, the yield was 92.1%, and the purity was 99.54%
  • 13
  • [ 594-45-6 ]
  • [ 161715-24-8 ]
  • [ 2241668-29-9 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; acetonitrile at 25℃; for 0.333333h; 1 EXAMPLE 1. CRYSTALLINE TEBIPENEM PIVOXIL ETHANE SULFONATE (ESA) SALT Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μ,), then the acid stock solution (1 M ethane sulfonic acid in THF) was added to 1 mol eq. and stirred at 25 °C, 500 rpm using a magnetic stir bar in a Polar Bear device (Cambridge Reactor Design for 20 minutes. The sample was then cooled to 0°C over a 2 hour period (0.2 °C/min) and then maintained at 0 °C for ~2 hours. No precipitation was observed. The sample was then cooled by 0.5 °C/min to -15 °C at 0.5 °C/min and stored at -20 °C for 2 days. The solution was transferred to a 20 mL scintillation vial and antisolvent (i1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (t, 7=7.45 Hz, 3 H) 1.07 - 1.16 (m, 15 H) 2.35 (q, 7=7.37 Hz, 2 H) 3.07 (s, 1 H) 3.28 (dd, 7=6.13, 2.72 Hz, 1 H) 3.34 (s, 17 H) 3.60 - 3.68 (m, 2 H) 3.93 (br t, 7=7.52 Hz, 3 H) 4.12 - 4.17 (m, 1 H) 4.19 (br d, 7=9.47 Hz, 2 H) 4.21 - 4.24 (m, 1 H) 4.40 - 4.49 (m, 1 H) 4.68 - 4.77 (m, 2 H) 5.11 (br d, 7=4.80 Hz, 1 H) 5.75 (d, 7=5.81 Hz, 1 H) 5.88 (d, 7=5.94 Hz, 1 H) 10.11 (br s, 1 H). 1H NMR was consistent with pure tebipenem pivoxil. 1.0 eq. of the esylate counterion was observed.
  • 14
  • [ 6915-15-7 ]
  • [ 161715-24-8 ]
  • [ 2241668-32-4 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; acetonitrile at 25℃; for 0.333333h; 5 EXAMPLE 5. CRYSTALLINE TEBIPENEM PIVOXIL MALATE (MAL) SALT FORM A Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μ,). The acid stock solution (1 M malic acid in THF) was added to 1 mol eq. and stirred at 25 °C, 500 rpm using a magnetic stir bar in a Polar Bear device for 20 minutes. The sample was then cooled to 0°C over a 2 hour period (0.2 °C/min) and maintained at 0 °C for about 2 hours. No precipitation was observed so the sample was cooled to -15 °C at 0.5 °C/min and stored at -20 °C for 2 days. The solution was transferred to a 20 mL scintillation vial and antisolvent (feri-methyl butyl ether, TBME) was added slowly while stirring at 25 °C, 500 rpm at a ratio of 4:1 antisolvent: solvent (v/v). A precipitate formed after stirring for 24 hours, which was filtered using a fritted filter and air-dried on a filter block at ambient for 15 minutes. The XPRD diffractogram for crystals prepared according to this procedure is shown in FIG. 9. The peak listing for this diffractogram is provided in Table 7. Crystalline tebipenem pivoxil malate salt was also obtained at equivalent purity using the method in the preceding paragraph but with the following changes. Tebipenem pivoxil was dissolved in EtOH (930 μ). The acid stock solution (1 M malic acid in THF) was added to 1 mol eq. and stirred at 25 °C, 500 rpm using a magnetic stir bar in a Polar Bear device for 20 minutes. The sample was then cooled to 5 °C over approximately 2 hours (0.2 °C/min) and maintained at 5 °C for about 2 hours. The sample was subsequently cooled to -15 °C at 0.2 °C/min and stored at -20 °C for 24 