[ CAS No. 99586-84-2 ]

Name: 99586-84-2|Methyl 3-chloro-2-methylbenzoate|98%
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Product Details of [ 99586-84-2 ]

CAS No. :	99586-84-2	MDL No. :	MFCD00230148
Formula :	C₉H₉ClO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LCWKTHHPYGUFHR-UHFFFAOYSA-N
M.W :	184.62	Pubchem ID :	5077673
Synonyms :

Safety of [ 99586-84-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 99586-84-2 ]

* 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 [ 99586-84-2 ]
Downstream synthetic route of [ 99586-84-2 ]

[ 99586-84-2 ] Synthesis Path-Upstream 1~1

1
[ 99586-84-2 ]
[ 188187-03-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 90℃; for 3.45 h;	A suspension of methyl 3-chloro-2-methylbenzoate obtained in Example 10b (1 g, 5.42 mmol), carbon tetrachloride (13.3 ml), N-bromosuccinimide (1.06 g, 5.96 mmol) and benzoyl peroxide (3.5 mg, 0.0108 mmol) was heated in a 90° C. oil bath under a nitrogen stream. After three hours and 45 minutes, heating was completed, and the mixture was diluted with water, ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (1.43 g, yield: 100percent). ¹H-NMR (400 MHz, CDCl₃) δ ppm; 4.00 (3H, s), 5.12 (2H, s), 7.32 (1H, t, J=8 Hz), 7.58 (1H, dd, J=2, 8 Hz), 7.86 (1H, dd, J=2, 8 Hz).
100%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 90℃; for 3.75 h; Inert atmosphere	(Example 10c) Methyl 2-(bromomethyl)-3-chlorobenzoate A suspension of methyl 3-chloro-2-methylbenzoate obtained in Example 10b (1 g, 5.42 mmol), carbon tetrachloride (13.3 ml), N-bromosuccinimide (1.06 g, 5.96 mmol) and benzoyl peroxide (3.5 mg, 0.0108 mmol) was heated in a 90°C oil bath under a nitrogen stream. After three hours and 45 minutes, heating was completed, and the mixture was diluted with water, ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (1.43 g, yield: 100percent). ¹H-NMR (400 MHz, CDCl₃) δ ppm; 4.00 (3H, s), 5.12 (2H, s), 7.32 (1H, t, J=8 Hz), 7.58 (1H, dd, J=2, 8 Hz), 7.86 (1H, dd, J=2, 8 Hz).
82%	With N-Bromosuccinimide; dibenzoyl peroxide In benzene	s 2-Chloro-6-methyl carboxylate benzylbromide To a solution of methyl 3-chloro-2-methylbenzoate (1.30 g, 7.04 mmol) in benzene (20 mL) was added NBS (1.50 g, 8.45 mmol) and benzoyl peroxide (0.20 g, 0.83 mmol). After stirring at reflux for 18 h, the mixture was poured into water, and the resulting mixture was extracted with ethyl acetate (3*50 mL). The combined organic extracts were washed with brine and dried (Na₂ SO₄). After removing the solvent under reduced pressure, flash column chromatography (1:1 ether/hexane) of the residue gave 1.87 g (82percent) of the title compound as a dark oil: ¹ H NMR (250 MHz, CDCl₃) d 7.72 (d, 1H), 7.55 (d, 1H), 7.21 (t, 1H), 5.09 (s, 2H), 3.92 (s, 3H.

Reference： [1] Patent: US2013/65925, 2013, A1, . Location in patent: Paragraph 0338; 0339
[2] Patent: EP2757103, 2014, A1, . Location in patent: Paragraph 0215
[3] Patent: US5958968, 1999, A,
[4] Patent: WO2004/58717, 2004, A1, . Location in patent: Page 77
[5] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 360 - 365
[6] Patent: WO2005/16913, 2005, A1, . Location in patent: Page/Page column 68-69
[7] Patent: WO2005/121130, 2005, A2, . Location in patent: Page/Page column 560

