[ CAS No. 28691-47-6 ] {[proInfo.proName]}

Name: 28691-47-6|Benzo[d]isoxazole-3-carboxylic acid|95%
Brand: Ambeed
SKU: A288343
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Quality Control of [ 28691-47-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 28691-47-6 ]

CAS No. :	28691-47-6	MDL No. :	MFCD06659786
Formula :	C₈H₅NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VPYXATIIMHQAPR-UHFFFAOYSA-N
M.W :	163.13	Pubchem ID :	2735445
Synonyms :

Calculated chemistry of [ 28691-47-6 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	40.97
TPSA :	63.33 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.18 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.35
Log Po/w (XLOGP3) :	1.57
Log Po/w (WLOGP) :	1.53
Log Po/w (MLOGP) :	0.72
Log Po/w (SILICOS-IT) :	1.25
Consensus Log Po/w :	1.28

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.33
Solubility :	0.764 mg/ml ; 0.00468 mol/l
Class :	Soluble
Log S (Ali) :	-2.51
Solubility :	0.504 mg/ml ; 0.00309 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.28
Solubility :	0.86 mg/ml ; 0.00527 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.26

Safety of [ 28691-47-6 ]

Signal Word:	Danger	Class:	4.1
Precautionary Statements:	P240-P210-P241-P264-P280-P302+P352-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313	UN#:	1325
Hazard Statements:	H315-H319-H228	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 28691-47-6 ]

* 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 [ 28691-47-6 ]
Downstream synthetic route of [ 28691-47-6 ]

[ 28691-47-6 ] Synthesis Path-Upstream 1~4

1
[ 57764-49-5 ]
[ 28691-47-6 ]

Reference： [1] Patent: EP1346982, 2003, A1,
[2] Journal of the American Chemical Society, 1975, vol. 97, p. 7305 - 7312
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2308 - 2314
[4] Patent: WO2005/63767, 2005, A2, . Location in patent: Page/Page column 44-45
[5] Patent: WO2005/111038, 2005, A2, . Location in patent: Page/Page column 66-67
[6] Patent: US2005/250808, 2005, A1, . Location in patent: Page/Page column 40
[7] Patent: US4853027, 1989, A,

2
[ 57764-48-4 ]
[ 28691-47-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2308 - 2314
[2] Journal of the American Chemical Society, 1975, vol. 97, p. 7305 - 7312

3
[ 3740-52-1 ]
[ 28691-47-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2308 - 2314

4
[ 31912-02-4 ]
[ 28691-47-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 15, p. 2308 - 2314

[ 28691-47-6 ] Synthesis Path-Downstream 1~36

1
[ 28691-47-6 ]
[ 611-20-1 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1929,vol. <2> 122,p. 243

2
methyl benzo[d]isoxazole-3-carboxylate [ No CAS ]
[ 28691-47-6 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1929,vol. <2> 122,p. 243
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6122 - 6126

3
[ 28691-47-6 ]
[ 28691-51-2 ]

Reference： [1]Journal of the American Chemical Society,1975,vol. 97,p. 7305 - 7312

4
[ 57764-49-5 ]
[ 28691-47-6 ]

