[ CAS No. 129101-37-7 ] {[proInfo.proName]}

Name: 129101-37-7|(R)-6-Fluorochroman-2-carboxylic acid|95%
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Quality Control of [ 129101-37-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 129101-37-7 ]

CAS No. :	129101-37-7	MDL No. :	MFCD09955074
Formula :	C₁₀H₉FO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZNJANLXCXMVFFI-SECBINFHSA-N
M.W :	196.18	Pubchem ID :	28242420
Synonyms :

Calculated chemistry of [ 129101-37-7 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.3
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	47.13
TPSA :	46.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.17 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.62
Log Po/w (XLOGP3) :	1.87
Log Po/w (WLOGP) :	2.02
Log Po/w (MLOGP) :	1.7
Log Po/w (SILICOS-IT) :	2.07
Consensus Log Po/w :	1.86

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.49
Solubility :	0.641 mg/ml ; 0.00327 mol/l
Class :	Soluble
Log S (Ali) :	-2.47
Solubility :	0.667 mg/ml ; 0.0034 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.39
Solubility :	0.792 mg/ml ; 0.00404 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.61

Safety of [ 129101-37-7 ]

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 [ 129101-37-7 ]

* 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 [ 129101-37-7 ]
Downstream synthetic route of [ 129101-37-7 ]

[ 129101-37-7 ] Synthesis Path-Upstream 1~1

1
[ 129050-25-5 ]
[ 129101-37-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 2 h;	General procedure: To a stirred solution of 2a–f in THF (2 mL) and MeOH (1 mL),0.25 M aqueous LiOH (1.05 equiv) was added dropwise at roomtemperature and stirred for 2 h. The reaction mixture was concentratedunder reduced pressure and then acidified with dil HCl. Thecrude product was extracted with ethyl acetate and concentrated.This organic layer was dried over anhydrous MgSO4, filtered, andevaporated under reduced pressure. The concentrate was furtherpurified by crystallization with n-hexane to afford 6a–f. 4.2.22 (R)-6-Fluorochroman-2-carboxylic acid 6a Compound 6a (89 mg) was obtained according to Section 4.2.21 from 2a (100 mg, 0.47 mmol). Yield 96percent. ¹H NMR: δ 6.88-6.80 (m, 2H), 6.75 (dd, ³J = 8.7, ⁴J_H-F = 2.6, 1H), 4.74 (dd, 1H, J = 7.6, 3.5), 2.90-2.75 (m, 2H), 2.33 (m, 1H), 2.18 (m, 1H); ¹³C NMR: δ 175.8, 157.2 (d, ¹J_C-F = 237.9), 148.9 (d, ⁴J_C-F = 2.1), 122.3 (d, ³J_C-F = 7.5), 117.8 (d, ³J_C-F = 8.1), 115.4 (d, ²J_C-F = 22.7), 114.5 (d, ²J_C-F = 23.2), 73.2, 24.1, 23.5 (d, ⁴J_C-F = 1.1); [α]_D²⁰ = -12.6 (c 1.0, DMF) {lit. ⁹ [α]_D²⁰ = -13.4 (c 1.0, DMF)}; ee >99percent, Chiralcel ODH column, n-hexane/2-propanol/trifluoroacetic acid = 90:10:0.5, flow rate = 1.0 mL/min, t_R = 6.92 (S) and 9.62 min (R). HRMS calcd for C₁₀H₉FO₃⁺ [M]⁺, 196.0530. Found 196.0531.
96%	With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 2 h;	General procedure: To the compound 2a-2f, THF (2 mL) and methanol (1 mL) were added. 0.25 M LiOH aqueous solution (1.05 eq) was slowly added thereto, stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The diluted hydrochloric acid aqueous solution and ethyl acetate were added thereto. The organic layer was separated and concentrated under reduced pressure. The concentrate was crystallized from hexane to obtain 2 g of the target compound.