[ 99586-84-2 ] Synthesis Path-Downstream 1~69

1
[ 7499-08-3 ]
[ 67-56-1 ]
[ 99586-84-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogenchloride; trimethyl orthoformate; at 60℃; for 16.3333h;	B. Alternatively, to a suspension of <strong>[7499-08-3]3-chloro-2-methylbenzoic acid</strong> (6.8 g, 40 MMOL) in methanol (40 mL) was added trimethyl orthoformate (4.4 mL, 40 MMOL). HCI gas was then bubbled through the suspension for 20 minutes. the resulting solution was then heated in a 60C oil bath. After stirring at 60C for 16 hours, the solution was allowed to cool to ambient temperature and concentrated under reduced pressure to afford a thick yellow paste. The semi-solid was melted under reduced pressure using a heat gun, and then cooled to afford 3-chloro-2- METHYLBENZOIC acid methyl ester (7.1 g, 95 % yield) as a yellow crystalline solid :'H- NMR (400 MHz, CDCI3) : 6 7.70 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.17 (1H, t, J = 7. 8 HZ), 3.91 (s, 3H), 2.60 (s, 3H) ppm.
88%	With sulfuric acid; for 18h;Heating / reflux;	r) Methyl 3-chloro-2-methylbenzoate To a solution of <strong>[7499-08-3]3-chloro-2-methylbenzoic acid</strong> (1.00 g, 5.86 mmol) in methanol (25 mL) was added 3 drops of sulfuric acid. The mixture was stirred at reflux for 18 h. After concentrating the residue was dissolved in ether, washed with 10% sodium hydroxide solution, brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave 0.95 g (88%) of the title compound as a white solid: 1H NMR (250 MHz, CDCl3) d 7.62 (d, 1H), 7.41 (d, 1H), 7.05 (t, 1H), 3.82 (s, 3H), 2.55 (s, 3H). s) 2-Chloro-6-methyl carboxylate benzylbromide
	With sulfuric acid;Reflux;	A solution of <strong>[7499-08-3]3-chloro-2-methylbenzoic acid</strong> (1 g, 5.86 mmol) and sulfuric acid (0.312 mL, 5.86 mmol) in Methanol (5 mL) was charged into a round bottom flask. The reaction was stirred at reflux overnight and cooled to RT. IN NaOH was added to adjust pEta to 7. The mixture was diluted with ether, which was washed with brine. The organic layer was dried over MgSO4 and the solvent was removed to afford 1.07g of crude product (99%). 1H NMR (400 MHz, CDC13) deltappm 7.71 (m, IH), 7.52 (m, IH), 7.20 (m, IH), 3.92 (s, 3H). 2.62 (s, 3H).

	With thionyl chloride; for 2h;Heating / reflux;	Example 28 1 - [ (5-CHLORO-1, 2,3, 4-tetrahydroisoquinolin-3-yl) METHYL]-1-METHYL-1, 2- dihydrospiro [indole-3, 4'-piperidine] (A) 5-CHLORO-L-OXO-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid To a stirred suspension of <strong>[7499-08-3]3-chloro-2-methylbenzoic acid</strong> (10.00 g, 58.6 mmol) in methanol (100 mL) was added dropwise thionyl chloride (8.5 mL, 117.2 mmol) at 0 C. The reaction mixture was refluxed for 2 h. After cooling down to room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (300 ML), washed with 1N NaOH solution (100 mL), water (100 mL) and brine (100 ML), dried (NA2S04), filtered, and concentrated to give 10.86 g of methyl ester as colorless oil. A mixture of this ester (10.80 g, 58.5 mmol), N-bromosuccinimide (10.45 g, 64.4 mmol), and benzoyl peroxide (0.71 g, 2.9 mmol) in carbon tetrachloride (70 mL) was refluxed for 3 h. After cooling down to room temperature, the reaction mixture was filtered and the filtrate wad concentrated to give 16.30 g of methyl 3-chloro-2-bromomethylbenzoate as a colorless oil. To a stirred suspension of NaH (2.45 g, 61.3 mmol) in DMF (50 mL) was added dropwise a solution of diethyl acetamidomalonate (12.10 g, 55.7 mmol) in DMF (50 mL) at room temperature. After 15 min stirreing, a solution of methyl 3-chloro-2- bromomethylbenzoate (16.3 g, 58. 5 mmol) in DMF (50 mL) at room temperature. After 18 h stirring, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate (800 ML), washed with water (200 mL x 2) and brine (200 mL), dried (NA2S04), filtered, and concentrated to give 21.5 g of yellow solid, which was purified by silica gel column chromatography (hexane/ethyl acetate: 2/1 to 111) to afford 14.33 g (64.3 %) of coupling product as a white solid. A mixture of this solid (13.90 g, 34.7 mmol) and 47 % HBr (160 mL) was refluxed for 24 h. After cooling down to room temperature, the solid formed was collected by filtration and dried togive 6.16 g (78.6 %) of title compound as a cream color solid. LHNMR (300MHZ, DMSO-D6) O8. 26 (1H, d, J = 4. 0 HZ), 7.85 (1H, dd, J = 1.1, 7.7 Hz), 7.64 (1H, dd, J = 1. 3, 8. 1 HZ), 7.39 (1H, dd, J = 7. 9,7. 9 HZ), 4.34-4. 28 (1H, m), 3.42-3. 36 (1H, overlapped with water peak at 3.36 ppm), 3.26 (1H, dd, J = 6.8, 16.9 Hz).
	sulfuric acid; for 14h;Heating / reflux;	Approximately two drops of sulfuric acid were added to a solution of <strong>[7499-08-3]3-chloro-2-methyl-benzoic acid</strong> (5.00 g, 29.30 mmol) in methanol and the resulting reaction mixture was refluxed for 14 hours. The reaction mixture was cooled to room temperature, and concentrated, then diluted with EtOAc. The organic layer was washed with saturated NaHCO3 (3×150 mL), H2O (2×250 mL), brine (1×250 mL) and dried over MgSO4. The crude product was purified by column chromatography using hex:EtOAc (4.5:0.5) as the eluant to give the title ester. Spectroscopic data: 1H NMR (300 MHz, CDCl3.) delta 2.60 (s, 3H), 3.90 (s, 3H), 7.16 (t, J=7.325 Hz, 1H), 7.49 (d, J=7.91 Hz, 1H), 7.69 (d, J=7.91 Hz, 1H).