Yield	Reaction Conditions	Operation in experiment
57%	With sulfuric acid;	(Step 3) Synthesis of benzo(d)isoxazole-3-carboxylic acid To ethyl benzo (d)isoxazole-3-carboxylate (2.0 g, 10.5 mmol) was added 50 ml of 70% H2SO4. The mixture was heated at 80ØC for 4 hours. The reaction mixture was poured in ice, followed by extraction with ether. The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, whereby benzo(d)isoxazole-3-carboxylic acid (980 mg, 57%) was obtained as a colorless solid. 1H-NMR (DMSO-d6) delta: 7.53 (dt, J=1.0,7.1Hz, 1H), 7.74 (dt, J=1.2,7.1Hz, 1H), 7.89 (dd, J=1.0,8.5Hz, 1H), 8.10 (dt, J=1.0,8.1Hz, 1H).
	With sodium hydroxide; water;	10% Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0. 081mol) in ethanol (300ml) at 0 C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96%). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A. Literature reference: Angell, R. M.; Baldwin, I. R.; Bamborough, P.; Deboeck, N. M.; Longstaff, T.; Swanson, S. W004010995A1 The following acid was prepared using this method: 1,2-Benzisoxazole-3-carboxylic acid.
	With sodium hydroxide;	Diethyl malonate (12.6 g, 79 mmol) was added to a suspension of sodium hydride (3.16 g, 132 mmol) in dimethylsulfoxide (60 ml) over 30 min. The temperature of the reaction rose to 60 C and the mixture clarified. 1,4-Dibromo-2-nitrobenzene (10 g, 36.0 mmol) was added and the solution was maintained for 2 h at 100 C. The reaction mixture was allowed to cool to rt and was poured into ice (300g-400g). The precipitated solids were isolated by filtration and dried to provide 11.0 g of the product (89%). The ester (11.0 g, 32.0 mmol) was diluted with a 2 N solution of sodium hydroxide (32 mL, 63 mmol) and the reaction mixture was maintained at room temperature for 16 h. The aqueous layer was extracted with dichloromethane (20 mL) and was acidified. The precipitated solids were isolated by filtration and dried to provide 7.00 g of the acid (89%). Sulfuric acid (1 mL) was added to a solution of the acid (7.00 g, 27.0 mmol) in ethanol (60 ml). The reaction mixture was warmed to reflux, maintained for 2 h, and was concentrated under reduce pressure. The residue was partitioned between ethyl acetate (250 mL) and saturated sodium carbonate (50 mL) and the organic layer was washed with saturated sodium carbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to provide 8.00 g (98%) of the ester as a liquid. Under N2 atmosphere, sodium ethylate was formed with sodium (33.5 g, 1.46 mol) in ethanol (1.0 L). Isoamylnitrite (225 mL) was added to a solution of the ester (420 g, 1.46 mol) in ethanol (3 L) in a 10 L three-necked round bottom flask and the mixture was warmed to 60 C. A solution of sodium ethoxide, prepared from sodium metal (33.5 g, 1.46 mmol) in ethanol (1 L) was added dropwise and the reaction mixture was maintained for 2 h. The reaction mixture was allowed to cool to rt and was neutralized with 2 N hydrochloric acid. The reaction mixture was extracted with ethyl acetate (4 x 2L) and the combined organic layers were washed with water (2 x 1 L) and brine (2 x 1 L) and dried (sodium sulfate). The residue was purified by chromatography (1/1 to 0/1 hexane/ethyl acetate) to provide 110 g of the product ( 28%). 10% Palladium on carbon (1.5g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20g, 0.081mol) in ethanol (300ml) at 0 C under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed'by filtration through Celite. The filter cake was washed with ethanol (3 x 50 mL) and the filtrates were concentrated. The residue was- dissolved in dichloromethane (200 mL) and the solution was washed with water (4 x 50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96%). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A.

	With sodium hydroxide; In water;	10% Palladium on carbon (1.5 g) and triethylamine (7.5 g, 82.4 mmol) were added to a solution of ethyl 6-bromobenzisoxazole-3-carboxylate (20 g, 0.081 mol) in ethanol (300ml) at 0 C. under an atmosphere of nitrogen. The nitrogen atmosphere was removed by evacuation and replaced with hydrogen gas, and the reaction mixture was maintained for 1 hour. The hydrogen atmosphere was removed by evacuation and replaced with nitrogen gas, and the palladium removed by filtration through Celite. The filter cake was washed with ethanol (3×50 mL) and the filtrates were concentrated. The residue was dissolved in dichloromethane (200 mL) and the solution was washed with water (4×50 mL), dried (sodium sulfate) and evaporated to provide 13.0 g of the product as a yellow solid (96%). The ester was saponified using sodium hydroxide to provide the acid. The acid was coupled with the bicyclobase according to procedure A.
	With sulfuric acid; In water;	8.6 g of 3B was mixed with 175 ml of 70% sulfuric acid and the mixture was heated at 80 C. for 4 hours. The mixture was cooled, 200 ml of cold water was added, the mixture was extracted with ether, and the extract was dried (Na2 SO4) and stripped of solvent. The residue was triturated with pentane, and the solid was collected and dried to give 3-benzisoxazolecarboxylic acid (3C), as a white solid, m.p.: 132-134 C. (with decomposition).
	With sulfuric acid; at 80℃; for 3.5h;	Compound 41-d (3.32 g, 17.37 mmol, 1.00 eq) was dissolved in 70% sulfuric acid solution (80.00 mL), and the resulting reaction solution was stirred at 80C for 3.5 hours. After the reaction was completed, the reaction solution was added with 150 mL of ice water, and extracted with ethyl acetate (300 mL). The organic phase was washed with water (100 mL 3 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the product of compound 41-e (1.50 g, crude) as a gray solid, which was used directly in the next step without purification. 1H NMR (400 MHz, DMSOd6) delta = 8.09 (d, J=8.03 Hz, 1H), 7.89 (d, J=8.53 Hz, 1H), 7.74 (t, J=7.53 Hz, 1H), 7.52 (t, J=7.53 Hz, 1H).