hours. The solution was transferred to a 20 mL scintillation vial and antisolvent (n-hexane) was added slowly whilst stirring at 25 °C, 500 rpm until a precipitate formed at a ratio of 3:1 antisolvent: solvent (v/v). The suspension obtained was filtered using a fritted filter and air-dried on a filter block at ambient for 15 minutes. The XPRD for crystals prepared by this method is shown in FIG. 10. Table 7. Characteristic angles (2Θ) Tebipenem Pivoxil Malate Salt Form A Characteristic angle (°) Relative intensity (%) 18.5 56.5 19.0 100 19.9 26.6 20.5 81.6 20.8 28.6 21.4 20.6 21.9 37.1 22.2 33.1 23.1 14.9 23.4 16.2 23.9 36.8 24.8 20.4 25.5 17.2 26.0 20.1 26.3 27.1 27.7 25.9 28.4 24.4. The DSC profile for crystalline tebipenem pivoxil (FIG. 11) malate salt Form A shows a melting endotherm having an onset of 32.1°C with a minima at 51.1 °C and an enthalpy of fusion of 9 J/g, with a second endotherm having an onset of 117.0 °C and a minima 127.6 °C, with a heat of melting of 23 J/g, and an exotherm with a peak at 131.6 °C with a heat of 44 J/g. TGA (also shown in FIG.11) shows 0.7 % weight loss from room temperature to 75 °C, and a 0.3% weight loss from 75 °C to 130 °C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 - 1.16 (m, 16 H) 2.41 (dd, 7=15.66, 7.20 Hz, 1 H) 2.59 (dd, 7=15.60, 5.75 Hz, 1 H) 3.07 (s, 1 H) 3.25 (dd, 7=6.32, 2.65 Hz, 1 H) 3.32 (br dd, 7=9.35, 7.33 Hz, 5 H) 3.39 (t, 7=7.52 Hz, 3 H) 3.68 - 3.68 (m, 1 H) 3.76 - 3.83 (m, 2 H) 3.88 (t, 7=7.58 Hz, 2 H) 3.96 (br s, 1 H) 4.15 - 4.18 (m, 1 H) 4.15 - 4.22 (m, 1 H) 4.29 - 4.44 (m, 3 H) 5.04 - 5.04 (m, 1 H) 5.09 (br s, 1 H) 5.74 (d, 7=5.94 Hz, 1 H) 5.89 (d, 7=5.94 Hz, 1 H). 1H NMR was consistent with pure tebipenem pivoxil. Approximately 1.09 eq. of the malate counterion was observed. XPRD was attempted one week post storage at 40 °C and 75% relative humidity. The sample was found to have deliquesced to an orange liquid. No HPLC analysis of the post storage sample was performed.
  • 15
  • [ 110-16-7 ]
  • [ 161715-24-8 ]
  • [ 2241668-31-3 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; acetonitrile at 25℃; for 0.333333h; 3 EXAMPLE 3. CRYSTALLINE TEBIPENEM PIVOXIL MALEATE (MAE) SALT FORM A Tebipenem pivoxil (J07492, 35 mg) was dissolved in MeCN (270 uL), then the acid stock solution (1 M maleic acid in THF) was added to 1 mol eq. and stirred at 25 °C, 500 rpm using a magnetic stir bar in a Polar Bear device for 20 minutes. The sample was then cooled to 0°C over a 2 hour period (0.2 °C/min) and maintained at 0 °C for approximately 1-2 hours. The solution was transferred to a 20 mL scintillation vial and antisolvent (i1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 - 1.18 (m, 16 H) 2.07 (s, 1 H) 3.07 (s, 1 H) 3.07 - 3.08 (m, 1 H) 3.12 - 3.12 (m, 1 H) 3.27 (dd, 7=6.19, 2.78 Hz, 2 H) 3.34 (br dd, 7=9.28, 7.26 Hz, 5 H) 3.60 (t, 7=7.52 Hz, 2 H) 3.89 - 4.01 (m, 3 H) 4.07 - 4.22 (m, 3 H) 4.38 - 4.47 (m, 1 H) 4.67 (td, 7=8.87, 3.85 Hz, 2 H) 5.11 (br d, 7=5.05 Hz, 1 H) 5.75 (d, 7=5.94 Hz, 1 H) 5.88 (d, 7=5.94 Hz, 1 H) 6.05 (s, 2 H). 1H NMR was consistent with pure tebipenem pivoxil. 0.97 eq. of the maleate counterion was observed.