Reference： [1]Patent: WO2004/58717,2004,A1 .Location in patent: Page 77
[2]Patent: US6353116,2002,B1 .Location in patent: Page column 24
[3]Patent: WO2010/135504,2010,A1 .Location in patent: Page/Page column 42
[4]Patent: WO2005/16913,2005,A1 .Location in patent: Page/Page column 68-69
[5]Patent: US2008/194650,2008,A1 .Location in patent: Page/Page column 22

2
[ 99586-84-2 ]
[ 188187-03-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 90℃; for 3.45h;	A suspension of methyl 3-chloro-2-methylbenzoate obtained in Example 10b (1 g, 5.42 mmol), carbon tetrachloride (13.3 ml), N-bromosuccinimide (1.06 g, 5.96 mmol) and benzoyl peroxide (3.5 mg, 0.0108 mmol) was heated in a 90 C. oil bath under a nitrogen stream. After three hours and 45 minutes, heating was completed, and the mixture was diluted with water, ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (1.43 g, yield: 100%). 1H-NMR (400 MHz, CDCl3) delta ppm; 4.00 (3H, s), 5.12 (2H, s), 7.32 (1H, t, J=8 Hz), 7.58 (1H, dd, J=2, 8 Hz), 7.86 (1H, dd, J=2, 8 Hz).
100%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 90℃; for 3.75h;Inert atmosphere;	(Example 10c) Methyl 2-(bromomethyl)-3-chlorobenzoate A suspension of methyl 3-chloro-2-methylbenzoate obtained in Example 10b (1 g, 5.42 mmol), carbon tetrachloride (13.3 ml), N-bromosuccinimide (1.06 g, 5.96 mmol) and benzoyl peroxide (3.5 mg, 0.0108 mmol) was heated in a 90C oil bath under a nitrogen stream. After three hours and 45 minutes, heating was completed, and the mixture was diluted with water, ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (1.43 g, yield: 100%). 1H-NMR (400 MHz, CDCl3) delta ppm; 4.00 (3H, s), 5.12 (2H, s), 7.32 (1H, t, J=8 Hz), 7.58 (1H, dd, J=2, 8 Hz), 7.86 (1H, dd, J=2, 8 Hz).
1.87 g (82%)	With N-Bromosuccinimide; dibenzoyl peroxide; In benzene;	s 2-Chloro-6-methyl carboxylate benzylbromide To a solution of methyl 3-chloro-2-methylbenzoate (1.30 g, 7.04 mmol) in benzene (20 mL) was added NBS (1.50 g, 8.45 mmol) and benzoyl peroxide (0.20 g, 0.83 mmol). After stirring at reflux for 18 h, the mixture was poured into water, and the resulting mixture was extracted with ethyl acetate (3*50 mL). The combined organic extracts were washed with brine and dried (Na2 SO4). After removing the solvent under reduced pressure, flash column chromatography (1:1 ether/hexane) of the residue gave 1.87 g (82%) of the title compound as a dark oil: 1 H NMR (250 MHz, CDCl3) d 7.72 (d, 1H), 7.55 (d, 1H), 7.21 (t, 1H), 5.09 (s, 2H), 3.92 (s, 3H.

