Name: 161715-24-8|(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|98%
Brand: Ambeed
SKU: A259534
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1
[ 161715-21-5 ]
[ 18997-19-8 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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%.

Reference： [1]Current Patent Assignee: LUNAN PHARM GROUP - CN104341421, 2017, B Location in patent: Paragraph 0028; 0029; 0033; 0035; 0037; 0039
[2]Isoda, Takeshi; Ushirogochi, Hideki; Satoh, Koichi; Takasaki, Tsuyoshi; Yamamura, Itsuki; Sato, Chisato; Mihira, Ado; Abe, Takao; Tamai, Satoshi; Yamamoto, Shigeki; Kumagai, Toshio; Nagao, Yoshimitsu [Journal of Antibiotics, 2006, vol. 59, # 4, p. 241 - 247]
[3]Current Patent Assignee: GUANGDONG BAIYUNSHAN PHARMACEUTICAL GENERAL FACTOR - CN103012406, 2016, B Location in patent: Paragraph 0048; 0049
[4]Current Patent Assignee: CHENGDU BRILLIANT PHARMACEUTICAL CO LTD - CN109096283, 2018, A Location in patent: Paragraph 0021; 0064; 0065

2
[ 179337-62-3 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Isoda, Takeshi; Ushirogochi, Hideki; Satoh, Koichi; Takasaki, Tsuyoshi; Yamamura, Itsuki; Sato, Chisato; Mihira, Ado; Abe, Takao; Tamai, Satoshi; Yamamoto, Shigeki; Kumagai, Toshio; Nagao, Yoshimitsu [Journal of Antibiotics, 2006, vol. 59, # 4, p. 241 - 247]

3
[ 161715-27-1 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Isoda, Takeshi; Ushirogochi, Hideki; Satoh, Koichi; Takasaki, Tsuyoshi; Yamamura, Itsuki; Sato, Chisato; Mihira, Ado; Abe, Takao; Tamai, Satoshi; Yamamoto, Shigeki; Kumagai, Toshio; Nagao, Yoshimitsu [Journal of Antibiotics, 2006, vol. 59, # 4, p. 241 - 247]

4
[ 161715-28-2 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Isoda, Takeshi; Ushirogochi, Hideki; Satoh, Koichi; Takasaki, Tsuyoshi; Yamamura, Itsuki; Sato, Chisato; Mihira, Ado; Abe, Takao; Tamai, Satoshi; Yamamoto, Shigeki; Kumagai, Toshio; Nagao, Yoshimitsu [Journal of Antibiotics, 2006, vol. 59, # 4, p. 241 - 247]

5
[ 161715-20-4 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Isoda, Takeshi; Ushirogochi, Hideki; Satoh, Koichi; Takasaki, Tsuyoshi; Yamamura, Itsuki; Sato, Chisato; Mihira, Ado; Abe, Takao; Tamai, Satoshi; Yamamoto, Shigeki; Kumagai, Toshio; Nagao, Yoshimitsu [Journal of Antibiotics, 2006, vol. 59, # 4, p. 241 - 247]
[2]Current Patent Assignee: HENAN QUANYU PHARMACEUTICAL - CN106083858, 2016, A

6
[ 179337-57-6 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Isoda, Takeshi; Ushirogochi, Hideki; Satoh, Koichi; Takasaki, Tsuyoshi; Yamamura, Itsuki; Sato, Chisato; Mihira, Ado; Abe, Takao; Tamai, Satoshi; Yamamoto, Shigeki; Kumagai, Toshio; Nagao, Yoshimitsu [Journal of Antibiotics, 2006, vol. 59, # 4, p. 241 - 247]
[2]Current Patent Assignee: GUANGDONG BAIYUNSHAN PHARMACEUTICAL GENERAL FACTOR - CN103012406, 2016, B
[3]Current Patent Assignee: HENAN QUANYU PHARMACEUTICAL - CN106083858, 2016, A
[4]Current Patent Assignee: CHENGDU BRILLIANT PHARMACEUTICAL CO LTD - CN109096283, 2018, A

7
[ 682747-73-5 ]
[ 179337-57-6 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Current Patent Assignee: KANEKA CORPORATION - EP1580191, 2005, A1 Location in patent: Page/Page column 16
[2]Current Patent Assignee: KANEKA CORPORATION - EP1582526, 2005, A1 Location in patent: Page/Page column 23
[3]Ahmad, Mohammad Naiyaz; Dasgupta, Chitralekha Nag; Chopra, Sidharth [Drugs of the Future, 2022, vol. 47, # 5, p. 311 - 323]

8
[ 692779-24-1 ]
[ 179337-57-6 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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)

Reference： [1]Current Patent Assignee: KANEKA CORPORATION - EP1580191, 2005, A1 Location in patent: Page/Page column 15

9
[ CAS Unavailable ]
[ 198696-59-2 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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% .