  • 16
  • [ 110-16-7 ]
  • [ 161715-24-8 ]
  • [ 2241668-31-3 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; acetonitrile at 25℃; for 0.333333h; 4 EXAMPLE 4. CRYSTALLINE TEBIPENEM PIVOXIL MALEATE (MAE) SALT FORM B Crystalline tebipenem pivoxil maleate salt Form B was prepared as follows. Tebipenem pivoxil (mg) was dissolved in MeCN (270 μ,). The acid stock solution (1 M maleic acid in THF) was then added to 1 mol eq. and stirred at 25 °C, 500 rpm using a magnetic stir bar in a Polar Bear device for 20 minutes. The sample was then cooled to 5 °C over a 2 hour period (0.25 °C/min) and maintained at 5 °C for approximately 2 hours. No precipitation was observed. The sample was then cooled to -15 °C at 0.5 °C/min and stored at -20 °C for 2 days. The solution was transferred to a 20 mL scintillation vial and antisolvent (i1H NMR was consistent with pure tebipenem pivoxil. Approximately 0.92 eq. of the maleate counterion was observed.
  • 17
  • [ 75-75-2 ]
  • [ 161715-24-8 ]
  • [ 2241668-33-5 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; tert-butyl methyl ether; acetonitrile at 25℃; 8 EXAMPLE 8. TEBEIPENEM PIVOXIL METHANE SULFONATE SALT (MSA) FORM C Tebipenem Pivoxil (1 g) was dissolved in MeCN (8 vol, 8 ml) and 1 mol eq. of the acid stock (1 M methane sulphonic acid in THF, 2 ml) added whilst stirring at 25 °C, 500 rpm. Antisolvent (TBME) was then added to a 2: 1 ratio (antisolvent: solvent (v/v) ratio) and a precipitate began to form. Further antisolvent was added to a ratio of 5: 1 and the precipitate was then cooled to 0 °C at 0.2 °C/min. On reaching 0 °C the sample was removed and rapidly cooled in a dry ice/acetone bath to complete precipitation. The solid was filtered under vacuum into a Buchner funnel and dried under vacuum at RT for 16 hours.
  • 18
  • [ 75-75-2 ]
  • [ 161715-24-8 ]
  • [ 2241668-33-5 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; acetonitrile at 25℃; for 0.333333h; 6 EXAMPLE 6. TEBEIPENEM PIVOXIL METHANE SULFONATE SALT (MSA) FORM B Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μ,). The acid stock solution (1 M methane sulfonic acid in THF) was then added to 1 mol eq. and stirred at 25 °C, 500 rpm using a magnetic stir bar in a Polar Bear device for 20 minutes. The sample was then cooled to 0°C over 2 hours (0.2 °C/min) and maintained at 0 °C for about 2 hours. No precipitation was observed so the sample was cooled to -15 °C at 0.5 °C/min and stored at - 20 °C for 2 days. The solution was transferred to a 20 mL scintillation vial and antisolvent (trimethyl butyl ether, TBME) was added slowly whilst stirring at 25 °C, 500 rpm until a precipitate formed at a ratio of 3: 1 antisolvent: solvent (v/v). The suspension obtained was filtered using a fritted filter and air-dried on a filter block at ambient for 15 minutes. Crystalline material obtained by this procedure was determined to be 99.5 % pure by HPLC, Method A. The XRPD diffractogram for this form is shown in FIG. 12. Characteristic peaks are listed in Table 8. The MSA salt was also obtained in the same crystalline form at equivalent purity using the method in the preceding paragraph but with the following changes. Tebipenem pivoxil was dissolved in EtOH (930 μ,). The acid stock solution (1 M methane sulfonic acid