	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 85℃; for 16h;Irradiation;	A. To a suspension of 3-chloro-2-methylbenzoic acid methyl ester (5.62 g, 30.4 MMOL), and N-bromosuccinimide (5.94 g, 33.4 MMOL) in carbon TETRACHLORIDE (200 mL) was added benzoyl peroxide (800 mg, 3.30 MMOL). The resulting suspension was immersed in an oil bath held at 85C, and illuminated with a 300W halogen worklight. After stirring for 16 hours with heat and illumination the reaction mixture was allowed to cool to ambient temperature, filtered to remove the insoluble succinimide, and concentrated under reduced pressure to afford 2- bromomethyl-3-chlorobenzoic acid methyl ester as a yellow semi-solid. This crude material was carried on to the next step without purification.
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Heating / reflux;	Example 28 1 - [ (5-CHLORO-1, 2,3, 4-tetrahydroisoquinolin-3-yl) METHYL]-1-METHYL-1, 2- dihydrospiro [indole-3, 4'-piperidine] (A) 5-CHLORO-L-OXO-1, 2,3, 4-tetrahydroisoquinoline-3-carboxylic acid To a stirred suspension of 3-chloro-2-methylbenzoic acid (10.00 g, 58.6 mmol) in methanol (100 mL) was added dropwise thionyl chloride (8.5 mL, 117.2 mmol) at 0 C. The reaction mixture was refluxed for 2 h. After cooling down to room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (300 ML), washed with 1N NaOH solution (100 mL), water (100 mL) and brine (100 ML), dried (NA2S04), filtered, and concentrated to give 10.86 g of methyl ester as colorless oil. A mixture of this ester (10.80 g, 58.5 mmol), N-bromosuccinimide (10.45 g, 64.4 mmol), and benzoyl peroxide (0.71 g, 2.9 mmol) in carbon tetrachloride (70 mL) was refluxed for 3 h. After cooling down to room temperature, the reaction mixture was filtered and the filtrate wad concentrated to give 16.30 g of methyl 3-chloro-2-bromomethylbenzoate as a colorless oil. To a stirred suspension of NaH (2.45 g, 61.3 mmol) in DMF (50 mL) was added dropwise a solution of diethyl acetamidomalonate (12.10 g, 55.7 mmol) in DMF (50 mL) at room temperature. After 15 min stirreing, a solution of methyl 3-chloro-2- bromomethylbenzoate (16.3 g, 58. 5 mmol) in DMF (50 mL) at room temperature. After 18 h stirring, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate (800 ML), washed with water (200 mL x 2) and brine (200 mL), dried (NA2S04), filtered, and concentrated to give 21.5 g of yellow solid, which was purified by silica gel column chromatography (hexane/ethyl acetate: 2/1 to 111) to afford 14.33 g (64.3 %) of coupling product as a white solid. A mixture of this solid (13.90 g, 34.7 mmol) and 47 % HBr (160 mL) was refluxed for 24 h. After cooling down to room temperature, the solid formed was collected by filtration and dried togive 6.16 g (78.6 %) of title compound as a cream color solid. LHNMR (300MHZ, DMSO-D6) O8. 26 (1H, d, J = 4. 0 HZ), 7.85 (1H, dd, J = 1.1, 7.7 Hz), 7.64 (1H, dd, J = 1. 3, 8. 1 HZ), 7.39 (1H, dd, J = 7. 9,7. 9 HZ), 4.34-4. 28 (1H, m), 3.42-3. 36 (1H, overlapped with water peak at 3.36 ppm), 3.26 (1H, dd, J = 6.8, 16.9 Hz).
	With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform; at 20℃; for 16h;Heating / reflux;	To compound 1190 (4.42 g, 0.0239 mol) dissolved in CCl4 (100 mL) was added n-bromosuccinimide (5.11 g, 0.287 mol) and benzoyl peroxide (0.58 g, 0.00239 mol). The reaction mixture was heated at reflux for 16 h then cooled to room temperature. The solid was removed by filtration and washed with CH2CI2. The filtrate was concentrated to give 7.80 g of the product 1193 with succinimide as a yellow oil and solid mixture
	With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; at 80℃; for 12h;	General procedure: A mixture of methyl 3-bromo-2-methylbenzoate (500 mg, 3.3 mmol), NBS (770.4 mg, 4.3 mmol), and di-benzoyl peroxide (BPO, 80.7 mg, 0.3 mmol) in 1,2-dichloroethane (10 mL) was heated at 80 C for 12 h. The reaction mixture was cooled to room temperature, and the precipitated solid was removed by filtration and washed with ethers (10 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 2 N NaHCO3 (15 mL) and ethers (15 mL). The organic layer was separated, dried over NaSO4, filtered and concentrated to give a crude product (683.2 mg, 89.6%), which was used in the next step reaction without further purification.

