[ CAS No. 113028-17-4 ] {[proInfo.proName]}

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Quality Control of [ 113028-17-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 113028-17-4 ]

SDS Specification

Alternatived Products of [ 113028-17-4 ]

Product Details of [ 113028-17-4 ]

CAS No. :	113028-17-4	MDL No. :	MFCD08063938
Formula :	C₁₈H₂₀FN₃O₃S	Boiling Point :	No data available
Linear Structure Formula :	-	InChI Key :	XWZXETKTFKCCPB-UHFFFAOYSA-N
M.W :	377.43	Pubchem ID :	10249018
Synonyms :

Calculated chemistry of [ 113028-17-4 ] Expand+

Physicochemical Properties

Num. heavy atoms :	26
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.44
Num. rotatable bonds :	4
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	106.48
TPSA :	88.87 ?2

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.67 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.87
Log Po/w (XLOGP3) :	2.72
Log Po/w (WLOGP) :	1.69
Log Po/w (MLOGP) :	1.78
Log Po/w (SILICOS-IT) :	2.77
Consensus Log Po/w :	2.37

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.91
Solubility :	0.046 mg/ml ; 0.000122 mol/l
Class :	Soluble
Log S (Ali) :	-4.24
Solubility :	0.0217 mg/ml ; 0.0000575 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.52
Solubility :	0.0114 mg/ml ; 0.0000302 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.8

Safety of [ 113028-17-4 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 113028-17-4 ]

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

Upstream synthesis route of [ 113028-17-4 ]
Downstream synthetic route of [ 113028-17-4 ]

[ 113028-17-4 ] Synthesis Path-Upstream 1~1

1
[ 113028-17-4 ]
[ 123447-62-1 ]

Reference： [1] Journal of Medicinal Chemistry, 1992, vol. 35, # 25, p. 4727 - 4738
[2] Patent: WO2012/1357, 2012, A1,

[ 113028-17-4 ] Synthesis Path-Downstream 1~16

1
[ 110-85-0 ]
[ 113046-72-3 ]
[ 113028-17-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	In dimethyl sulfoxide; at 60℃; for 4h;	50 g of ethyl 6,7-difluoro-1-methyl-4-oxo-4H- [1,3] thiazine [3,2-a] Dissolve in 5 volumes of DMSO at 60C, add 40 g of piperazine, and stir at 60C for 4 hours. The mixture was cooled to room temperature, then 5 volumes of acetonitrile were added and stirring was continued for 4 hours at room temperature. The precipitate was collected by filtration and dried to give 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazacyclo [3,2-a] Ethyl acid 52.8g, yield 87%. The yield of 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazacyclo [3,2-a] quinoline-3-carboxylic acid B Ester purity 99%.
87%	In dimethyl sulfoxide; at 60℃; for 4h;	Take the ethyl 6,7-difluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate 50g,Dissolve in 5 volumes of DMSO at 60C.Then add 40 g of piperazine,Stir at 60C for 4 hours.Cool the mixture to room temperatureThen add 5 volumes of acetonitrile,Stirring was continued for 4 hours at room temperature.Filter, collect the precipitate, dry,This gives 52.8 g of ethyl 6-fluoro-1-methyl-4-oxo-7-(piperazin-1-yl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate.Yield 87%.HPLC detection, ethyl 6-fluoro-1-methyl-4-oxo-7-(piperazin-1-yl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate purity 99% .
	In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;	EXAMPLE 4 Ethyl 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate Ethyl 6,7-difluoro-1-methyl-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate (5.0 g) was suspended in 150 ml of N,N-dimethylformamide and the suspension was stirred with 4.6 g of piperazine at room temperature for 48 hours. N,N-Dimethylformamide was evaporated in vacuo and to the residue was added ice water to collect the crystals by filtration. Purification by a column chromatography (silica gel/chloroform-methanol (1:1)) gave 3.0 g of desired compound, m.p. 224 C. (decompn.). Elementary analysis calculated for C18 H20 FN3 O3 S.3/4H2 O. Calcd (%): C 55.30, H 5.54, N 10.74. Found (%): C 55.29, H 5.52, N 10.37.

In N,N-dimethyl-formamide; at 20 - 25℃;Product distribution / selectivity;

Example 7: Preparation of Ulifloxacin ethyl ester; Method A: Dimethylformamide (13.94 It), ethyl 6,7-difluoro-l-methyl-4-oxo-4H- (l,3)thiazeto(3,2-a)quinoline-3-carboxylate (1.39kg) and piperazine (1.39kg) were stirred at 20- 25C for 20-22 hours. Reaction completion was checked by TLC. Water (69.5 It) was added and the reaction mixture was filtered, washed with water and dried to obtain 1.11kg of ulifloxacin ethyl ester having purity 97.47 % by HPLC.

Reference： [1]Patent: CN107383069,2017,A .Location in patent: Paragraph 0061; 0062
[2]Patent: CN107501298,2017,A .Location in patent: Paragraph 0055; 0056
[3]Journal of Medicinal Chemistry,1992,vol. 35,p. 4727 - 4738
[4]Patent: US4843070,1989,A
[5]Patent: WO2009/93268,2009,A1 .Location in patent: Page/Page column 15

2
[ 80715-22-6 ]
[ 113028-17-4 ]
ethyl 6-fluoro-1-methyl-7-<4-<(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl>-1-piperazyl>-4-oxo-4H-<1,3>thiazeto<3,2-a>-quinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydrogencarbonate; In N,N-dimethyl-formamide;	EXAMPLE 1 Ethyl 6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4yl)methyl-1-piperazinyl]-4oxo-4H-[1,3-]thiazeto[3,2-a]quinoline-3-carboxylate. Ethyl 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate (3.88 g) and 1.23 g of potassium bicarbonate were suspended in 20 ml of N,N-dimethylformamide, 2.38 g of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one was dropped thereinto with ice cooling, and the mixture was stirred for 3 hours. After the reaction, the solvent was evaporated in vacuo therefrom at 50 C. and the residue was extracted with chloroform containing a few amount of methanol. The extract was washed with water, dried, the solvent was evaporated therefrom and the residue was purified by a column chromatography (chloroform-methanol/silica gel) to give 3.32 g of desired product. M.p. 241-243 C. (decompn.) Elem. Anal. for C23 H24 FN3 O6 S; Calcd. (%) C: 56.43 H: 4.94 N: 8.58; Found (%) C: 56.13 H: 4.99 N: 8.26. IR (KBr) nu (cm-1): 1820, 1720 (carbon-yl). NMR (CF3 CO2 D)(ppm) 1.51(3H, COOCH2 CH3, t), 2.31(3H, STR10 s), 2.35(3H, STR11 d), 3.40~4.30(8H, proton in piperazine ring, m), 4.55(2H, STR12 s), 4.65(2H, COOCH2 CH3, q), 6.51(1H, STR13 q), 7.05(1H, 8-proton, d), 8.11(1H, 5-proton, d).

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4727 - 4738
[2]Patent: US5086049,1992,A

3
[ 113028-17-4 ]
[ 112984-60-8 ]

Yield	Reaction Conditions	Operation in experiment
97%		Ethyl-6-fluoro-1 -methyl-4-oxo-7-(1 -piperazinyl)-4H-(1 ,3)-thiazeto-[3,2-a]-quinoline-3- carboxylate (100 gms, 0.265 moles) was stirred in water (600 ml) at 25-30C. To this potassium hydroxide solution (50 gms of potassium hydroxide flakes is dissolved in 200 ml of water) was added and the reaction mass was heated to 80-85C. The contents were stirred for 1 hour and after completion of reaction, the reaction mass was cooled to 25-30C. The pH of the reaction mass was adjusted to 6.5-7.0 using 1:1 aqueous acetic acid solution. The contents were stirred at room temperature for 1 hour. The precipitated solid was filtered, washed with water (2 x 100 ml). The solid was slurried in methanol (300 ml) for 1 hour at 25-30C, filtered, washed with methanol (2 x 50 ml) and dried under vacuum at 70-75C to yield the title compound [90 gms, 97% yield, 96% HPLC purity].
97.3%	With water; potassium hydroxide; at 60 - 70℃;Large scale;	the reaction vessel 8. 0kg a compound of formula (II), 112kg water, 6. 0kg potassium hydroxide, and heated to 60~ 70 C the hydrolysis reaction, 2 to 3 hours. After completion of the reaction, was cooled to room temperature, 30. 4kg washed with ethyl acetate, the aqueous layer was separated, stirred, adjusted with concentrated hydrochloric acid rhoEta 6~7, stirring was continued for 0.5 hours, the filter cake was suction filtration, an appropriate amount of ethyl washing the filter cake drying, cake was collected, 60~70 C hot air circulation drying, to obtain a compound of formula (III) finished 7. 36kg, yield (mol) 96.4%, purity 97.3%;
90%	With potassium hydroxide; at 20℃; for 5h;	30 g of ethyl 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazepino [3,2-a] 120ml concentration of 1mol / L of potassium hydroxide solution dissolved, And stirred at room temperature for 5 hours. The solution was neutralized with a 20% (v/v) acetic acid solution and the pH was adjusted to 7-8 and stirred well. The precipitate was collected by filtration, and the precipitate was washed three times with deionized water and acetonitrile, respectively. The precipitate was then dried in vacuo at 60 C to give 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazacyclo [3,2-a] 3-carboxylic acid 29g, 90% yield. The obtained 6-fluoro-7-piperazine-1-methyl-4-oxo- [1,3] thiazepino [3,2-a] quinoline-3-carboxylic acid was 99.1% pure.

Example 8: Preparation of Ulifloxacin;Tertiary butanol (5.55It), 6-fluoro-l-methyl-4-oxo-7-(l-piperazinyl)-4H-[l,3]thiazeto [3,2- a]quinoline-3-carboxylic acid ethyl ester (1.1 lkg), potassium hydroxide (0.37kg) and water (2.75 It) were added at room temperature. The reaction mixture was heated to 600C and maintained for 1.5 hours. Reaction completion was checked by TLC. This was followed by the addition of water (22.2 It) and acetic acid (0.39 It). The reaction mixture was filtered, washed with water followed by slurry wash with acetone (2.22 It) twice and dried to obtain 0.95 kg of ulifloxacin having purity 97.56% by HPLC.

Reference： [1]Patent: WO2012/1357,2012,A1 .Location in patent: Page/Page column 22
[2]Patent: CN103113392,2016,B .Location in patent: Paragraph 0024; 0037; 0038; 0039
[3]Patent: CN107383069,2017,A .Location in patent: Paragraph 0063; 0064
[4]Journal of Medicinal Chemistry,1992,vol. 35,p. 4727 - 4738
[5]Patent: WO2009/93268,2009,A1 .Location in patent: Page/Page column 15

4
[ 113028-17-4 ]
[ 598-31-2 ]
ethyl 7-(4-acetonyl-1-piperazinyl)-6-fluoro-1-methyl-4-oxo-4H-<1,3>thiazeto<3,2-a>quinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;	EXAMPLE 5 Ethyl 7-(4-acetonyl-1-piperazinyl)-6-fluoro-1-methyl-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate Ethyl 6-fluoro-1-methyl-7-(1-piperazinyl)-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate (3.8 g) was suspended in 50 ml of N,N-dimethylformamide, 1.66 g of potassium carbonate was added thereto, 1.65 g of bromoacetone was dropped in with ice cooling and stirring, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured over into ice water and the crystals separated out were collected by filtration, washed with water, dried and recrystallized from ethanol to give 3.7 g of desired compound in colorless powdery crystals, m.p. 196-200 C. (decompn.). Elementary analysis calculated for C21 H24 FN3 O4 S: Calcd (%): C 58.18, H 5.58, N 9.69. Found (%): C 57.93, H 5.39, N 9.46.

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4727 - 4738
[2]Patent: US4843070,1989,A

5
[ 113028-75-4 ]
[ 113028-17-4 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4727 - 4738
[2]Journal of Medicinal Chemistry,1992,vol. 35,p. 4727 - 4738

6
[ 84339-06-0 ]
[ 113028-17-4 ]