Reference： [1] Tetrahedron Asymmetry, 2015, vol. 26, # 17, p. 912 - 917
[2] Patent: KR2017/37154, 2017, A, . Location in patent: Paragraph 0291-0293

[ 129101-37-7 ] Synthesis Path-Downstream 1~20

Yield	Reaction Conditions	Operation in experiment
		b) A mixture of 6.1 parts of intermediate 6, 75 parts of acetic acid and 36 parts of concentrated hydrochloric acid was stirred for 24 hours at reflux temperature. The reaction mixture was poured into water. The product was extracted with 1,1'-oxybisethane. The extract was washed twice with water, dried, filtered and evaporated in vacuo. The residue was crystallized from petroleum ether. The product was filtered off and dried, yielding 0.9 parts of (-)-(R)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid; mp. 102.5 C. [alpha]D25=-13.39 (c=1% in DMF) (int. 7).

2
6-fluoro-3,4-dihydro-2H-benzopyran-2-carboxylic acid ethyl ester [ No CAS ]
[ 129101-37-7 ]
[ 1335103-90-6 ]

Yield	Reaction Conditions	Operation in experiment
		As described in EP-0687305, a strain of recombinant E. Coli containing the esterase originally expressed in Ophiostoma novo-ulmi is cultivated according to techniques well-known to a person skilled in the art. A cell fraction is lysed by sonication and the lysate centrifuged to obtain a cell-free supernatant solution. 1.6 mL of solution containing the esterase (lipase) enzyme obtained from Ophiostoma novo-ulmi (6800 units/mL) and a suspension of about 25 g of ethyl 6-fluorochroman- 2-carboxylic acid (1) in 25 mL of deionized water with 100 muL of Tween 80, are added to 500 mL of a 0. IN NaHC03 buffer solution (pH 9.7), optionally adjusting the pH with 2N NaOH to a value of 9.7. The mixture thus obtained is gently stirred.pH is automatically maintained at the value of 9.7 with controlled additions of a 2N NaOH solution.Evolution of the reaction is controlled by HPLC.At the end of the hydrolysis reaction, the mixture is extracted with dichloromethane so as to obtain the ester in the organic phase. The aqueous solution is acidified with IN hydrochloric acid to pH 1, and then extracted with dichloromethane for recovery of the acid.The two organic phases are separately washed with brine, and concentrated to obtain respectively 12.2 g of ethyl ester and 11.0 g of acid.Enantiomers ratio (HPLC) :(S) ester (3) /(R) ester: 95.31/4.69(R) acid (2)/(S) acid: 95.36/4.64Evaluation of rotatory power in DMF at 25C for the mixture of acids (comprising the acid (2) ) shows said mixture to be levorotatory and in accordance with what reported in EP0334429 for the R isomer.ACID (2) 1H-N R (DMS0-D6, 400 MHz): 6H. (PPm): 2.04 (2H, m, 0CHC¾CH2), 2.64 (1H, m, 0CHCH2C¾) , 2.79 (1H, m, 0CHCH2C¾) , 4.75 (1H, t, J= .5 Hz, OCtfCO) , 6.80-7.00 (3H, m, CHar), 13.00 (1H, b, COOH) . ETHYL ESTER (3) 1H-NMR (DMSO-D6, 400 MHz) : 5H. (PPm) : 1.19 (3H, t, J=7.2 Hz, CH3), 2.04 (1H, m, OCHC¾CH2) , 2.14 (1H, m, OCH<¾CH2), 2.62 (1H, m, OCHCH2C¾) , 2.80 (1H, m, OCHCH2C¾) , 4.86 (1H, t, J=4.5 Hz, OCHCO) , 6.80-7.00 (3H, m, CHar)Analysis process: Kromasil 5-AmyCoat (4.6 x 250 mm) column; eluents: (A) hexane (0.1% TFA) , (B) isopropanol, isocratic (A) / (B) 85/15; flow: 1 mL/min, temperature: 40 C; Detector: UV at 280 nm;