Reference： [1]Patent: US2013/65925,2013,A1 .Location in patent: Paragraph 0338; 0339
[2]Patent: EP2757103,2014,A1 .Location in patent: Paragraph 0215
[3]Patent: US5958968,1999,A
[4]Patent: WO2004/58717,2004,A1 .Location in patent: Page 77
[5]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365
[6]Patent: WO2005/16913,2005,A1 .Location in patent: Page/Page column 68-69
[7]Patent: WO2005/121130,2005,A2 .Location in patent: Page/Page column 560
[8]European Journal of Medicinal Chemistry,2019,vol. 180,p. 509 - 523

3
[ 7499-08-3 ]
[ 74-88-4 ]
[ 99586-84-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18.5h;	Iodomethane (1.96 ml, 31.5 mmol) was added to a mixture of <strong>[7499-08-3]3-chloro-2-methylbenzoic acid</strong> (3.58 g, 21 mmol), potassium carbonate (5.8 g, 42 mmol) and N,N-dimethylformamide (35.9 ml), followed by stirring at mom temperature for 18 hours and 30 minutes. Water and ethyl acetate were added to the reaction liquid, and the organic layer was extracted. The organic layer was sequentially washed with a saturated aqueous ammonium chloride solution and brine, and then dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to give the title compound (3.67 g, yield: 97%). 1H-NMR (400 MHz, CDCl3) delta ppm; 2.60 (3H, s), 3.91 (3H, s), 7.13-7.21 (1H, m), 7.50 (1H, dd, J=1, 8 Hz), 7.70 (1H, dd, J=1, 8 Hz).
97%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18.5h;	(Example 10b) Methyl 3-chloro-2-methylbenzoate Iodomethane (1.96 ml, 31.5 mmol) was added to a mixture of <strong>[7499-08-3]3-chloro-2-methylbenzoic acid</strong> (3.58 g, 21 mmol), potassium carbonate (5.8 g, 42 mmol) and N,N-dimethylformamide (35.9 ml), followed by stirring at room temperature for 18 hours and 30 minutes. Water and ethyl acetate were added to the reaction liquid, and the organic layer was extracted. The organic layer was sequentially washed with a saturated aqueous ammonium chloride solution and brine, and then dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate) to give the title compound (3.67 g, yield: 97%). 1H-NMR (400 MHz, CDCl3) delta ppm; 2.60 (3H, s), 3.91 (3H, s), 7.13-7.21 (1H, m), 7.50 (1H, dd, J=1, 8 Hz), 7.70 (1H, dd, J=1, 8 Hz).
83%	With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 20h;	To <strong>[7499-08-3]3-chloro-2-methylbenzoic acid</strong> 1189 (4.95 g, 0.0290 mol) dissolved in DMF (70 mL) was added cesium carbonate (14.18 g, 0.0435 mol) and methyl iodide (5.35 g, 2.3 mL, 0.0377 mol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated, and EtOAc (200 mL) was added. The organic solution was washed with water (2 x 100 mL), dried (MgS04), filtered, and concentrated to give 4.43 g (83%) of the product 1190 as a yellow oil. MS for M-CI:149