Reference： [1]Patent: EP1346982,2003,A1
[2]Journal of the American Chemical Society,1975,vol. 97,p. 7305 - 7312
[3]Journal of Medicinal Chemistry,1994,vol. 37,p. 2308 - 2314
[4]Patent: WO2005/63767,2005,A2 .Location in patent: Page/Page column 44-45
[5]Patent: WO2005/111038,2005,A2 .Location in patent: Page/Page column 66-67
[6]Patent: US2005/250808,2005,A1 .Location in patent: Page/Page column 40
[7]Patent: US4853027,1989,A
[8]Patent: EP3456711,2019,A1 .Location in patent: Paragraph 0300; 0304

5
[ 28691-47-6 ]
[ 87571-88-8 ]
Benzo[d]isoxazole-3-carboxylic acid ((1R,3R,5S)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amide; hydrochloride [ No CAS ]

Reference： [1]Arzneimittel-Forschung/Drug Research,1993,vol. 43,p. 913 - 918

6
[ 28691-47-6 ]
[ 120-29-6 ]
Benzo[d]isoxazole-3-carboxylic acid (1R,3R,5S)-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester [ No CAS ]

Reference： [1]Arzneimittel-Forschung/Drug Research,1993,vol. 43,p. 913 - 918

7
[ 28691-47-6 ]
[ 943036-14-4 ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 2308 - 2314
[2]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2347 - 2350
[3]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6122 - 6126
[4]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6346 - 6349

8
[ 28691-47-6 ]
[ 129295-49-4 ]
Benzo[d]isoxazole-3-carboxylic acid (1-benzyl-4-methyl-[1,4]diazepan-6-yl)-amide [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1995,vol. 43,p. 1912 - 1930

9
[ 28691-47-6 ]
[ 129295-47-2 ]
Benzo[d]isoxazole-3-carboxylic acid (1,4-dimethyl-[1,4]diazepan-6-yl)-amide [ No CAS ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1995,vol. 43,p. 1912 - 1930

10
[ 28691-47-6 ]
[ 785024-25-1 ]
(S)-2-[(Benzo[d]isoxazole-3-carbonyl)-amino]-N¹-[(1S,2S)-1-benzyl-3-((2S,4S)-2-tert-butylcarbamoyl-4-chloro-pyrrolidin-1-yl)-2-hydroxy-3-oxo-propyl]-succinamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,1996,vol. 4,p. 1365 - 1377

11
[ 28691-47-6 ]
[ 611-20-1 ]
[ 124-38-9 ]

Reference： [1]Journal of Organic Chemistry,1997,vol. 62,p. 7305 - 7309
[2]Journal of Organic Chemistry,1997,vol. 62,p. 7305 - 7309

13
[ 3740-52-1 ]
[ 28691-47-6 ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 2308 - 2314
[2]Patent: EP3456711,2019,A1

14
[ 31912-02-4 ]
[ 28691-47-6 ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 2308 - 2314
[2]Patent: EP3456711,2019,A1

15
[ 57764-48-4 ]
[ 28691-47-6 ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 2308 - 2314
[2]Journal of the American Chemical Society,1975,vol. 97,p. 7305 - 7312
[3]Patent: EP3456711,2019,A1

17
[ 28691-47-6 ]
[ 6638-79-5 ]
[ 894789-40-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;	A mixture of benzisoxazole acid a (1.23 g, 7.5 mmol) prepared according to the procedures described by Kemp et al. (7. Am. Chem. Soc. 1975, 97, 7305-7312), amine HCl salt (736 mg, 7.5 mmol), EDC ( 1.44 g, 7.5 mmol), and DIPEA (1.2 mL, 6.7 mmol) in MeCN (50 mL) was stirred at RT for overnight. It was concentrated in vacuo, dissolved in EtOAc (200 mL), washed with 0.5 N HCl and water, dried (MgSO4), and concentrated to afford 1.4 g (88%) of benzisoxazole amide b as an off white solid.
	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 20h;	11.3 N-Methoxy-N-methylbenzo[d] isoxazole-3-carboxamide 1.0 g of <strong>[28691-47-6]benzo[d]isoxazole-3-carboxylic acid</strong>, 0.7 g of N,O-dimethylhydroxylamine hydrochloride, 2.3 g of 1-(3-dimethylaminopropyl-3-ethylcarbodiimide) hydrochloride and 1 ml of pyridine in 40 ml of tetrahydrofuran are placed in a round-bottomed flask. The mixture is stirred at ambient temperature for 20 h. The mixture is concentrated and the residue is taken up in 40 ml of ethyl acetate and 20 ml of water. The organic phase is washed with 20 ml of a 1N solution of sodium hydroxide and 20 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 1.1 g of compound are obtained. 1H NMR (CDCl3, delta in ppm): 3.4 (s, 3H); 3.8 (s, 3H); from 7.25 to 7.55 (m, 3H); 7.95 (d, 1H). M+H=207.

Reference： [1]Patent: WO2006/69063,2006,A1 .Location in patent: Page/Page column 89
[2]Patent: US2011/65727,2011,A1 .Location in patent: Page/Page column 18

18
[ 3405-77-4 ]
[ 28691-47-6 ]
[ 124999-24-2 ]

Yield	Reaction Conditions	Operation in experiment
		3 was prepared, as a white solid, m.p. 225.5-228 C., from 3C, by procedures described in Example 1 for preparing 1 from 1B.

Reference： [1]Patent: US4853027,1989,A

19
ethylene dichloride hydrochloride [ No CAS ]
[ 441717-78-8 ]
[ 28691-47-6 ]
[4-(benzo[d]-3-isoxazolylcarboxamido)-5-chloro-2-fluorophenyl]acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	With dmap; sodium hydroxide; benzotriazol-1-ol; In tetrahydrofuran; hydrogenchloride; N,N-dimethyl-formamide;	(Step 4) Synthesis of (4-((benzo(d)isoxazole-3-carbonyl)amino)-5-chloro-2-fluorophenylacetic acid Benzo(d)isoxazole-3-carboxylic acid (475 mg, 2.91 mmol), ethyl 4-amino-5-chloro-2-fluorophenylacetate (675 mg, 2.91 mmol), HOBt (747 mg, 5.53 mmol), EDC HCl (837 mg, 4.37 mmol) and DMAP (catalytic amount) were dissolved in DMF (15 ml). The resulting solution was stirred for 24 hours at room temperature. The reaction mixture was poured in 1M HCl, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (middle pressure chromatography system from Yamazen, chloroform, 8 ml/min, phi 15 mm x 300 mm). The ester thus obtained was added with THF (30 ml) and 0.25M NaOH (17.5 ml, 4.37 mmol), followed by stirring at room temperature for 18 hours. The reaction mixture was poured in 1M HCl to acidify the mixture. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (4-((benzo(d)isoxazole-3-carbonyl)amino) -5-chloro-2-fluorophenyl)acetic acid (100 mg, 10%) as a white solid. 1H-NMR (DMSO-d6) delta: 3.66 (s, 2H), 7.58 (t, J=8.0Hz, 1H), 7.62 (d, J=7.1Hz, 1H), 7.68 (d, J=11.4Hz, 1H), 7.79 (d, J=9.0Hz, 1H), 8.15 (d, J=8.8Hz, 1H), 10.61 (d, J=4.2Hz, 1H). MS (ESI) m/z 349 (M+1)+.

Reference： [1]Patent: EP1346982,2003,A1

20
[ 28691-47-6 ]
[ 52727-57-8 ]
[ 1356854-62-0 ]

Yield	Reaction Conditions	Operation in experiment
50%		[1,] [2-BENZISOXAZOLE-3-CARBOXYLIC] acid (815 mg, 5.0 mmol) was suspended in dichloroethane (DCE) (10 mL). Oxalyl chloride (0.545 [ML,] 6.25 mmol) was added followed by a catalytic amount of DMF. The reaction was stirred at room temperature for 5 hrs. The solvent was removed in vacuo, and the resulting oil was redissolved in [DCB] (10 mL). Methyl [2-AMINO-5-BROMOBENZOATE] was added dropwise as a solution in [THF/PYRIDINE] [(5 ML/2 ML).] The mixture was stirred for 48 hrs. The resulting solid was filtered and washed with MeOH, giving 925 mg (50%) of the desired amide.

Reference： [1]Patent: WO2004/18428,2004,A1 .Location in patent: Page 97-98

21
[ 28691-47-6 ]
[ 1042591-87-6 ]
[ 1092768-69-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 5601 - 5604

22
[ 441717-78-8 ]
[ 28691-47-6 ]
C₁₈H₁₄ClFN₂O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7974 - 7992

23
[ 28691-47-6 ]
[ 75290-76-5 ]

Reference： [1]Patent: US2011/65727,2011,A1

24
[ 28691-47-6 ]
[ 894789-41-4 ]

Reference： [1]Patent: US2011/65727,2011,A1

25
[ 28691-47-6 ]
[ 1198567-69-9 ]

Reference： [1]Patent: US2011/65727,2011,A1

26
[ 28691-47-6 ]
C₂₀H₂₆N₂O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6346 - 6349

27
[ 28691-47-6 ]
[ 1078691-95-8 ]
N-(3-benzisoxazole)formylamino-2-deoxyglucose [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: A4 was prepared by the same method as A1. A solution of 3-phenyl-5-methyl-4-isoxazole formic acid (0.2 g, 1 mmol) in DMF (5 mL) was stirred. EDCI (1-(3-dimethylamino propyl)-3-2 ethyl carbon imine hydrochloride) (0.22 g, 1.2 mmol) and HOBt (N-hydroxybenzotrizole) (0.16 g, 1.2 mmol) were added sequentially and activated for approximately 1 h. Glucosamine hydrochloride (0.43 g, 2 mmol) and triethylamine (0.4 g, 4 mmol) were then added, and the solution was stirred for an additional 24 h at room temperature. The reaction was monitored by TLC. The mixture was extracted with ethyl acetate (EA) after the end of the reaction. The organic layer was separated, washed with a saturated sodium chloride solution, dried over MgSO4, and concentrated in vacuo. The residue was washed with ethanol/dichloromethane (v/v = 2:5), and the title compound. 1H NMR (400 MHz, DMSO) delta 8.42-7.72 (m, 4H), 6.57 (s, 1H), 5.58 (d, 1H), 4.76 (q, 1H), 3.73 (q, J = 37.5 Hz, 1H), 3.55 (m 1H), 3.44 (d, 1H), 3.39 (d, 2H), 1.65 (s, 1H), 1.29 (s, 1H), 1.24 (s, 1H), 1.05 (s, 1H). 13C NMR (100 MHz, DMSO-d6) delta 162.52, 161.57, 150.60, 133.55, 124.14, 121.90, 117.28, 111.20, 93.90, 75.23, 71.19, 69.81, 61.95, 56.05. HRMS (ESI) calcd for C14H16N2O7 [M+H]+: 325.1037, found 325.1045.

Reference： [1]Carbohydrate Research,2016,vol. 433,p. 73 - 79

28
[ 28691-47-6 ]
(R)-1-(2-fluorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-amine hydrochloride [ No CAS ]
N-[(4R)-1-(2-fluorophenyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-1,2-benzoxazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 20h;	(R)-1-(2-fluorophenyl)-4,5,6,7-tetrahydro-1 H-indazol-4-amine hydrochloride (S8) (25 mg, 0.093 mmol), <strong>[28691-47-6]benzo[d]isoxazole-3-carboxylic acid</strong> (17 mg, 0.103 mmol), HATU (39 mg, 0.103 mmol) and DIPEA (65 muIota, 0.37 mmol) were dissolved in dichlorometane (1.5 ml) and DMF (0.2 ml) and was stirred at RT for 20 h. The reaction mixture was purified by column chromatography eluting with a gradient of EtOAc in hexanes (20-70%). The fractions containing product were evaporated and dried under vacuum to give a white solid (27.6 mg, 78%). 1H NMR (400 MHz, Chloroform-d) delta 8.34 (dt, J = 8.0, 1.1 Hz, 1 H), 7.73 (s, 1 H), 7.70 - 7.56 (m, 2H), 7.53 - 7.37 (m, 3H), 7.34 - 7.12 (m, 3H, overlapping with solvent), 5.43 (dd, J = 8.0, 4.8 Hz, 1 H), 2.70 - 2.50 (m, 2H), 2.19 (ddt, J = 12.6, 8.6, 4.1 Hz, 1 H), 2.04 - 1.91 (m, 3H); m/z (ES+) 377 [M+H]+.

