[ CAS No. 377734-27-5 ] {[proInfo.proName]}

Name: 377734-27-5|Methyl 3-bromo-5-formylbenzoate|98%
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SKU: A169514
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3d Animation Molecule Structure of 377734-27-5

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Quality Control of [ 377734-27-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 377734-27-5 ]

SDS Specification

Alternatived Products of [ 377734-27-5 ]

Product Details of [ 377734-27-5 ]

CAS No. :	377734-27-5	MDL No. :	MFCD22381229
Formula :	C₉H₇BrO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GFZITIUEBBDMMN-UHFFFAOYSA-N
M.W :	243.05	Pubchem ID :	11436457
Synonyms :

Calculated chemistry of [ 377734-27-5 ] Expand+

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.11
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	50.81
TPSA :	43.37 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) :	-6.12 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.0
Log Po/w (XLOGP3) :	2.34
Log Po/w (WLOGP) :	2.05
Log Po/w (MLOGP) :	2.0
Log Po/w (SILICOS-IT) :	2.54
Consensus Log Po/w :	2.19

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.96
Solubility :	0.264 mg/ml ; 0.00108 mol/l
Class :	Soluble
Log S (Ali) :	-2.89
Solubility :	0.313 mg/ml ; 0.00129 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.28
Solubility :	0.127 mg/ml ; 0.000524 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.7

Safety of [ 377734-27-5 ]

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 [ 377734-27-5 ]

* 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.

Downstream synthetic route of [ 377734-27-5 ]

[ 377734-27-5 ] Synthesis Path-Downstream 1~48

1
[ 377734-27-5 ]
dimethyl 3,3'-diformylbiphenyl-5,5'-dicarboxylate [ No CAS ]

Reference： [1]Tetrahedron,2002,vol. 58,p. 2803 - 2811

2
[ 52178-50-4 ]
[ 377734-27-5 ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-Bromosuccinimide; sulfuric acid; at 0 - 20℃; for 48h;	A mixture of methyl 3-formylbenzoate (5.0 g, 30.5 mmol) in concentrated sulfuricacid (50 mL) was added with N-bromosuccinimide (5.4 g, 30.5 mmol) in one portion at0C. After warming to room temperature, the reaction mixture was stirred for 2 days before being poured into 400 mL of ice/water. Once the ice had melted, the aqueous phase was extracted with DCM (2 x 400 mL). The combined organic phases were passed through a hydrophobic fit. The solvent was removed in vacuo and the residue waspurified via silica gel chromatography, eluting with 0-10% EtOAc in isohexane, to give the title compound as an oil that solidified upon standing (4.6 g, 63%). ?H NMR (400 MHz, CDC13): oe 10.02 (s, 1 H), 8.45 (t, J = 1.5 Hz, 1 H), 8.41 (t, J = 1.7 Hz, 1 H), 8.20 (t,J = 1.7 Hz, 1 H), 3.98 (s, 3 H).
	With N-Bromosuccinimide; In 2-Methylpentane; sulfuric acid;	Methyl 3-bromo-5-formylbenzoate (I-53) To a mixture of methyl 3-formylbenzoate (5.0 g, 30.5 mmol) in concentrated sulfuric acid (50 mL) was added N-bromosuccinimide (5.4 g, 30.5 mmol) in one portion at 0 C. After warming to room temperature, the reaction mixture was stirred for 2 days before being poured into 400 mL of ice/water. Once the ice had melted, the aqueous phase was extracted with DCM (2*400 mL). The combined organic phases were passed through a hydrophobic fit. The solvent was removed in vacuo and the residue was purified via silica gel chromatography, eluting with 0-10% EtOAc in isohexane, to give the title compound as an oil that solidified upon standing (4.6 g, 63%). 1H NMR (400 MHz, CDCl3): delta 10.02 (s, 1H), 8.45 (t, J=1.5 Hz, 1H), 8.41 (t, J=1.7 Hz, 1H), 8.20 (t, J=1.7 Hz, 1H), 3.98 (s, 3H).