Reference： [1]Patent: US2013/65925,2013,A1 .Location in patent: Paragraph 0336; 0337
[2]Patent: EP2757103,2014,A1 .Location in patent: Paragraph 0214
[3]Patent: WO2005/121130,2005,A2 .Location in patent: Page/Page column 559
[4]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365

4
[ 7499-08-3 ]
[ 99586-84-2 ]

Yield	Reaction Conditions	Operation in experiment
0.95 g (88%)	With sulfuric acid; In methanol;	r Methyl 3-chloro-2-methylbenzoate To a solution of <strong>[7499-08-3]3-chloro-2-methylbenzoic acid</strong> (1.00 g, 5.86 mmol) in methanol (25 mL) was added 3 drops of sulfuric acid. The mixture was stirred at reflux for 18 h. After concentrating the residue was dissolved in ether, washed with 10% sodium hydroxide solution, brine and dried (Na2 SO4). Removal of the solvent under reduced pressure gave 0.95 g (88%) of the title compound as a white solid: 1 H NMR (250 MHz, CDCl3) d 7.62 (d, 1H), 7.41 (d, 1H), 7.05 (t, 1H), 3.82 (s, 3H), 2.55 (s, 3H).

Reference： [1]Patent: US5958968,1999,A

5
[ 99586-84-2 ]
[ 90369-75-8 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of lithium aluminium hydride (29.8 mL, 29.8 mmol) in THF was cooled to 0 0C, and a solution of methyl 3-chloro-2-methylbenzoate (2.5 g, 13.54 mmol) in Tetrahydrofuran (THF) (20 mL) was added dropwise. The mixture was stirred at 0 0C for half hour, warmed up to RT gradually, and stirred at RT for 2 hours. Water and 6N NaOH (4ml) were added to quench the reaction. The mixture was filtered and the filtrate was concentrated to afford the crude product as a white solid (2.Og, 94%). 1H NMR (400 MHz, CDC13) deltappm 7.30-7.35 (m, 2H), 7.16 (m, IH), 4.74 (s, 2H), 2.40 (s, 3H).
		LAH (61.00 mL, 1.0 M in THF, 61.00 mmol) was added to a solution of 3-chloro-2-methyl-benzoic acid methyl ester (4.50 g, 24.40 mmol) in THF at 0 C. The reaction mixture was stirred for 1 hour, water was added to quench the reaction. The aqueous layer was extracted with Et2O (3×150 mL), and the combined organic phases were washed with brine (1×150 mL) and dried over MgSO4. Purification by column chromatography using hex:EtOAc (4:1) as the eluant afforded 3.97 g of the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3.) delta 1.94 (br s, 1H), 2.36 (s, 3H), 4.67 (br s, 2H), 7.11 (t, J=7.765 Hz, 1H), 7.245 (d, J=7.03 Hz, 1H), 7.30 (d, J=7.91 Hz, 1H).

Reference： [1]Patent: WO2010/135504,2010,A1 .Location in patent: Page/Page column 42-43
[2]Patent: US2008/194650,2008,A1 .Location in patent: Page/Page column 22

6
[ 99586-84-2 ]
[ 1198299-48-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365
[2]Patent: WO2021/126973,2021,A1

7
[ 99586-84-2 ]
[ 1379313-10-6 ]

Reference： [1]Patent: US2013/65925,2013,A1
[2]Patent: EP2757103,2014,A1

8
[ 99586-84-2 ]
[ 1379323-52-0 ]

Reference： [1]Patent: US2013/65925,2013,A1
[2]Patent: EP2757103,2014,A1

9
[ 99586-84-2 ]
[ 1427058-75-0 ]

Reference： [1]Patent: US2013/65925,2013,A1
[2]Patent: EP2757103,2014,A1

10
[ 99586-84-2 ]
[ 1427309-42-9 ]

Reference： [1]Patent: US2013/65925,2013,A1
[2]Patent: EP2757103,2014,A1

11
[ 99586-84-2 ]
[ 1427058-40-9 ]

Reference： [1]Patent: US2013/65925,2013,A1
[2]Patent: EP2757103,2014,A1

12
[ 99586-84-2 ]
[ 1427309-44-1 ]

Reference： [1]Patent: US2013/65925,2013,A1
[2]Patent: EP2757103,2014,A1

13
[ 99586-84-2 ]
C₂₅H₃₆ClF₂N₃O₃ [ No CAS ]