Reference： [1]Patent: WO2017/77280,2017,A1 .Location in patent: Page/Page column 70

29
[ 28691-47-6 ]
1-isopropyl-1H-pyrazolo [3, 4-d] pyrimidine-3, 4-diamine [ No CAS ]
N-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]isoxazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%		General procedure: To a solution of aryl or alkyl acid (1 equiv) in CH2Cl2 (10 mL), was added oxalyl chloride (2.5 equiv) and DMF (0.01 equiv) at 0C and then stirring for 2h. To the resulting solid were added THF (10 mL) and 20 (1.2 equiv) after concentrating under reduced pressure, subsequent cooling to -10C, DIPEA (2.5 equiv) was added dropwise, and the reaction proceed for 3 h. The mixture was added H2O and extracted with chloroform. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH/DCM=30/1) to afford the corresponding product.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 2544 - 2548

30
[ 28691-47-6 ]
C₂₁H₂₈F₄N₂O₅ [ No CAS ]
C₂₉H₃₁F₄N₃O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 27℃; for 18h;Inert atmosphere;	Compound 34-d (250.00 mg, 538.27 mmol, 1.00 eq) was dissolved in dichloromethane (5.00 mL), and compound 41-e (87.81 mg, 538.27 mmol, 1.00 eq), EDCI (141.37 mg, 737.43 mmol, 1.37 eq), HOBt (99.64 mg, 737.43 mmol, 1.37 eq) and NMM (163.34 mg, 1.61 mmol, 177.54 mL, 3.00 eq) were added thereto. The reaction solution was stirred at 27C for 18 hours under the protection of nitrogen gas. After the reaction was completed, the reaction solution was added with 100 mL of water, and extracted with dichloromethane (100 mL 3 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was subjected to column chromatography (petroleum ether : ethyl acetate = 1:0?1:1) to give the product of compound 41-f (185.00 mg, yield: 50%) as a pale yellow oil. LCMS m/z = 632.2 [M+Na]+.

Reference： [1]Patent: EP3456711,2019,A1 .Location in patent: Paragraph 0300; 0305

31
[ 28691-47-6 ]
C₂₉H₂₉F₄N₃O₇ [ No CAS ]

Reference： [1]Patent: EP3456711,2019,A1

32
[ 28691-47-6 ]
(S)-3-(1-(benzo[d]isoxazole-3-carbonyl)piperidine-4-carboxamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid [ No CAS ]

Reference： [1]Patent: EP3456711,2019,A1

33
[ 28691-47-6 ]
C₃₀H₃₁F₄N₃O₇ [ No CAS ]

Reference： [1]Patent: EP3456711,2019,A1

34
[ 28691-47-6 ]
C₂₆H₂₃F₄N₃O₇ [ No CAS ]

Reference： [1]Patent: EP3456711,2019,A1

35
[ 28691-47-6 ]
C₂₂H₃₀F₄N₂O₅ [ No CAS ]
C₃₀H₃₃F₄N₃O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39.75%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 25℃; for 15h;	Compound 115-d (143.19 mg, 877.78 mmol, 1.05 eq) was dissolved in dichloromethane (40.00 mL), and HATU (476.80 mg, 1.25 mmol, 1.50 eq), DIEA (540.21 mg, 4.18 mmol, 730.01 mL, 5.00 eq) and compound 115-c (399.77 mg, 835.98 mmol, 1.00 eq) were added thereto. The reaction solution was stirred at 25C for 15 hours. After the reaction was completed, the reaction solution was directly concentrated to give a crude product. The crude product was subjected to flash column chromatography on silica gel (petroleum ether : ethyl acetate = 65:35) to give compound 115-e (280 mg, yield: 39.75%) as a colorless oil. LCMS m/z = 624.3 [M+H]+.

Reference： [1]Patent: EP3456711,2019,A1 .Location in patent: Paragraph 0678; 0681

36
[ 28691-47-6 ]
[ 255051-14-0 ]
benzo[d]isoxazol-3-yl(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 5470 - 5500

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P378
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P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
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P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
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P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
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P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
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Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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Physical hazards
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H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
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H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
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H332	Harmful if inhaled
H333	May be harmful if inhaled
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Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 28691-47-6 ] {[proInfo.proName]}

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[ 28691-47-6 ] Synthesis Path-Upstream 1~4

[ 28691-47-6 ] Synthesis Path-Downstream 1~36

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Carboxylic Acids

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Benzisoxazoles

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[ 28691-47-6 ]

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