in THF) was added to 1 mol eq. and stirred at 25 °C, 500 rpm using a magnetic stir bar in a Polar Bear device for 20 minutes. The sample was then cooled to 5 °C over approximately 2 hours (0.2 °C/min) and maintained at 5 °C for about 2 hours. The sample was subsequently cooled to -15 °C at 0.2 °C/min and stored at -20 °C for 24 hours. The solution was transferred to a 20 mL scintillation vial and antisolvent (n-hexane) was added slowly whilst stirring at 25 °C, 500 rpm until a precipitate formed at a ratio of 3 : 1 antisolvent: solvent (v/v). The suspension obtained was filtered using a fritted filter and air- dried on a filter block at ambient for 15 minutes. Table 8. Characteristic angles (2Θ) of Tebipenem Pivoxil Methane Sulfonate Salt Form B Characteristic angle (°) Relative intensity (%) 12.6 24.6 13.9 27 14.6 6.2 15.4 54.5 17.2 90.1 17.5 12.4 18.2 17.2 18.4 41.7 18.7 30.7 19.4 100 19.6 66.5 19.8 33.1 20.4 67.1 20.6 20.5 21.5 46.9 21.9 17.1 22.2 99.8 22.9 18 23.6 23.4 24.5 12.2 25.3 11.1 25.6 13.8 26.4 16.3 26.9 22.3 27.1 15.8 27.5 9 27.8 13.1 28.0 24.1 28.6 32.1 29.4 25.8 29.8 13.8. The DSC profile for crystalline tebipenem pivoxil (FIG. 13) methane sulfonate salt Form B shows a melting endotherm having an onset of 57.8°C with a minima at 88.5 °C and a heat of melting of 105 J/g, a second endotherm having an onset of 175.2°C and a minima 177.0 °C, with a heat of melting of 48 J/g prior to degradation. TGA (also shown in FIG.13) shows 2.9 % weight loss from room temperature to 100°C. No other thermal events were note until the onset of degradation. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 - 1.18 (m, 16 H) 2.07 (s, 1 H) 2.30 (s, 2 H) 2.27 - 2.31 (m, 1 H) 3.07 (s, 1 H) 3.28 (dd, 7=6.13, 2.59 Hz, 1 H) 3.30 - 3.46 (m, 6 H) 3.61 - 3.69 (m, 2 H) 3.90 - 4.01 (m, 3 H) 4.13 - 4.28 (m, 3 H) 4.40 - 4.50 (m, 1 H) 4.70 - 4.79 (m, 2 H) 5.11 (br s, 1 H) 5.75 (d, 7=5.94 Hz, 1 H) 5.88 (d, 7=5.94 Hz, 1 H) 10.12 (br s, 1 H). *H NMR (not shown) was consistent with pure tebipenem pivoxil. Approximately 1.06 eq. of the methane sulfonate counterion was observed when the analysis was adjusted for solvent by TGA. XPRD and HPLC were performed one week post storage at 40 °C and 75% relative humidity. The XPRD diffractogram was consistent with pure tebipenem pivoxil methane sulfonate crystalline Form B. The sample was 99.0% pure by HPLC, Method A.
  • 19
  • [ 161715-24-8 ]
  • [ 211558-19-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In tetrahydrofuran; water; acetonitrile at 25℃; for 0.333333h; 2 COMPARATIVE EXAMPLE 2. CRYSTALLINE TEBIPENEM PIVOXIL HYDROCHLORIDE (HCL) SALT FORM A Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μ,). The acid stock solution (1 M HCl in THF) was then added to 1 mol eq. and stirred at 25 °C, 500 rpm using a magnetic stir bar in a Polar Bear device for 20 minutes. The sample was then cooled to 0°C over a 2 hour period (0.2 °C/min) and maintained at 0 °C for about 2 hours. The suspension obtained was filtered using a fritted filter and air-dried on a filter block at ambient for 15 minutes. This sample was found to be 99.5% pure by HPLC (Method A). The XRPD diffractogram for this crystalline form is provided in FIG. 19 and the peak listing appears in Table 2. Crystalline tebipenem pivoxil