Reference： [1]Patent: WO2014/86852,2014,A1 .Location in patent: Page/Page column 67
[2]Journal of the American Chemical Society,2002,vol. 124,p. 5934 - 5935
[3]Patent: US2014/155427,2014,A1 .Location in patent: Page/Page column

3
[ 107-21-1 ]
[ 377734-27-5 ]
methyl 3-bromo-5-(2,5-dioxacyclopentyl)benzoate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2002,vol. 124,p. 5934 - 5935

4
[ 619-21-6 ]
[ 377734-27-5 ]

Reference： [1]Journal of the American Chemical Society,2002,vol. 124,p. 5934 - 5935

5
[ 377734-27-5 ]
2-[2-(2-methoxyethoxy)ethoxy]ethyl 3-formyl-5-ethynylbenzoate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2002,vol. 124,p. 5934 - 5935

6
[ 377734-27-5 ]
2-[2-(2-methoxyethoxy)ethoxy]ethyl 3-bromo-5-(2,5-dioxacyclopentyl)benzoate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2002,vol. 124,p. 5934 - 5935

7
[ 377734-27-5 ]
3-[1,3]dioxolan-2-yl-5-ethynyl-benzoic acid 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2002,vol. 124,p. 5934 - 5935

8
[ 377734-27-5 ]
2-[2-(2-methoxyethoxy)ethoxy]ethyl 3-(2,5-dioxacyclopentyl)-5-[2-(1,1,1-trimethylsilyl)-1-ethynyl]benzoate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2002,vol. 124,p. 5934 - 5935

9
[ 377734-27-5 ]
C₃₁H₃₇BrO₁₁ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2002,vol. 124,p. 5934 - 5935

10
[ 150255-96-2 ]
[ 377734-27-5 ]
[ 307353-34-0 ]

Yield	Reaction Conditions	Operation in experiment
84.5%	With sodium hydrogencarbonate;palladium diacetate; In DMF (N,N-dimethyl-formamide); water; at 80℃; for 6.5h;	In a three-necked flask with a capacity of 2 liters, 3-cyanophenylboronic acid in an amount of 67.65g and sodium hydrogen carbonate in an amount of 116.0g were placed and then a solution of 111.9g of <strong>[377734-27-5]methyl 5-bromo-3-formylbenzoate</strong> prepared in step (A) in 142 ml of dimethyl formamide (DMF) was placed. The resultant mixture liquid in the flask was mixed with 592 ml of DMF and 149 ml of water. The flask was gas-tightly sealed, the air inside the flask was replaced by an argon gas and then 0.2231g of palladium acetate was fed into the flask. The resultant reaction mixture liquid in the flask was heated to a temperature of 80C and agitated at this temperature for 6.5 hours. Thereafter, the resultant reaction mixture liquid was subjected to a hot-filtration to remove an insoluble fraction from the reaction mixture liquid, and the resultant filtrate was heated to a temperatures of 80C and agitated. The heated and agitated filtrate was gradually added with 585 ml of water, and the resultant filtrate mixture was left to cool to room temperature. The precipitate generated in the filtrate mixture was collected by filtration, and the collected precipitate was washed with 590 ml of water and then dried. A crude product of the target compound, methyl 5-(3-cyanophenyl)-3-formylbenzoate was obtained in an amount of 103.15g which corresponded to a yield of 84.5%. The crude product was subjected to a purification procedure as follows. The dried crude product in an amount of 50g was placed in a three-necked flask with a capacity of 2 liters and mixed with 150 ml of hydrous THF having a water content of 3%. The resultant mixture was heated to a temperature of 80C to provide a solution of the crude product. The solution was subjected to a hot-filtration. The filtrate was again heated to a temperature of 80C and mixed with 750 ml of 2-propyl alcohol. The resultant mixture liquid was left to cool to room temperature, to recrystallize the target compound. After cooling, the resultant precipitate generated in the cooled mixture liquid was collected by filtration. A purified product of the target compound, methyl 5-(3-cyanophenyl)-3-formylbenzoate was obtained in an amount of 45.19g which corresponded to a recrystallization yield of 90%. The result of the 1H-NMR (200 MHz, delta ppm, CDCl3) of the purified product was as follows. 4.02 (s, 3H), 7.5 - 7.8 (m, 2H), 7.8 - 8.0 (m, 2H), 8.2 - 8.3 (s, 1H), 8.4 - 8.6 (m, 2H), 10.2 (s, 1H)