Reference： [1]Patent: WO2012/95707,2012,A1 .Location in patent: Page/Page column 16-18

3
[ 129101-37-7 ]
[ 1219914-99-4 ]

Reference： [1]Patent: WO2012/95707,2012,A1
[2]Patent: US2015/232441,2015,A1
[3]Patent: WO2015/121452,2015,A1
[4]Patent: CN108997297,2018,A
[5]Patent: CN108997297,2018,A
[6]Patent: CN108997297,2018,A
[7]Patent: CN108997297,2018,A

4
[ 129101-37-7 ]
[ 1219915-02-2 ]

Reference： [1]Patent: WO2012/95707,2012,A1

5
[ 129101-37-7 ]
C₁₀H₈ClFO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1.5h;Inert atmosphere;	28 g of resolved (R) acid are solubilized in 250 mL anhydrous dichloromethane; to the resulting solution, 1.4 equivalents of oxalyl chloride and DMF dropwise are added. The solution is maintained under stirring at room temperature and under N2; after 1.5 hours solvent is evaporated, obtaining an oil that is redissolved into 200 mL anhydrous dichloromethane. Separately, Meldrum' s acid (1.05 equivalents) and pyridine (2 equivalents) are dissolved in anhydrous dichloromethane (150 mL) and left under stirring at 0C for 15 min. To this solution the previously formed acid chloride is added. At the end of the adding the mixture is left under stirring at 0C for 1 hour, and other 45 min at room temperature. Then, it is diluted with other 500 mL dichloromethane and the organic phase is washed with H20 (2 x 200 mL) , 2N HCl (100 mL) , water, and brine, and dried on Na2S04. An oil is obtained which is taken up with 20 volumes of diisopropyleter, obtaining a brown solid (40 g, HPLC purity = 81%, lambda = 280 nm) which is filtered and dried. The obtained solid is used in the subsequent reaction without further purification.

Reference： [1]Patent: WO2012/95707,2012,A1 .Location in patent: Page/Page column 18

6
[ 129101-37-7 ]
C₁₆H₁₅FO₆ [ No CAS ]

Reference： [1]Patent: WO2012/95707,2012,A1

7
[ 129101-37-7 ]
[ 1388095-25-7 ]

Reference： [1]Patent: WO2012/95707,2012,A1
[2]Patent: US2015/232441,2015,A1
[3]Patent: WO2015/121452,2015,A1

8
[ 129101-37-7 ]
[ 1388095-27-9 ]

Reference： [1]Patent: WO2012/95707,2012,A1
[2]Patent: US2015/232441,2015,A1
[3]Patent: WO2015/121452,2015,A1

9
[ 129101-37-7 ]
[ 1219915-04-4 ]

Reference： [1]Patent: WO2012/95707,2012,A1

10
methyl (S)-4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-oxo-butanoate [ No CAS ]
[ 129101-37-7 ]

Reference： [1]Tetrahedron Asymmetry,2015,vol. 26,p. 912 - 917
[2]Patent: KR2017/37154,2017,A

11
methyl (R)-6-fluoro-4-oxochroman-2-carboxylate [ No CAS ]
[ 129101-37-7 ]

Reference： [1]Tetrahedron Asymmetry,2015,vol. 26,p. 912 - 917
[2]Patent: KR2017/37154,2017,A