Reference： [1]Current Patent Assignee: CHINA NATIONAL PHARMACEUTICAL GROUP CORPORATION - CN102775410, 2016, B Location in patent: Paragraph 0058-0060

10
[ CAS Unavailable ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Current Patent Assignee: GUANGDONG BAIYUNSHAN PHARMACEUTICAL GENERAL FACTOR - CN103012406, 2016, B

11
[ 90776-59-3 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Current Patent Assignee: HENAN QUANYU PHARMACEUTICAL - CN106083858, 2016, A
[2]Current Patent Assignee: CHENGDU BRILLIANT PHARMACEUTICAL CO LTD - CN109096283, 2018, A

12
[ 211558-19-9 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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%

Reference： [1]Current Patent Assignee: HENAN QUANYU PHARMACEUTICAL - CN106083858, 2016, A Location in patent: Paragraph 0046

13
[ 594-45-6 ]
[ 161715-24-8 ]
[ 2241668-29-9 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Current Patent Assignee: SPERO THERAPEUTICS INC - WO2018/145089, 2018, A1 Location in patent: Paragraph 0164-0169

14
[ 6915-15-7 ]
[ 161715-24-8 ]
[ 2241668-32-4 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Current Patent Assignee: SPERO THERAPEUTICS INC - WO2018/145089, 2018, A1 Location in patent: Paragraph 0189-0193

15
[ 110-16-7 ]
[ 161715-24-8 ]
[ 2241668-31-3 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Current Patent Assignee: SPERO THERAPEUTICS INC - WO2018/145089, 2018, A1 Location in patent: Paragraph 0176-0181

16
[ 110-16-7 ]
[ 161715-24-8 ]
[ 2241668-31-3 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Current Patent Assignee: SPERO THERAPEUTICS INC - WO2018/145089, 2018, A1 Location in patent: Paragraph 0182-0188

17
[ 75-75-2 ]
[ 161715-24-8 ]
[ 2241668-33-5 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Current Patent Assignee: SPERO THERAPEUTICS INC - WO2018/145089, 2018, A1 Location in patent: Paragraph 0200

18
[ 75-75-2 ]
[ 161715-24-8 ]
[ 2241668-33-5 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Current Patent Assignee: SPERO THERAPEUTICS INC - WO2018/145089, 2018, A1 Location in patent: Paragraph 0194-0198

19
[ 161715-24-8 ]
[ 211558-19-9 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Current Patent Assignee: SPERO THERAPEUTICS INC - WO2018/145089, 2018, A1 Location in patent: Paragraph 0159-0163

20
[ 161715-24-8 ]
[ 1381788-20-0 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Current Patent Assignee: SPERO THERAPEUTICS INC - WO2018/145089, 2018, A1 Location in patent: Paragraph 0206-0210; 0211; 0214; 0221

21
[ 161715-24-8 ]
[ 2348368-72-7 ]
[ 1198157-94-6 ]

Yield	Reaction Conditions	Operation 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.

Reference： [1]Current Patent Assignee: Oxford University Innovation (in: Oxford University); UNIVERSITY OF OXFORD - WO2019/111020, 2019, A1 Location in patent: Paragraph 00168; 00159-00160

22
[ 161715-21-5 ]
[ 53064-79-2 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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).

Reference： [1]Current Patent Assignee: BEIJING LEADINGPHARM MEDICAL TECH DEVELOPMENT - CN111592543, 2020, A Location in patent: Paragraph 0029-0037
[2]Current Patent Assignee: Sun Yan - CN109897042, 2019, A Location in patent: Paragraph 0084-0098
[3]Current Patent Assignee: SHANDONG HUALU PHARMACEUTICAL - CN112812116, 2021, A Location in patent: Paragraph 0059; 0063-0072; 0076-0086; 0091-0098

23
[ CAS Unavailable ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Current Patent Assignee: SHANDONG HUALU PHARMACEUTICAL - CN112812116, 2021, A

24
[ 682747-70-2 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Ahmad, Mohammad Naiyaz; Dasgupta, Chitralekha Nag; Chopra, Sidharth [Drugs of the Future, 2022, vol. 47, # 5, p. 311 - 323]

25
[ 682747-71-3 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Ahmad, Mohammad Naiyaz; Dasgupta, Chitralekha Nag; Chopra, Sidharth [Drugs of the Future, 2022, vol. 47, # 5, p. 311 - 323]

26
[ 682747-72-4 ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation 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

Reference： [1]Ahmad, Mohammad Naiyaz; Dasgupta, Chitralekha Nag; Chopra, Sidharth [Drugs of the Future, 2022, vol. 47, # 5, p. 311 - 323]

27
[ CAS Unavailable ]
[ 161715-24-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 4-dimethylaminopyridine; N-ethyl-N,N-diisopropylamine / dichloromethane 2: N-ethyl-N,N-diisopropylamine / acetonitrile

Reference： [1]Ahmad, Mohammad Naiyaz; Dasgupta, Chitralekha Nag; Chopra, Sidharth [Drugs of the Future, 2022, vol. 47, # 5, p. 311 - 323]

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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

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 Å²

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

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

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

Quality Control of [ 161715-24-8 ]

Related Doc. of [ 161715-24-8 ]

Product Details of [ 161715-24-8 ]

Calculated chemistry of [ 161715-24-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 161715-24-8 ]

Application In Synthesis of [ 161715-24-8 ]

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

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

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

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

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:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed