[ CAS No. 106939-34-8 ] {[proInfo.proName]}

Name: 106939-34-8|(S)-Ethyl 9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate|97%
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SKU: A136327
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Quality Control of [ 106939-34-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 106939-34-8 ]

Product Details of [ 106939-34-8 ]

CAS No. :	106939-34-8	MDL No. :	MFCD09030626
Formula :	C₁₅H₁₃F₂NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	TZSXJUSNOOBBOP-ZETCQYMHSA-N
M.W :	309.26	Pubchem ID :	834957
Synonyms :

Calculated chemistry of [ 106939-34-8 ]

Physicochemical Properties

Num. heavy atoms :	22
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.33
Num. rotatable bonds :	3
Num. H-bond acceptors :	6.0
Num. H-bond donors :	0.0
Molar Refractivity :	74.66
TPSA :	57.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.62 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.58
Log Po/w (XLOGP3) :	2.2
Log Po/w (WLOGP) :	3.25
Log Po/w (MLOGP) :	2.0
Log Po/w (SILICOS-IT) :	3.23
Consensus Log Po/w :	2.65

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.28
Solubility :	0.162 mg/ml ; 0.000523 mol/l
Class :	Soluble
Log S (Ali) :	-3.04
Solubility :	0.281 mg/ml ; 0.000907 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.25
Solubility :	0.0172 mg/ml ; 0.0000556 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.3

Safety of [ 106939-34-8 ]

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 [ 106939-34-8 ]

* 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.

Upstream synthesis route of [ 106939-34-8 ]
Downstream synthetic route of [ 106939-34-8 ]

[ 106939-34-8 ] Synthesis Path-Upstream 1~12

1
[ 106939-34-8 ]
[ 100986-89-8 ]

Yield	Reaction Conditions	Operation in experiment
4.81 g	With sulfuric acid; acetic acid In N,N-dimethyl-formamide for 1 h; Reflux; Green chemistry	The residue after the recovery of DMF was added acetic acid at room temperature, 65ml of water was stirred, dropping sulfuric acid, dropping end, heated to reflux, incubated for 1 hour, cooled to room temperature, filtered. The filter cake was washed with 65ml water and dried to obtain 43.98g of levoxycyclic acid with a content of 96.22percent. Acetic acid was swirled back by acetic acid and swirled to dryness. The filtrate was washed with water, filtered, and filtered to give 4.81g g levulinic acid, content 61.28percent. Recycled water and acetic acid can be recycled respectively to reduce the amount of waste and the original cost. In terms of tetrafluorobenzoyl chloride, the overall yield for the four steps was 87percent.

Reference： [1] Patent: EP368410, 1990, A3,
[2] Chemical and pharmaceutical bulletin, 1987, vol. 35, # 5, p. 1896 - 1902
[3] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 23, p. 4213 - 4216
[4] Patent: WO2006/48889, 2006, A1, . Location in patent: Page/Page column 18
[5] Patent: US4985557, 1991, A,
[6] Patent: CN103360410, 2016, B, . Location in patent: Paragraph 0019; 0030; 0031
[7] Patent: CN107118223, 2017, A, . Location in patent: Paragraph 0019; 0023; 0027
[8] Patent: CN107163063, 2017, A, . Location in patent: Paragraph 0018; 0019; 0022; 0023; 0026; 0027
[9] Patent: CN107141306, 2017, A, . Location in patent: Paragraph 0019; 0023; 0027

2
[ 2749-11-3 ]
[ 141-78-6 ]
[ 94695-48-4 ]
[ 109-94-4 ]
[ 106939-34-8 ]

Yield	Reaction Conditions	Operation in experiment
99.4%	Stage #1: With sodium hydride In toluene Stage #2: at 20℃; Reflux Stage #3: With potassium fluoride In N,N-dimethyl-formamideReflux	step 1, 2.6 g of sodium hydride, 50 ml of toluene and 8.8 g of ethyl acetate were sequentially placed in the reaction flask.Stir until it is gray and turbid.Then, 8.8 g of ethyl formate was slowly added dropwise, and stirring was continued while the bubbles were released.After the reaction was completed, it was filtered under reduced pressure, and the cake was dried in vacuo.Obtaining white formyl ethyl acetate sodium salt; Step 2. Add to the flask containing 50 ml of tolueneSodium formylacetate sodium salt 5.5gAnd ZIF-67ZnCoZIF catalyst 1.5g,Slowly add 7.7 g of 2,3,4,5-tetrafluorobenzoyl chloride at room temperature.After the reaction is completed, slowly add S-(+)-2-aminopropanol dropwise3.2g, heated to reflux,After the reaction is completed, a water layer is added, the water layer is extracted with toluene, the organic layers are combined, and toluene is distilled off to obtain a preliminary product; Step 3.The obtained initial product was slowly added dropwise to 30 ml of a DMF solution containing 5.8 g of KF, stirred, heated to reflux, and azeotropically dehydrated.After completion of the reaction, the solvent was evaporated, and washed with water to give a brown-yellow viscous solid.Drying to get the intermediate(S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7-hydropyrido[1,2,3-de][1,4 ] Benzoxazine-6-carboxylic acid ethyl ester.

Reference： [1] Patent: CN108440562, 2018, A, . Location in patent: Paragraph 0008; 0010-0015; 0016-0018; 0029

3
[ 106939-42-8 ]
[ 87-13-8 ]
[ 106939-34-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With ethyl phosphate In diethyl ether	Example 6 Ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate A mixture of 2.66 g of (S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine, as such produced in example 4, and 3.11 g of diethyl ethoxymethylenemalonate was stirred under a nitrogen atmosphere and heated at 140-145°C for 2 hours. After cooling 20 g of ethyl polyphosphate were added and the mixture was again heated at 140-145°C for 1 hour. After cooling the reaction mixture was poured into ice water and extracted three times with chloroform. The collected organic layers were washed with 5percent sodium carbonate solution and water. The organic solution was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Diethyl ether was added to the residue and the crystalline material was filtered, washed and dried to afford 3.1g of title product (70percent). M.p. 254-255°C.[α] [22/D ] = -64.8° (c=0.25, acetic acid). ¹H NMR (CF₃COOD, ppm) delta = 1.19 (tr, 3H), 1.44 (d, 3H), 4.38 (m, 4H), 4.84 (m, 1H), 7.75 (dd, 1H), 8.97 (s, 1H).

Reference： [1] Patent: EP368410, 1990, A3,
[2] Patent: US4985557, 1991, A,

4
[ 110548-02-2 ]
[ 106939-34-8 ]

Reference： [1] Patent: WO2006/48889, 2006, A1, . Location in patent: Page/Page column 16-17

5
[ 113472-54-1 ]
[ 106939-34-8 ]

Reference： [1] Chemical and pharmaceutical bulletin, 1987, vol. 35, # 5, p. 1896 - 1902

6
[ 924-99-2 ]
[ 106939-34-8 ]

Reference： [1] Patent: CN103360410, 2016, B,
[2] Patent: CN107118223, 2017, A,
[3] Patent: CN107163063, 2017, A,
[4] Patent: CN106565745, 2017, A,
[5] Patent: CN107141306, 2017, A,

7
[ 94695-48-4 ]
[ 106939-34-8 ]

Reference： [1] Patent: CN107118223, 2017, A,
[2] Patent: CN107163063, 2017, A,
[3] Patent: CN106565745, 2017, A,
[4] Patent: CN107141306, 2017, A,

8
[ 138998-47-7 ]
[ 106939-34-8 ]

Reference： [1] Patent: CN107118223, 2017, A,
[2] Patent: CN107163063, 2017, A,
[3] Patent: CN107141306, 2017, A,

9
[ 91040-39-0 ]
[ 106939-34-8 ]

Reference： [1] Chemical and pharmaceutical bulletin, 1987, vol. 35, # 5, p. 1896 - 1902

10
[ 100986-87-6 ]
[ 106939-34-8 ]

Reference： [1] Chemical and pharmaceutical bulletin, 1987, vol. 35, # 5, p. 1896 - 1902

11
[ 100986-91-2 ]
[ 106939-34-8 ]

Reference： [1] Chemical and pharmaceutical bulletin, 1987, vol. 35, # 5, p. 1896 - 1902

12
[ 106939-31-5 ]
[ 106939-34-8 ]

Reference： [1] Chemical and pharmaceutical bulletin, 1987, vol. 35, # 5, p. 1896 - 1902

[ 106939-34-8 ] Synthesis Path-Downstream 1~87

1
[ 106939-34-8 ]
[ 100986-89-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With hydrogenchloride; acetic acid;	Example 7 (S)-(-)-9,10-Difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid A mixture of 3.2 g of ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate, 32 ml of acetic acid and 8 ml of conc. hydrochloric acid was heated at reflux temperature for 3 hours. After cooling to 5C the precipitated crystals were collected by filtration and washed successively with water, ethanol and diethyl ether. After drying 2.64 g of title product were obtained. Yield: 91%. M.p. >300C. [alpha] [22/D ] = -64.9 (c=1.0, DMSO). 1H NMR (CF3COOD, ppm) delta = 1.46 (d, 3H), 4.38 (ABq, 2H), 4.85 (m, 1H), 7.75 (dd, 1H), 9.04 (s, 1H).
	With hydrogenchloride; water; In acetic acid; at 75 - 80℃; for 6h;	Into a 1 L 3 neck round bottom flask equipped with mechanical stirrer, thermometer socket and condenser, 125 ml water, 125 ml concentrated hydrochloric acid, 250 ml acetic acid and 100 g (0.32 mol) (-)-ethyl-9,10-difluoro-2,3-dihiydro-3-methyl-7-oxo-7H' pyrido [l,2,3-cfe]-l,4-benzoxazine-6-carboxylate were charged. The contents were heated to 75-800C and maintained for 6 hrs at 75-80C. After 6 hrs the conversion of reaction was monitored by TLC. The reaction mixture was cooled to 15-20C and maintained for 1 hr. at 15-20C. Material was filtered and washed with water. Wet material was slurred with water at 45-500C and filtered. Dried at 70-80C to give 80 g of (-)9, 10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H"-pyrido[l ,2,3-fe]- 1 ,4-benzoxazine-6- carboxylic acid. EtaPLC purity : 99.33%.
	With hydrogenchloride; In acetic acid;	EXAMPLE 15 Preparation of S-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido-[1,2,3-de][1,4]Benzoxazine-6-Carboxylic Acid In 150 ml of acetic acid was dissolved 19.5 g of the ester compound obtained in Example 14, and 400 ml of concentrated hydrochloric acid was added thereto, followed by refluxing for 3 hours. After cooling, the precipitated crystals were collected by filtration, washed successively with water, ethanol and diethyl ether and dried to obtain 16.2 g of the corresponding carboxylic acid having a melting point of 300 C or higher. [alpha]D =-65.6 (c=0.985, DMSO).

	With sulfuric acid; acetic acid; In water; for 4h;Reflux;	500ml three-neck flask was added 64g (), 210ml glacial acetic acid, 60ml water, 13ml of concentrated sulfuric acid. Stirring warming up toReflux. After () were dissolved under reflux insulation 4h.Bi insulation, vacuum recovery of glacial acetic acid, keeping the temperature <80 , vacuum <-. 09MPa. No liquid effluent to stop,300ml of water was added to the residue, cooled with stirring to 30 , filtered, the filter cake was washed well with water until the filtrate was neutral, filteredThat cake was dried (). Dry goods weight of 55.5g, a yield of 111% by weight.
4.81 g	With sulfuric acid; acetic acid; In N,N-dimethyl-formamide; for 1h;Reflux; Green chemistry;	The residue after the recovery of DMF was added acetic acid at room temperature, 65ml of water was stirred, dropping sulfuric acid, dropping end, heated to reflux, incubated for 1 hour, cooled to room temperature, filtered. The filter cake was washed with 65ml water and dried to obtain 43.98g of levoxycyclic acid with a content of 96.22%. Acetic acid was swirled back by acetic acid and swirled to dryness. The filtrate was washed with water, filtered, and filtered to give 4.81g g levulinic acid, content 61.28%. Recycled water and acetic acid can be recycled respectively to reduce the amount of waste and the original cost. In terms of tetrafluorobenzoyl chloride, the overall yield for the four steps was 87%.
	With sulfuric acid; acetic acid; In water; at 20℃; for 3h;Reflux;	Potassium carbonate, DMF was added to a three-necked flask, heated to 150 C,DMF was slowly added dropwise to set the volume of liquid, dropping 4 hours, incubated for 4 hours,Thermal recovery of potassium carbonate, potassium fluoride salt applied. DMF recovery DMF recovery application.The resulting intermediate directly into the next hydrolysis.The residue after the recovery of DMF was added acetic acid at room temperature, 65ml of water was stirred, dropping sulfuric acid, dropping end, heated to reflux,Insulation for 3 hours, cooled to room temperature, filtered. The filter cake was washed with 65ml water and dried to give 46.54g levulinic acid at a content of 96.40%. The acetic acid solution was swirled to recover the acetic acid and then swirled to dryness. The filter cake was washed with water, stirred and cooled, and filtered to obtain 4.73 g levulinic acid, content 61.21%. Recycled water and acetic acid can be recycled respectively to reduce the amount of waste and the original cost. In terms of tetrafluorobenzoyl chloride, the overall yield for the four steps was 86%.
	With sulfuric acid; acetic acid; In N,N-dimethyl-formamide; for 1h;Reflux;	The residue was recovered at room temperature was added acetic acid in DMF,Stir in 65ml water, add sulfuric acid dropwise,Heat to reflux, keep warm for 1 hour,Cool to room temperature and filter.Wash the filter cake with 65ml water and dry it.43.98g of L-Oxalic acid,Content 96.22%,The acetic acid filtrate was rotovaped to recover aceticRotate to dryness, add the previous filter cake washed phase,Stir and cool, filter,Obtained 4.81 g of L-Oxalic acid,Content 61.28%.The recovered aqueous phase and acetic acid can be recycled separately.To reduce the volume of waste and the original cost.Calculated with tetrafluorobenzoyl chloride,The four-step total yield was 87%.
	With water; sodium hydroxide; In ethanol; at 20℃; for 1h;	To compound A1.3 (2.018 g, 6.53 mmol, i eq) was added ethanol (20 mL) and a i% w/v aqueous solution of sodium hydroxide (20 mL) and the suspension stirred at room temperature for one hour. The mixture was then acidified to pH 3 using a iM hydrochloric acid and a few drops of 37% hydrochloric acid, vacuum filtered and washed with distilled water ( x 100 mL). Powder was collected and dried for i hourmore on a Schlenk line to afford the crude A1.4 (1.599 g, 87.2% yield)as an off white solid. This material was used in subsequent reactions without further purification. 1H NMR (400 MHz, DMSO-c16) 6 14.80 (s, iH, H2), 9.09 (s, iH, H3), 7.80 (dcl, J = 7.79,10.36 Hz, iH, Hi), 5.02 (q, J = 6.48 Hz, iH, H5), 4.64 - 4.73 (m, iH, H4), 4.44 - 4.55(m, iH, H4), 1.47 (ci, J = 6.79 Hz, 3H, H6); 13C NMR (100 MHz, DMSO-c16) 6 176.4,176.4, 165.6, 150.2, 150.1, 147.7, 147.6, 147.1, 143.0, 142.8, 140.5, 140.3, 136.0, 135.9,135.9, 135.8, 125.3, 125.3, 121.4, 121.4, 121.3, 121.3, 107.7, 103.6, 103.4, 68.9, 55.0, 17.8;1F NMR (400 MHz, DMSO-c16) 6 -135.9 (ci, J = 22.47 Hz, iF), -151.0 (ci, J = 22.48 Hz,iF); LC-MS (Method B) Retention time 3.11 minutes, purity = 81%, Found 282.1[M+H] calculated for C13H9F2N04 282.22 [M+H] Rf 0.30, streaks (ioo% acetone);[a]259D, -20 (c = 0.088, CH2C12)

Reference： [1]Patent: EP368410,1990,A3
[2]Chemical and pharmaceutical bulletin,1987,vol. 35,p. 1896 - 1902
[3]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 4213 - 4216
[4]Patent: WO2006/48889,2006,A1 .Location in patent: Page/Page column 18
[5]Patent: US4985557,1991,A
[6]Patent: CN103360410,2016,B .Location in patent: Paragraph 0019; 0030; 0031
[7]Patent: CN107118223,2017,A .Location in patent: Paragraph 0019; 0023; 0027
[8]Patent: CN107163063,2017,A .Location in patent: Paragraph 0018; 0019; 0022; 0023; 0026; 0027
[9]Patent: CN107141306,2017,A .Location in patent: Paragraph 0019; 0023; 0027
[10]Patent: WO2018/220365,2018,A1 .Location in patent: Page/Page column 77; 78

2
[ 113472-54-1 ]
[ 106939-34-8 ]

Reference： [1]Chemical and pharmaceutical bulletin,1987,vol. 35,p. 1896 - 1902

3
[ 106939-34-8 ]
[ 853336-60-4 ]

Reference： [1]Tetrahedron Letters,2005,vol. 46,p. 3855 - 3858

4
[ 106939-34-8 ]
(R)-9-(4-{4-[(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 4213 - 4216

5
[ 91040-39-0 ]
[ 106939-34-8 ]

Reference： [1]Chemical and pharmaceutical bulletin,1987,vol. 35,p. 1896 - 1902

6
[ 100986-87-6 ]
[ 106939-34-8 ]

Reference： [1]Chemical and pharmaceutical bulletin,1987,vol. 35,p. 1896 - 1902

7
[ 100986-91-2 ]
[ 106939-34-8 ]

Reference： [1]Chemical and pharmaceutical bulletin,1987,vol. 35,p. 1896 - 1902

8
[ 106939-31-5 ]
[ 106939-34-8 ]

Reference： [1]Chemical and pharmaceutical bulletin,1987,vol. 35,p. 1896 - 1902

9
[ 110548-02-2 ]
[ 106939-34-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;	into a 3 lit 3 neck round bottom flask is provided with a mechanical stirrer, thermometer socket and a condenser, DM water (1265 ml),diethyl-253,4,5-tetrafluoro benzoyl malonate 790.58 g (2.35 mol) and para toluene sulphonic acid (3.4 g) were charged. The contents of the flask were refluxed (80-90C) under stirring and maintained at the same temperature for 3 hrs. After completion of 3 hrs. maintenance, TLC was checked for ketodiester content. If ketodiester content is more than 1.0%, then para toluene sulphonic acid (3.4 g)was charged into the reaction mixture and maintained 3 hrs. at reflux temperature. TLC was checked for ketodiester content present in the reaction mixture. If ketodiester content was more than 1.0% then again para toluene sulphonic acid (3.4 g) was charged and refluxed for 3 hrs. same thing was repeated till TLC shows the content of ketodiester was below 1.0%. The reaction mixture was cooled to 30-35C and separated both layers. Aqueous layer was extracted with toluene (2x500 ml) twice. Organic layers were mixed and washed with 5% sodium bicarbonate solution (500 ml) following by DM water (2x500 ml) twice. The aqueous layer of second washing was checked for sulfate test. If sulfates present the organic layer was again washed with DM water (500 ml) till sulfates absent. Organic layer was concentrated under vacuum (650-750mm/Hg) at 60-65C to give 608 g of ethyl-2,3 ,4,5-tetrafluorobenzoyl acetate (ketoester). To ketoester without further purification, 544 ml (5.76 mol) Acetic anhydride EPO <DP n="18"/>and 511 g (3.45 mol) triethyl orthoformate were charged into above reaction mixture. The contents of the RB flask were heated to 120-1250C and maintained for 4 hrs. at 120-1250C, low boilers were collected at receiver end while maintaining the reaction at 120-1250C. After 4 hrs maintenance, the contents of the RJB flask was cooled to 90-1000C, vacuum (650-700mm/Hg) was applied to the reaction mixture and solvent was distilled off upto mass temperature 125C. The reaction mixture was cooled to 80-85C and 250 ml toluene was charged. Again vacuum (650-700mni/Hg) was applied and solvent was distilled off upto 125C. The distillation was continued at 125C till distillation ceases. The reaction mixture was cooled to 30-350C. 800 ml methylene chloride was charged and further cooled to 0-50C while stirring. 133 g (1.77 mol) (S)-(+)-2-amino-l-propanol with 270 ml methylene chloride was charged into reaction mixture at 0-50C over a period of 1-2 hrs. After addition, reaction mixture was allowed to 30-350C gradually and maintained at 30-350C for 2 hrs. Reaction mixture was washed with water twice and dried with anhydrous sodium sulfate. Meanwhile 850 ml N5N- dimethyl formamide, 444 g potassium carbonate were charged into another flask provided with mechanical stirrer and distillation set-up. The contents were stirred and heated to 120C. The methylene chloride layer was added during 2 hrs. at 1200C and methylene chloride was collected at receiver end. Stirring was continued for another 30 minutes the reaction mixture was cooled to 65-700C. Vacmxm (650-700 mm of Hg) was applied to the reaction mixture and distilled off the solvent till half quantity of charged N,N-dimethyl formamide was collected. The reaction mixture was cooled to 20-250C. DM water (4 L) was charged into the reaction mixture while stirring. Stirring was continued for 1 hr. at 25-300C and filtered. Material was washed with DM water (500 ml) and suck dried. 650 ml acetone and wet material were charged into the flask. The contents of the flask were cooled to 0-5C and maintained 30 minutes at 0-50C. Material was filtered and washed with 650 ml acetone. Th.e material was dried at 70-750C to give 315 g (-)-ethyl-9s10-difluoro-2,3-dihydro-3-rnethyl-7-oxo-7H-rhoyrido- [l,2,3-de]-l,4-benzoxazine-6-carboxylate. EtaPLC purity : 99.23/.

Reference： [1]Patent: WO2006/48889,2006,A1 .Location in patent: Page/Page column 16-17

10
[ 106939-42-8 ]
[ 87-13-8 ]
[ 106939-34-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With ethyl phosphate; In diethyl ether;	Example 6 Ethyl (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate A mixture of 2.66 g of (S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine, as such produced in example 4, and 3.11 g of diethyl ethoxymethylenemalonate was stirred under a nitrogen atmosphere and heated at 140-145C for 2 hours. After cooling 20 g of ethyl polyphosphate were added and the mixture was again heated at 140-145C for 1 hour. After cooling the reaction mixture was poured into ice water and extracted three times with chloroform. The collected organic layers were washed with 5% sodium carbonate solution and water. The organic solution was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Diethyl ether was added to the residue and the crystalline material was filtered, washed and dried to afford 3.1g of title product (70%). M.p. 254-255C.[alpha] [22/D ] = -64.8 (c=0.25, acetic acid). 1H NMR (CF3COOD, ppm) delta = 1.19 (tr, 3H), 1.44 (d, 3H), 4.38 (m, 4H), 4.84 (m, 1H), 7.75 (dd, 1H), 8.97 (s, 1H).
	With sodium chloride; sulfuric acid; sodium hydrogencarbonate; potassium carbonate; In ice-water; diethyl ether; acetic anhydride;	EXAMPLE 14 Preparation of Ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (XII) To 15.8 g of the (S)-(-)-benzoxazine derivative as obtained in Example 13 was added 24.0 g of diethyl ethoxymethylenemalonate, and the mixture was stirred at 130 to 140 C. for 1 hour under reduced pressure. After cooling, the reaction mixture was dissolved in 50 ml of acetic anhydride, and 80 ml of a mixture of acetic anhydride and concentrated sulfuric acid (2:1 by volume) was slowly added dropwise to the solution while stirring under ice-cooling. After continuing the stirring for additional one hour at room temperature, the reaction mixture was stirred in a hot bath of 50 to 60 C. for 30 minutes. Ice-water was added to the reaction mixture, and powdery potassium carbonate was added thereto for neutralization. The mixture was extracted with chloroform, and the extract was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The chloroform was removed by distillation, and to the residue was added diethyl ether. The crystals thus formed were collected by filtration to give 20.0 g of the titled compound having a melting point of 257-258 C. [alpha]D =-68.1 (c=0.250, acetic acid).

Reference： [1]Patent: EP368410,1990,A3
[2]Patent: US4985557,1991,A

11
[ 11113-50-1 ]
[ 108-24-7 ]
[ 106939-34-8 ]
bis(acetato-O)[(3S)-9,10-difluoro-2,3-dihydro-3-methyl-7-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylato-O⁶,O⁷]boron [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		Boric acid (48.00 g) was added to a dry three-necked flask,Acetic anhydride (220ml)And zinc chloride (0.88 g),Stirred at room temperature for 30 min,(S) -9,10-difluoro-3-methyl-7-carbonyl-3,7-dihydro-2H- [1,4] (1) (80.00 g) was added to the above solution at 60 C for 16 h and concentrated under reduced pressure. To the concentrate was slowly added dichloromethane (0.50 g) (2 x 1400 ml), the organic layer was washed with NaCl solution, dried over anhydrous Na2S04, filtered and the filtrate was concentrated to give a solid. Then, 900 ml of anhydrous ether was added, stirred for 30 min, filtered, solid vacuum Dried to give bis (acetyl-O) [(3S) _9,10-di-2,3-dihydro-3'methyl_7_dihydro-7H-pyridine [1,2,3-de] [1 , 4] benzoxazine-6-carboxylate-06,07] boron (2) 87.67 g, yield 83%.

Reference： [1]Chemical and Pharmaceutical Bulletin,2019,vol. 67,p. 481 - 486
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 3238 - 3249
[3]Patent: CN104098588,2016,B .Location in patent: Paragraph 0072

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[ 106939-34-8 ]
(S)-9-fluoro-3-methyl-7-oxo-10-((1r,4s)-4-(phenoxymethyl)cyclohexanecarboxamido)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid [ No CAS ]