Reference： [1]Patent: EP1460059,2004,A1 .Location in patent: Page 10

11
[ 307353-32-8 ]
[ 377734-27-5 ]

Yield	Reaction Conditions	Operation in experiment
94.3%	With manganese dioxide; In toluene; at 105℃; for 7.0h;	In a three-necked flask with a capacity of 3 liters, 253.11g of <strong>[307353-32-8]methyl 5-bromo-3-(hydroxymethyl)benzoate</strong> were placed and mixed with 2000 ml of toluene, and the resultant mixture was agitated to prepare a solution. The resultant solution was mixed with 44g of manganese dioxide, and the resultant reaction mixture liquid was heated to a temperature of 105C and agitated for 7 hours. The resultant reaction mixture liquid was allowed to be cooled to room temperature and filtered to remove a solid fraction therefrom, and the resultant filtrate was concentrated. The target compound, methyl 5-bromo-3-formylbenzoate was obtained in an amount of 236.79g which corresponded to a yield of 94.3%. The results of the 1H-NMR (200 MHz, delta ppm, CDCl3) of the resultant compound were as follows. 3.98 (s, 3H), 8.1 - 8.3 (m, 1H), 8.3 - 8.6 (m, 2H), 10.0 (s, 1H)
	With manganese(IV) oxide; In dichloromethane; at 20℃;	A mixture of <strong>[307353-32-8]methyl 3-bromo-5-(hydroxymethyl)benzoate</strong> (149 mg, 0.61 mmol) and manganese(IV) oxide (529 mg, 6.08 mmol), and CH2Cl2 (3 mL) was stirred at rt overnight. The mixture was filtered through Celite and the filter cake was washed with CH2Cl2. The filtrate was concentrated to afford the title compound.

Reference： [1]Patent: EP1460059,2004,A1 .Location in patent: Page 9-10
[2]Patent: WO2009/110985,2009,A2 .Location in patent: Page/Page column 123

12
[ 67-56-1 ]
[ 398119-27-2 ]
[ 377734-27-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at -10 - 20℃; for 20h;	Methyl 3-bromo-5-formylbenzoate 6.2 g (27.1 mmol) of 3-bromo-5-formylbenzoic acid (J. Org. Chem., 2002, 67, 3548-3554) are dissolved in 110 ml of acetonitrile under argon. 330 mg (2.7 mmol) of 4-dimethylaminopyridine and 1.73 ml (54.2 mmol) of methanol are added thereto. The mixture is cooled to -10 C., and 6.23 g (32.5 mmol) of EDC are added. The mixture is slowly allowed to reach RT and is then stirred for 20 h. The solvent is then evaporated in vacuo, and the residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate (6:1)). Yield: 5.1 g (77% of theory). HPLC (method 11): Rt=4.41 min. 1H-NMR (200 MHz, CDCl3): delta=3.95 (s, 3H), 8.20 (m, 1H), 8.43 (m, 1H), 8.47 (m, 1H), 10.03 (s, 1H).
54%	With sulfuric acid; at 60℃; for 15h;	To a solution of 3-bromo-5-formylbenzoic acid (66a, 500 mg, 2.18 mmol) in methanol (25 mL) was added concentrated H2SO4 (1.16 mL, 21.8 mmol) at room (0610) temperature, and this reaction mixture was stirred at 60 C for 15 h. After the solvent was evaporated under reduced pressure, the residue was partitioned ethyl acetate (20 mL) and saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed brine (5 mL), dried over MgSCL, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50: l) to afford compound 66b (287 mg, 54%) as a white solid; *H NMR (400 MHz, CDCl3) d 10.04 (s, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 8.22 (s, 1H), 4.00 (s, 3H); MS (ESI, m/z) 243.0, 245.0 [M+lf; ESI-HRMS calcd. m/z for (0611) C9H80379Br 242.9657, found 242.9656 [M+lf.