HCl salt of the same form was also obtained at equivalent purity using the method in the preceding paragraph with the following changes. Tebipenem pivoxil was dissolved in EtOH (930 μ,). The acid stock solution (1 M HCl in THF) was then added to 1 mol eq. and stirred at 25 °C, 500 rpm using a magnetic stir bar in a Polar Bear device for 20 minutes. The sample was then cooled to 5 °C over 2 hours (0.2 °C/min) and maintained at 5 °C for about 2 hours. Table 2. Characteristic angles (2Θ) of Tebipenem Pivoxil Hydrochloride Salt Form A Characteristic angle (°) Relative intensity (%) 13 7.8 14.1 3.7 15.4 9.9 15.8 2.3 17.9 100 18.1 4.1 19.1 4.8 20.2 29.4 20.9 29.1 21.1 9.2 21.9 1.9 22.1 3.4 22.8 6.1 23.7 12.8 23.8 10.5 25.2 5.6 25.5 7.1 25.7 4.7 26.1 3.9 26.3 8.5 26.8 3.3 27.1 7.5 27.7 8.4 28.3 3.6 28.6 8.1 29.1 2.7 29.4 3.3 30 5. The DSC profile for crystalline tebipenem pivoxil (FIG. 20) hydrochloride salt Form A shows a broad endotherm having an onset of 29.4 °C with a minima at 56 °C and an enthalpy of fusion of 38 J/g. The DSC also shows an exotherm at the onset of degradation at 194.8 °C. TGA (also shown in FIG.17) showed at 2.2% weight loss from room temperature to 100 °C. No other thermal events were recorded until the onset of degradation at about 150 °C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 - 1.16 (m, 15 H) 1.19 (s, 1 H) 1.98 - 1.99 (m, 1 H) 2.73 (s, 1 H) 2.89 (s, 1 H) 3.07 (s, 1 H) 3.24 (dd, 7=6.25, 2.59 Hz, 1 H) 3.27 - 3.27 (m, 1 H) 3.31 - 3.38 (m, 3 H) 3.73 (td, 7=6.79, 3.60 Hz, 2 H) 3.87 (t, 7=7.58 Hz, 2 H) 3.91 - 4.01 (m, 1 H) 4.03 (d, 7=7.07 Hz, 1 H) 4.18 (dd, 7=9.35, 2.65 Hz, 1 H) 4.27 - 4.39 (m, 3 H) 5.09 (d, 7=5.18 Hz, 1 H) 5.74 (d, 7=5.94 Hz, 1 H) 5.89 (d, 7=5.94 Hz, 1 H) 7.95 (s, 1 H). 1H NMR and HPLC were repeated 1 week post storage at 40 °C/ 75% relative humidity. Tebipenem pivoxil hydrochloride salt crystalline form A was obtained and determined to be 98.9% pure by HPLC.
  • 20
  • [ 161715-24-8 ]
  • [ 1381788-20-0 ]
YieldReaction ConditionsOperation in experiment
With hydrogen bromide In tetrahydrofuran; acetonitrile at 25℃; for 0.333333h; 10-12; 14 EXAMPLE 10. CRYSTALLINE TEBIPENEM PIVOXIL HYDROBROMIDE (HBR) SALT FORM B Tebipenem pivoxil (35 mg) was dissolved in MeCN (270 μ,). The counterion (1 M HBr stock in THF) was added to 1 mol eq. and stirred at 25 °C, 500 rpm using a magnetic stir bar in a Polar Bear device for 20 minutes. The sample was then cooled to 0°C over 2 hours (0.2 °C/min) and maintained at 0 °C for ~2 hours. The suspension obtained was filtered using a fritted filter and air-dried on a filter block at ambient for 15 minutes. This material was 99.4% pure by HPLC, Method A. The XRPD diffractogram for tebipenem pivoxil HBr crystalline Form B prepared by this method is shown in FIG. 14 and the peak listing is provided in Table 14. HBr salt was also obtained at equivalent purity using the method in the preceding paragraph but with the following changes. Tebipenem pivoxil was dissolved in EtOH (930 μl,). The counterion (1 M HBr stock in THF) was added to 1 mol eq. and stirred at 25 °C, 500 rpm using a magnetic stirrer bar in a Polar Bear device for 20 minutes. The sample was then cooled to 5 °C over 2 hours (0.2 °C/min) and maintained at 5 °C for about 2 hours.Table 