Reference： [1]Patent: US2013/65925,2013,A1

14
[ 99586-84-2 ]
[ 1449754-12-4 ]

Reference： [1]Patent: EP2757103,2014,A1

15
[ 99586-84-2 ]
1'-[(5-chloro-1,2,3,4-tetrahydroisoquinolin-3-yl)methyl]-1-methyl-1,2-dihydrospiro[indole-3,4'-piperidine] [ No CAS ]

Reference： [1]Patent: WO2005/16913,2005,A1

16
[ 99586-84-2 ]
5-chloro-3-(2,3-dihydro-1'H-spiro[indene-1,4'-piperidin]-1'-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one [ No CAS ]

Reference： [1]Patent: WO2005/16913,2005,A1

17
[ 99586-84-2 ]
[ 845552-91-2 ]

Reference： [1]Patent: WO2005/16913,2005,A1

18
[ 99586-84-2 ]
[ 845552-89-8 ]

Reference： [1]Patent: WO2005/16913,2005,A1

19
[ 99586-84-2 ]
C₂₃H₂₆ClN₃O [ No CAS ]

Reference： [1]Patent: WO2005/16913,2005,A1

20
[ 99586-84-2 ]
[ 871723-37-4 ]

Reference： [1]Patent: WO2005/121130,2005,A2
[2]Patent: US2021/78996,2021,A1

21
[ 99586-84-2 ]
1-azidomethyl-3-chloro-2-methyl-benzene [ No CAS ]

Reference： [1]Patent: US2008/194650,2008,A1

22
[ 99586-84-2 ]
(R)-2-((8-(3-aminopiperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)-3-chlorobenzoic acid hydrochloride [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 180,p. 509 - 523

23
[ 99586-84-2 ]
methyl (R)-2-((8-(3-aminopiperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3,6,7- tetrahydro-1H-purin-1-yl)methyl)-3-chlorobenzoate hydrochloride [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 180,p. 509 - 523

24
[ 99586-84-2 ]
C₂₈H₃₃ClN₆O₆ [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 180,p. 509 - 523

25
[ 99586-84-2 ]
C₂₉H₃₅ClN₆O₆ [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 180,p. 509 - 523

26
[ 99586-84-2 ]
C₁₉H₁₆BrClN₄O₄ [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 180,p. 509 - 523

27
[ 667-27-6 ]
[ 99586-84-2 ]
methyl 3-chloro-4-(2-ethoxy-1,1-difluoro-2-oxoethyl)-2-methylbenzoate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2020,vol. 85,p. 10740 - 10749

28
[ 99586-84-2 ]
C₁₀H₈BrClN₂O [ No CAS ]

Reference： [1]Monatshefte fur Chemie,2021,vol. 152,p. 121 - 135

29
[ 99586-84-2 ]
C₁₀H₉ClN₂O₂ [ No CAS ]

Reference： [1]Monatshefte fur Chemie,2021,vol. 152,p. 121 - 135

30
[ 99586-84-2 ]
C₁₂H₁₁ClN₂O₃ [ No CAS ]

Reference： [1]Monatshefte fur Chemie,2021,vol. 152,p. 121 - 135

31
[ 99586-84-2 ]
3-chloro-2-methyl-benzoic acid hydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate; In methanol; at 80℃; for 4.0h;	General procedure: At the 250 cm3double-mouth bottle, 13.5 mmol of themethyl benzoate derivatives was added to 100 cm3of methanol,added 6.75 cm3of hydrazine hydrate (108 mmol) tothe reaction mixture slowly. After that warming to 80 Cand reflux for 4 h until the reaction was completed, thenconcentrated under reducing pressure to remove methanol,filtering and drying to get white solid 2.

Reference： [1]Monatshefte fur Chemie,2021,vol. 152,p. 121 - 135

32
[ 99586-84-2 ]
(Z)‑(1‑methyl‑1H‑tetrazol‑5‑yl)(phenyl)methanone O‑[[5‑(3‑chloro‑2‑methylphenyl)‑1,3,4‑oxadiazol‑2‑yl]methyl]oxime [ No CAS ]

Reference： [1]Monatshefte fur Chemie,2021,vol. 152,p. 121 - 135

33
[ 99586-84-2 ]
4-chloro-7-nitro-isoindolin-1-one [ No CAS ]