Reference： [1]Patent: US2007/99885,2007,A1 .Location in patent: Page/Page column 21
[2]Patent: WO2019/157417,2019,A1 .Location in patent: Paragraph 0217-0218

13
[ 3034-53-5 ]
[ 377734-27-5 ]
[ 1186519-21-0 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of 2-bromothiazole (0.40 g, 24.4 mmol) in THF (60 mL) under nitrogen at rt was added 2M isopropylmagnesium chloride solution in THF (10 mL, 20 mmol). The mixture was stirred at rt for 1 h and then cooled to 00C. <strong>[377734-27-5]Methyl 3-bromo-5-formylbenzoate</strong> (1.0 g, 4.1 mmol) was added and the reaction mixture was stirred at O0C for 30 minutes. The reaction mixture was quenched with water (30 mL) and extracted with CH2Cl2 (60 mL x 3). The combined organic layers were dried over anhydrous MgSO4 and concentrated. The residue was purified by flash chromatography to afford the title compound (0.90 g).

Reference： [1]Patent: WO2009/110985,2009,A2 .Location in patent: Page/Page column 123

14
[ 124-40-3 ]
[ 377734-27-5 ]
[ 1186520-08-0 ]

Yield	Reaction Conditions	Operation in experiment
93%		To a solution of <strong>[377734-27-5]methyl 3-bromo-5-formylbenzoate</strong> (1.8 g, 7.4 mmol, prepared as described in WO 2003048111 from dimethyl 5-bromoisophthalate, Alfa Aesar) in methylene chloride (20 mL) was added a solution of 2.0 M dimethylamine in tetrahydrofuran (7.4 mL, 15 mmol). This mixture was stirred for 15 minutes, followed by the addition of sodium triacetoxyborohydride (4.7 g, 22 mmol). The resulting mixture was stirred overnight. Saturated sodium bicarbonate solution was added and the product was extracted with ethyl acetate. The combined organic extracts were washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford a light yellow oil. Yield: 1.87 g (93%); LC-MS: 272.0, 274.0 (M+H)+. 1H NMR (400 MHz, CDCl3): delta 8.06 (dd, 1H), 7.89 (dd, 1H), 7.69 (dd, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 2.24 (s, 6H).
93%		Step A. Methyl 3-bromo-5- [(dimethylamino)methyl] benzoateTo a solution of <strong>[377734-27-5]methyl 3-bromo-5-formylbenzoate</strong> (1.8 g, 7.4 mmol, prepared as described in WO2003/048111 starting from dimethyl 5-bromoisophthalate (Alfa Aesar) in methylene chloride (20 mL) was added a solution of 2.0 M dimethylamine in tetrahydrofuran (7.4 mL, 15 mmol) and the reaction was stirred for 15 min. Sodium triacetoxyborohydride (4.7 g, 22 mmol) was then added and the resulting mixture was stirred overnight. Saturated sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate. The organic extract was washed twice with water, once with brine, dried over sodium sulfate, filtered and concentrated to afford product as a light yellow oil (1.87 g, 93%). 1H NMR (400 MHz, CDC13) delta 8.08 - 8.03 (m, 1H), 7.90 - 7.87 (m, 1H), 7.70 - 7.67 (m, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 2.24 (s, 6H); LCMS (M+H)+: 272.0, 274.0.
	With sodium cyanoborohydride; zinc(II) chloride; In tetrahydrofuran; methanol; at 0℃; for 1h;	A mixture of <strong>[377734-27-5]methyl 3-bromo-5-formylbenzoate</strong> (200 mg, 0.82 mmol), methanol (3 mL),2.0 M dimethylamine solution in THF (0.3 mL, 6 mmol), zinc dichloride (30 mg, 0.22 mmol), and sodium cyanoborohydride (200 mg, 3.2 mmol) was stirred at 0 0C for Ih. The mixture was diluted with water (10 mL) and the aqueous layer was extracted with EtOAc (15 mL x 3). The combined organic layers were dried over anhydrous MgSO4 and concentrated. The residue was purified by silica gel chromatography to afford the title compound.

Reference： [1]Patent: US2011/224190,2011,A1 .Location in patent: Page/Page column 124
[2]Patent: WO2012/68450,2012,A1 .Location in patent: Page/Page column 152
[3]Patent: WO2009/110985,2009,A2 .Location in patent: Page/Page column 133

15
[ 1779-49-3 ]
[ 377734-27-5 ]
[ 1186519-96-9 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of methyltriphenylphosphonium bromide (350 mg, 0.97 mmol) inTHF (3 mL) at -78 0C under nitrogen was added dropwise 2.5 M of n-butyllithium in tetrahydrofuran (0.31 mL, 0.78 mmol). The mixture was gradually warmed until a yellow color persisted. The mixture was cooled to 0 0C and a solution of <strong>[377734-27-5]methyl 3-bromo-5-formylbenzoate</strong> (157 mg, 0.65 mmol) in THF (2 mL) was added dropwise. After being stirred for 20 min at 0 0C, the mixture was quenched with saturated aq. NH4Cl and extracted with EtOAc. The organic layer was spearated and washed with brine, dried, and concentrated. The residue was purified by flash column to afford the title compound.

Reference： [1]Patent: WO2009/110985,2009,A2 .Location in patent: Page/Page column 126

16
[ 81290-20-2 ]
[ 377734-27-5 ]
[ 1186519-94-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred mixture of <strong>[377734-27-5]methyl 3-bromo-5-formylbenzoate</strong> (0.60 g, 2.5 mmol), tetra-N- butylammonium bromide (0.90 g, 2.8 mol), potassium fluoride (10 mg, 0.17 mmol), and toluene (10 mL) at -20 0C was added (trifiuoromethyl)trimethylsilane (0.74 mL, 5.0 mmol). The reaction mixture was stirred for 20 min, and then quenched with water. To the mixture were added 1 M HCl aqueous solution (2 mL) and 1,4-dioxane (12 mL), and the mixture was stirred for 30 min. The aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash column to afford the title compound.

Reference： [1]Patent: WO2009/110985,2009,A2 .Location in patent: Page/Page column 125

17
[ 377734-27-5 ]
[ 1334302-74-7 ]

Reference： [1]Patent: US2011/224190,2011,A1

18
[ 377734-27-5 ]
[ 1334304-10-7 ]

Reference： [1]Patent: US2011/224190,2011,A1
[2]Patent: WO2012/68450,2012,A1

19
[ 377734-27-5 ]
[ 1379375-48-0 ]

Reference： [1]Patent: WO2012/68450,2012,A1

20
[ 377734-27-5 ]
[ 1379375-49-1 ]

Reference： [1]Patent: WO2012/68450,2012,A1

21
[ 377734-27-5 ]
3-[(4-{trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperazin-1-yl)methyl]-5-[(dimethylamino)methyl]benzonitrile [ No CAS ]

Reference： [1]Patent: WO2012/68450,2012,A1

22
[ 377734-27-5 ]
C₃₆H₄₈N₁₀OSi [ No CAS ]

Reference： [1]Patent: WO2012/68450,2012,A1

23
methyl 3-(aminomethyl)-5-bromobenzoate [ No CAS ]
[ 377734-27-5 ]
C₁₈H₁₅Br₂NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane;	A solution of methyl 3-(aminomethyl)-5-bromobenzoate (1 .306 g, 5.350 mmol) and methyl 3- bromo-5-formylbenzoate (1 .238 g, 5.096 mmol) in DCM (10 mL) was evaporated per vacuum techniques and left over high vacuum overnight. The residue was taken up in THF (30 mL) and treated under vigorous stirring with sodium triacetoxyborohydride (3.240 g, 15.29 mmol). This mixture was quenched after 18 h by the addition of a saturated aqueous solution of ammonium chloride (50 mL). The obtained mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried with brine and solid sodium sulfate. Upon filtration, all the volatiles were evaporated. The desired product was isolated by normal phase liquid chromatography using an Isco CombiFlash liquid chromatograph eluted with 1 % to 50% hexanes and ethylacetate. Yield 1 .61 1 g, 67%. Ions found by LCMS: (M+H)+ = 470.0, 472.1 , 474.0.