14. Characteristic angles (2Θ) of Tebipenem Pivoxil HBrSalt Form BCharacteristic angle (°) Relative intensity (%)21.9 10.322.6 11.823.5 27.223.7 11.424.9 11.625.3 11.525.5 17.425.8 11.726.1 18.426.5 10.726.8 19.927.3 17.127.6 1628.4 1928.8 13.129.4 12.129.7 15.229.9 8.6. The DSC profile for crystalline tebipenem pivoxil (FIG. 15) hydrogen bromide salt Form B shows a broad melting endotherm having an onset of 32.9°C with a minima at 66.3 °C and a heat of melting of 34.1 J/g, and an exotherm having an onset of 186.8 °C, with a maxima of 190.8 prior to degradation. TGA (also shown in FIG.15) shows 1.9 % weight loss from room temperature to 100°C. No other thermal events were noted until the onset of degradation. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 - 1.18 (m, 15 H) 3.28 (dd, 7=6.19, 2.65 Hz, 1 H) 3.30 - 3.40 (m, 5 H) 3.61 - 3.69 (m, 2 H) 3.90 - 4.01 (m, 3 H) 4.13 - 4.27 (m, 3 H) 4.41 - 4.50 (m, 1 H) 4.69 - 4.79 (m, 2 H) 5.00 - 5.01 (m, 1 H) 5.11 (br s, 1 H) 5.75 (d, 7=5.94 Hz, 1 H) 5.88 (d, 7=5.94 Hz, 1 H) 10.11 (s, 1 H). 1H NMR was consistent with pure tebipenem pivoxil. Approximately 1.04 eq. of the hydrogen bromide counterion was observed when the analysis was adjusted for solvent by TGA. XPRD and HPLC were performed one week post storage at 40 °C and 75% relative humidity. The XPRD diffractogram was consistent with pure tebipenem pivoxil HBr crystalline Form B. The sample was 99.2% pure by HPLC.
  • 21
  • [ 161715-24-8 ]
  • [ 2348368-72-7 ]
  • [ 1198157-94-6 ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate; water-d2 5 Example 5 - Tebipenem-derived lactone General procedure: [00168] 2 mM tebipenem was mixed with 5 mM OXA-48 in 50 mM sodium phosphate (pH 7.5), 10 % D2O, and the lactone product was characterised by NMR [via 1 H, correlation spectroscopy (COSY), heteronuclear single quantum coherence (HSQC), and heteronuclear multiple bond correlation (HMBC) experiments]. The 1H- and 13C-NMR chemical shift assignments for Example 5 are listed in Table 5.
  • 22
  • [ 161715-21-5 ]
  • [ 53064-79-2 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
91.9% With caesium carbonate In N,N-dimethyl-formamide for 0.5h; Large scale; 1-3 Example 1 Into a 100L reactor, add 50kg DMF and compound I (7.80kg, 16.95mol, 1.0eq) in sequence, stir and cool to -20-10; add cesium carbonate (5.52kg, 16.95mol, 1.0eq), and add dropwise Iodomethyl pivalate (4.31kg, 17.80mol, 1.05eq); after dripping, stir for 0.5 hour (the reaction is monitored by TLC); add 200kg of ethyl acetate and the reaction solution to a 500L reactor, stir for 10min and then filter. Keep the filtrate and add it back to the 500L reactor, add 50kg of purified water, use saturated potassium bicarbonate aqueous solution to adjust the pH = 7.5 ~ 8.0; liquid separation, the organic phase is washed with 50kg purified water, 50kg purified water 5% sodium chloride; Add 2kg of anhydrous sodium sulfate and 0.5kg of activated carbon to the organic phase solvent, stir and dry for 1 hour, filter; add the filtrate to a 50L reactor in batches and concentrate the filtrate to 10 liters under reduced pressure; centrifuge and vacuum dry at 4045 to obtain an off-white powder 7.75 kg (theoretical value is 8.43 kg), the yield is 91.9%, and the purity is greater than 99%.