12
[ 129050-25-5 ]
[ 129101-37-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With lithium hydroxide; In tetrahydrofuran; methanol; water; at 20℃; for 2h;	General procedure: To a stirred solution of 2a-f in THF (2 mL) and MeOH (1 mL),0.25 M aqueous LiOH (1.05 equiv) was added dropwise at roomtemperature and stirred for 2 h. The reaction mixture was concentratedunder reduced pressure and then acidified with dil HCl. Thecrude product was extracted with ethyl acetate and concentrated.This organic layer was dried over anhydrous MgSO4, filtered, andevaporated under reduced pressure. The concentrate was furtherpurified by crystallization with n-hexane to afford 6a-f. 4.2.22 (R)-6-Fluorochroman-2-carboxylic acid 6a Compound 6a (89 mg) was obtained according to Section 4.2.21 from 2a (100 mg, 0.47 mmol). Yield 96%. 1H NMR: delta 6.88-6.80 (m, 2H), 6.75 (dd, 3J = 8.7, 4JH-F = 2.6, 1H), 4.74 (dd, 1H, J = 7.6, 3.5), 2.90-2.75 (m, 2H), 2.33 (m, 1H), 2.18 (m, 1H); 13C NMR: delta 175.8, 157.2 (d, 1JC-F = 237.9), 148.9 (d, 4JC-F = 2.1), 122.3 (d, 3JC-F = 7.5), 117.8 (d, 3JC-F = 8.1), 115.4 (d, 2JC-F = 22.7), 114.5 (d, 2JC-F = 23.2), 73.2, 24.1, 23.5 (d, 4JC-F = 1.1); [alpha]D20 = -12.6 (c 1.0, DMF) {lit. 9 [alpha]D20 = -13.4 (c 1.0, DMF)}; ee >99%, Chiralcel ODH column, n-hexane/2-propanol/trifluoroacetic acid = 90:10:0.5, flow rate = 1.0 mL/min, tR = 6.92 (S) and 9.62 min (R). HRMS calcd for C10H9FO3+ [M]+, 196.0530. Found 196.0531.
96%	With lithium hydroxide; In tetrahydrofuran; methanol; water; at 20℃; for 2h;	General procedure: To the compound 2a-2f, THF (2 mL) and methanol (1 mL) were added. 0.25 M LiOH aqueous solution (1.05 eq) was slowly added thereto, stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The diluted hydrochloric acid aqueous solution and ethyl acetate were added thereto. The organic layer was separated and concentrated under reduced pressure. The concentrate was crystallized from hexane to obtain 2 g of the target compound.

Reference： [1]Tetrahedron Asymmetry,2015,vol. 26,p. 912 - 917
[2]Patent: KR2017/37154,2017,A .Location in patent: Paragraph 0291-0293

13
C₁₂H₁₃FO₅ [ No CAS ]
[ 129101-37-7 ]

Reference： [1]Tetrahedron Asymmetry,2015,vol. 26,p. 912 - 917
[2]Patent: KR2017/37154,2017,A

14
[ 129101-37-7 ]
[ 1315508-95-2 ]

Reference： [1]Patent: US2015/232441,2015,A1
[2]Patent: WO2015/121452,2015,A1

15
[ 2033-24-1 ]
[ 129101-37-7 ]
C₁₆H₁₅FO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 3 CDI-Process (0125) CDI (100.7 kg) were charged in a vessel and suspended with acetonitrile (192 kg). A solution of (2R) 6-fluorochromanic acid 2a (110.7 kg) in acetonitrile (150 kg) was added over 45 min at 15-20 C. and stirred for additional 60 min until conversion has completed. A solution of Meldrum's acid (93.6 kg) in acetonitrile (97 kg) was added to the mixture at 15 C. After stirring for 12 h tert. butanol (169.5 kg) was added. The resulting mixture was cooled to 0-5 C. Trifluoroacetic acid (168 kg) was dropped to the mixture at 5 C. over 2 h and stirred for 6-7 h at 15-20 C. After complete conversion of the Meldrumate the solvent was removed by distillation. The resulting oily residue was dissolved in of toluene (279 kg) and washed with water (203 l), then twice with saturated aqueous NaHCO3-solution (67 kg) and again with water (185 l). After phase separation, the aqueous layers were discarded and the toluene phase distilled off to give a slightly yellow oil which was azeotropically dried with toluene. The oily residue of (R)-FCA-beta-ketoester in the reactor was dissolved in ethyl acetate (742 kg). Na3PO4 (92.5 kg) was added and the suspension transferred to a further vessel. Sulfurylchloride (87.6 kg) was added slowly at 0-5 C. over a period of 2 hours. The mixture was heated to 20 C. and stirred until completion of the reaction. Water (284 l) was added under stirring keeping the temperature below 15 C. After phase separation, the lower aqueous layer was discarded and the upper organic layer was washed water (138 l). The solvent was stripped under reduced pressure to give the (R)-FCA-alpha-chloro-beta-ketoester as a yellow oily residue which was dissolved in glacial acetic acid (389.8 kg). Subsequently, 37% HCl (83.4 kg) was added and the mixture heated to 40 C. for 4 h. The mixture was cooled to 10 C. and 204 kg of sat. NaCl solution (204 kg) and toluene (162 kg) were added. After phase separation the organic phase was washed twice with brine (108 kg). The combined aqueous phases were re-extracted once with toluene (45 kg). Under vigorous stirring, saturated NaHCO3-solution (65 l) was carefully added to the combined organic phase. After phase separation, the lower aqueous layer was discarded and the upper organic layer was washed twice with an aqueous solution of Na2SO4. Phases were separated and the organic phase concentrated under reduced pressure to yield an oily residue. Isopropanol (131 kg) was added and the residue dissolved at 40 C. A precipitate was obtained by cooling to 0 C. After additional stirring for 2 h the precipitate was filtered off. The filter cake was washed three times with ice-cold isopropanol and subsequently dried under reduced pressure. The mother liquor was reduced to the third part and crystallization was induced again by cooling to 0 C. The crystals were filtered off and both crops combined to yield 1b (92.45 kg; 71.6% of theoretical yield). Purity was 99% as determined by HPLC with e.e. 97.9% as determined by chiral GC. (0126) Manufacturing of the corresponding (S)-chloroketone 1a was performed in the same manner.
		Example 12: (0222) CDI-Process: (0223) CDI (100.7 kg) were charged in a vessel and suspended with acetonitrile (192 kg). A solution of (2R) 6-fluorochromanic acid 2a (1 10.7 kg) in acetonitrile (150 kg) was added over 45 min at 15-20C and stirred for additional 60 min until conversion has completed. A solution of Meldrum's acid (93.6 kg) in acetonitrile (97 kg) was added to the mixture at 15C. After stirring for 12 h tert. butanol (169.5 kg) was added. The resulting mixture was cooled to 0- 5C. Trifluoroacetic acid (168 kg) was dropped to the mixture at 5C over 2 h and stirred for 6-7 h at 15-20C. After complete conversion of the Meldrumate the solvent was removed by distillation. The resulting oily residue was dissolved in of toluene (279 kg) and washed with water (203 I), then twice with saturated aqueous NaHC03-solution (67 kg) and again with water (185 I). After phase separation, the aqueous layers were discarded and the toluene phase distilled off to give a slightly yellow oil which was azeotropically dried with toluene. The oily residue of (R)-FCA-3-ketoester in the reactor was dissolved in ethyl acetate (742 kg). Na3P04 (92.5 kg) was added and the suspension transferred to a further vessel. (0224) Sulfurylchloride (87.6 kg) was added slowly at 0-5C over a period of 2 hours. The mixture was heated to 20C and stirred until completion of the reaction. Water (284 I) was added under stirring keeping the temperature below 15C. After phase separation, the lower aqueous layer was discarded and the upper organic layer was washed water (138 I). The solvent was stripped under reduced pressure to give the (R)-FCA-a-chloro-3-ketoester as a yellow oily residue which was dissolved in glacial acetic acid (389.8 kg). Subsequently, 37% HCI (83.4 kg) was added and the mixture heated to 40C for 4 h. The mixture was cooled to 10C and 204 kg of sat. NaCI solution (204 kg) and toluene (162 kg) were added. After phase separation the organic phase was washed twice with brine (108 kg). The combined aqueous phases were re-extracted once with toluene (45 kg). Under vigorous stirring, saturated NaHC03-solution (65 I) was carefully added to the combined organic phase. After phase separation, the lower aqueous layer was discarded and the upper organic layer was washed twice with an aqueous solution of Na2S04. Phases were separated and the organic phase concentrated under reduced pressure to yield an oily residue. Isopropanol (131 kg) was added and the residue dissolved at 40C. A precipitate was obtained by cooling to 0C. After additional stirring for 2 h the precipitate was filtered off. The filter cake was washed three times with ice-cold isopropanol and subsequently dried under reduced pressure. The mother liquor was reduced to the third part and crystallization was induced again by cooling to 0C. The crystals were filtered off and both crops combined to yield 1 b (92.45 kg; 71.6% of theoretical yield). Purity was 99% as determined by HPLC with e.e. 97.9 % as determined by chiral GC.

Reference： [1]Patent: US2015/232441,2015,A1 .Location in patent: Paragraph 0125; 0126
[2]Patent: WO2015/121452,2015,A1 .Location in patent: Page/Page column 26-27

16
[ 129101-37-7 ]
[ 15886-84-7 ]
C₂₃H₂₂F₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In N,N-dimethyl acetamide; at 130℃; for 2h;	2.5 g of color full acid (R configuration, 12.75 mmol), 1.76 g of potassium carbonate (12.75 mmol), N,N-dimethylacetamide (15 mL) were added to the reaction flask and heated to 130 C. Then 1.2 g of 1,3-propanediol bis-methanesulfonate (5.1 mmol) was added Into the reaction system, the reaction was continued for 2 hours, and the reaction was completed by HPLC. The reaction system was cooled to room temperature, and acetic acid (0.22 g) was added to quench the reaction. Distill off most of the solvent under reduced pressure and add water (10 mL). Extracted in three portions with ethyl acetate (30 mL). The combined organic phases were washed with water (15 mL) The resulting organic phase is distilled under reduced pressure to a thick oil. Beat with isopropanol / petroleum ether (4mL, 4:1), Obtained 1.89g of a white solid, high-performance liquid chromatography showed a single peak, The chromatographic purity was 98% and the yield was 86%

Reference： [1]Patent: CN108997297,2018,A .Location in patent: Paragraph 0098-0101

17
[ 129101-37-7 ]
[ 5469-66-9 ]
C₂₃H₂₂F₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate; In N,N-dimethyl acetamide; at 130℃; for 2h;	2.5 g of color saturated with acid (R configuration, 12.75 mmol), 1.76 g of potassium carbonate (12.8 mmol), N,N-dimethylacetamide (15 mL) was added to the reaction flask. Heat to 130 C, Then, 1.96 g of 1,3-di-p-tosylatepropane (5.1 mmol) was added to the reaction system, and the reaction was continued for 2 hours, and the reaction was confirmed by HPLC. The reaction system was cooled to room temperature, and acetic acid (0.22 g) was added to quench the reaction. Distill off most of the solvent under reduced pressure and add water (10 mL). Extracted in three portions with ethyl acetate (30 mL). The combined organic phases were washed with water (15 mL) The resulting organic phase was distilled under reduced pressure to a viscous oil. Beat with isopropanol / petroleum ether (4mL, 4:1), Obtained 2.02g of a white solid, high-performance liquid chromatography showed a single peak, The chromatographic purity was 98% and the yield was 92%.

Reference： [1]Patent: CN108997297,2018,A .Location in patent: Paragraph 0102-0105

18
[ 129101-37-7 ]
[ 63256-90-6 ]
C₂₃H₂₂F₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 2h;	2.5 g of chroman acid (R configuration, 12.8 mmol), 1.76 g of potassium carbonate (12.8 mmol), N,N-dimethylformamide (15 mL) were added to the reaction flask, heated to 130 C, then 1.73 g 1,3-propanediol bis-p-trifluoromethanesulfonate (5.1 mmol) was added to the reaction system, and the reaction was continued for 2 hours, and the reaction was confirmed by HPLC. The reaction system was cooled to room temperature, and the reaction was quenched by the addition of acetic acid (0.22 g). The solvent was evaporated to remove the solvent. After washing, the obtained organic phase was evaporated under reduced pressure to a thick oil, which was then purified with isopropyl alcohol/ petroleum ether (4mL, 4:1) to give 1.98 g of white solid. High performance liquid chromatography showed a single peak with a chromatographic purity of 98% and a yield of 90%.

Reference： [1]Patent: CN108997297,2018,A .Location in patent: Paragraph 0106-0109

19
[ 129101-37-7 ]
2-bromo-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethanone [ No CAS ]

Reference： [1]Patent: CN108997297,2018,A
[2]Patent: CN108997297,2018,A
[3]Patent: CN108997297,2018,A

20
[ 129101-37-7 ]
[ 142-28-9 ]
C₂₃H₂₂F₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate; In N,N-dimethyl-formamide; toluene; at 120℃; for 4h;	21.0 g of Chroman acid (R configuration, 107 mmol), 14.8 g of potassium carbonate (107 mmol), N,Ndimethylformamide(100 mL) and toluene (40 mL) were mixed and heated to 120 C, then 5.8 g of 1,3-dichloropropane (51 mmol) was added to the reaction system, and the reaction was continued for 4 hours, andthe reaction was completed by TLC. The reaction system was cooled to room temperature, and acetic acid (2.2g) was added to quench the reaction. Most of the solvent was evaporated under reduced pressure, water (100mL) was added, and ethyl acetate (150 mL) was extracted in three portions. After washing, the obtained organicphase was evaporated under reduced pressure to a viscous oil, which was recrystallized from isopropyl alcohol(40 mL) to give 20.3 g of white solids, which showed a single peak, chromatographic purity 99%, yield 92%.

Reference： [1]Patent: CN108997297,2018,A .Location in patent: Paragraph 0061-0068

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[ 82060-91-1 ]

6-Fluorochroman-8-carbaldehyde

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[ 26018-66-6 ]

6-Fluorobenzofuran-2-carboxylic acid

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[ 128942-39-2 ]

7-Fluoro-4-oxo-4H-chromene-2-carboxylic acid

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Carboxylic Acids

[ 1374516-07-0 ]

3-(4-((4-Fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoic acid

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[ 53188-07-1 ]

6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid

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[ 51939-71-0 ]

Chromane-2-carboxylic acid

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[ 99199-69-6 ]

6-Methoxychroman-2-carboxylic acid

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5-Methoxy-2,3-dihydrobenzofuran-2-carboxylic acid

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Related Parent Nucleus of
[ 129101-37-7 ]

Other Aromatic Heterocycles

[ 874649-82-8 ]

Methyl 6-fluorochroman-2-carboxylate

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6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid

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[ 51939-71-0 ]

Chromane-2-carboxylic acid

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Ghs Precautionary Statements

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

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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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
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
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
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
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. 129101-37-7 ] {[proInfo.proName]}

Quality Control of [ 129101-37-7 ]

Related Doc. of [ 129101-37-7 ]

Product Details of [ 129101-37-7 ]

Calculated chemistry of [ 129101-37-7 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 129101-37-7 ]

Application In Synthesis of [ 129101-37-7 ]

[ 129101-37-7 ] Synthesis Path-Upstream 1~1

[ 129101-37-7 ] Synthesis Path-Downstream 1~20

Related Functional Groups of [ 129101-37-7 ]

Fluorinated Building Blocks

Carboxylic Acids

Related Parent Nucleus of [ 129101-37-7 ]

Other Aromatic Heterocycles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 129101-37-7 ]

Related Parent Nucleus of
[ 129101-37-7 ]