Reference： [1]Patent: WO2018/6063,2018,A1 .Location in patent: Page/Page column 415-416

24
methyl 3-(aminomethyl)-5-bromobenzoate [ No CAS ]
[ 377734-27-5 ]
methyl 3-((N-(1'-(3'-carboxymethyl-5-bromo)phenylene)methylene)methyl)-5-bromobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%		A solution of methyl 3-(aminomethyl)-5-bromobenzoate (1 .306 g, 5.350 mmol) and methyl 3- bromo-5-formylbenzoate (1 .238 g, 5.096 mmol) in DCM (10 mL) was evaporated and left over high vacuum overnight. The residue was taken up in THE (30 mL) and treated under vigorous stirring with sodium triacetoxyborohydride (3.240 g, 1 5.29 mmol). This mixture was quenched after 18 h by theaddition of a saturated aqueous solution of ammonium chloride (50 mL). The obtained mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried with brine and solid sodium sulfate. Upon filtration, all the volatiles were evaporated. The desired product was isolated by normal phase liquid chromatography using an Isco CombiElash liquid chromatograph eluted with 1% to 50% hexanes and ethylacetate. Yield 1 .611 g, 67% of 3-((N-(1 -(3-carboxymethyl-5-bromo)phenylene)methylene)methyl)-5-bromobenzoate. Ions found by LCMS: (M+H)+ 470.0, 472.1,474.0.
67%		A solution of methyl 3-(aminomethyl)-5-bromobenzoate (1 .306 g, 5.350 mmol) and methyl 3- bromo-5-formylbenzoate (1 .238 g, 5.096 mmol) in DCM (10 ml_) was evaporated and left over high vacuum overnight. The residue was taken up in THF (30 ml_) and treated under vigorous stirring with sodium triacetoxyborohydride (3.240 g, 1 5.29 mmol). This mixture was quenched after 18 h by the addition of a saturated aqueous solution of ammonium chloride (50 ml_). The obtained mixture was extracted with DCM (3 x 30 ml_). The combined organic layers were dried with brine and solid sodium sulfate. Upon filtration, all the volatiles were evaporated. The desired product was isolated by normal phase liquid chromatography using an Isco CombiFlash liquid chromatograph eluted with 1 % to 50% hexanes and ethylacetate. Yield 1 .61 1 g, 67% of 3-((N-(1 '-(3'-carboxymethyl-5- bromo)phenylene)methylene)methyl)-5-bromobenzoate. Ions found by LCMS: (M+H)+ = 470.0, 472.1 , 474.0.
67%		A solution of methyl 3-(aminomethyl)-5-bromobenzoate (1 .306 g, 5.350 mmol) and methyl 3- bromo-5-formylbenzoate (1 .238 g, 5.096 mmol) in DCM (10 ml_) was evaporated and left over high vacuum overnight. The residue was taken up in THF (30 ml_) and treated under vigorous stirring with sodium triacetoxyborohydride (3.240 g, 1 5.29 mmol). This mixture was quenched after 18 h by the addition of a saturated aqueous solution of ammonium chloride (50 ml_). The obtained mixture was extracted with DCM (3 x 30 ml_). The combined organic layers were dried with brine and solid sodium sulfate. Upon filtration, all the volatiles were evaporated. The desired product was isolated by normal phase liquid chromatography using an Isco CombiFlash liquid chromatograph eluted with 1 % to 50% hexanes and ethylacetate. Yield 1 .61 1 g, 67% of 3-((N-(1 '-(3'-carboxymethyl-5- bromo)phenylene)methylene)methyl)-5-bromobenzoate. Ions found by LCMS: (M+H)+ = 470.0, 472.1 , 474.0.

Reference： [1]Patent: WO2017/218922,2017,A2 .Location in patent: Page/Page column 285; 286
[2]Patent: WO2018/128826,2018,A1 .Location in patent: Page/Page column 313; 314; 315
[3]Patent: WO2019/126341,2019,A2 .Location in patent: Page/Page column 436-438
[4]Patent: WO2020/14469,2020,A1 .Location in patent: Page/Page column 218-220

25
[ 51760-21-5 ]
[ 377734-27-5 ]