With potassium carbonate In acetonitrile at 20℃; 3.3.1-3.3.9 (3.1), put acetonitrile into the 50L dry reactor, intermediate TB-2,Potassium carbonate, start stirring;(3.2),The methyl iodide pivalate was added dropwise with a 2 L constant pressure funnel to control the drop rate and the reaction temperature was ≤ 25 ° C;(3.3), keep the reaction at room temperature after the addition, and check the TLC every 0.5 hours.Until the conversion of the raw material intermediate TB-2 is completed;(3.4) Transfer the vacuum pumping material from the reactor to a 500L layered kettle.The purified water and dichloromethane were added, and the mixture was stirred at room temperature for 1 hour, and then allowed to stand for separation; the organic layer was retained.Discharge the water layer to the launching system;(3.5), adding anhydrous sodium sulfate to the layered kettle, stirring at room temperature for ≤ 3 hours,The material is suction filtered, the filter residue is treated as an inorganic salt solid waste, and the filtrate is transferred to a 100 L concentrator;(3.6), the filtrate was concentrated under reduced pressure at 35 ° C or less until no liquid was discharged, and the concentrated mother liquor was transferred to a 10 L stainless steel drum;(3.7), adding ethanol to the crystallizer, dropping into a freezer to -20 ° C, crystallization ≥ 5 hours;(3.8), discharge suction filtration, filter cake tray into a vacuum drying oven,The filtrate is transferred to a solvent recovery system.(3.9), at 45±3°C, -0.06MPa, drying time ≥5 hours,That is, the crude product of pemphalin was 1410 g; the molar yield was 62.4%.
Stage #1: (4R,5S,6S)-3-[1-(4,5-dihydro-1,3-thiazol-2-yl)azetidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid With caesium carbonate In N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Stage #2: iodomethyl pivaloate In N,N-dimethyl-formamide for 1h; 1-3 Turn on the stirring, add YKTP-3 and DMF in a ratio of 1:5 to the reactor, turn on the nitrogen protection, stir and cool to -10°C; add 1 times the weight of YKTP-3 of cesium carbonate, keep warm and stir for 0.5 hours; Add 1.5 times of iodomethyl pivalate; keep warm and stir for 1 hour.Turn on the stirring, add 12 times the weight of YKTP-3 ethyl acetate and the above reaction liquid to the reaction kettle, filter, save the filtrate; add purified water, use 1N citric acid to adjust the pH of the water phase to 4.1, separate, and saturate the water layer The pH was adjusted to 7.5 with an aqueous potassium bicarbonate solution.Extract twice with ethyl acetate and combine the organic layers; wash the organic phase with 8% sodium thiosulfate solution, purified water, and 10% sodium chloride solution in turn; add anhydrous sodium sulfate and activated carbon to the organic phase solvent and stir and dry Decolorize and filter.The filtrate was concentrated under reduced pressure to twice the weight of YKTP-3, crystallization and centrifugation, the filter cake was rinsed with ethyl acetate, and the filter cake was vacuum dried for 6 hours to obtain a white or off-white powder (YKTP-4).
  • 23
  • [ CAS Unavailable ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 4 h / 0 °C 2.1: palladium 10% on activated carbon; hydrogen / ethyl acetate / 1 h / 30 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 0.5 h / Inert atmosphere 3.2: 1 h
  • 24
  • [ 682747-70-2 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: triethylamine; 4-dodecylbenzenesulphonyl azide / dichloromethane 2: hydrogenchloride / lithium hydroxide monohydrate; methanol; dichloromethane 3: dirhodium(II) tetraoctanoate / dichloromethane / Reflux 4: 4-dimethylaminopyridine; N-ethyl-N,N-diisopropylamine / dichloromethane 5: N-ethyl-N,N-diisopropylamine / acetonitrile
  • 25
  • [ 682747-71-3 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: hydrogenchloride / lithium hydroxide monohydrate; methanol; dichloromethane 2: dirhodium(II) tetraoctanoate / dichloromethane / Reflux 3: 4-dimethylaminopyridine; N-ethyl-N,N-diisopropylamine / dichloromethane 4: N-ethyl-N,N-diisopropylamine / acetonitrile
  • 26
  • [ 682747-72-4 ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: dirhodium(II) tetraoctanoate / dichloromethane / Reflux 2: 4-dimethylaminopyridine; N-ethyl-N,N-diisopropylamine / dichloromethane 3: N-ethyl-N,N-diisopropylamine / acetonitrile
  • 27
  • [ CAS Unavailable ]
  • [ 161715-24-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: 4-dimethylaminopyridine; N-ethyl-N,N-diisopropylamine / dichloromethane 2: N-ethyl-N,N-diisopropylamine / acetonitrile
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