[ CAS No. 33295-37-3 ] {[proInfo.proName]}

Name: 33295-37-3|1-Bromo-8-methylnaphthalene|98%
Brand: Ambeed
SKU: A178464
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Quality Control of [ 33295-37-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 33295-37-3 ]

SDS Specification

Alternatived Products of [ 33295-37-3 ]

Product Details of [ 33295-37-3 ]

CAS No. :	33295-37-3	MDL No. :	MFCD00229485
Formula :	C₁₁H₉Br	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QTWVRVGVJURUFK-UHFFFAOYSA-N
M.W :	221.09	Pubchem ID :	4250949
Synonyms :

Calculated chemistry of [ 33295-37-3 ] Expand+

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.09
Num. rotatable bonds :	0
Num. H-bond acceptors :	0.0
Num. H-bond donors :	0.0
Molar Refractivity :	56.61
TPSA :	0.0 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.65 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.5
Log Po/w (XLOGP3) :	4.23
Log Po/w (WLOGP) :	3.91
Log Po/w (MLOGP) :	4.32
Log Po/w (SILICOS-IT) :	4.14
Consensus Log Po/w :	3.82

Druglikeness

Lipinski :	1.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-4.49
Solubility :	0.00712 mg/ml ; 0.0000322 mol/l
Class :	Moderately soluble
Log S (Ali) :	-3.94
Solubility :	0.0253 mg/ml ; 0.000115 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.32
Solubility :	0.00106 mg/ml ; 0.0000048 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.21

Safety of [ 33295-37-3 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 33295-37-3 ]

* 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 [ 33295-37-3 ]

[ 33295-37-3 ] Synthesis Path-Downstream 1~26

1
[ 4044-58-0 ]
[ 33295-37-3 ]

Reference： [1]Journal of the American Chemical Society,1939,vol. 61,p. 136,140

2
[ 130523-30-7 ]
[ 33295-37-3 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1930,vol. 2,p. 145,156

3
[ 60-29-7 ]
[ 4044-58-0 ]
magnesium [ No CAS ]
[ 569-41-5 ]
[ 33295-37-3 ]

Reference： [1]Journal of the American Chemical Society,1939,vol. 61,p. 136,140

4
[ 62456-34-2 ]
[ 33295-37-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aqueous H₂SO₄ / Diazotization_.Erwaermen der Diazoniumsalz-Loesung mit KI 2: magnesium; diethyl ether / anschliessende Umsetzung mit Dimethylsulfat in Benzol

Reference： [1]Fieser; Seligman [Journal of the American Chemical Society, 1939, vol. 61, p. 136,140]

5
[ 33295-37-3 ]
ammonium chloride [ No CAS ]
[ 25503-91-7 ]
[ 76064-47-6 ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium In tetrahydrofuran; diethyl ether; ethanol	16 8-Methyl-1-naphthyl 4-piperidyl ketone hydrochloride EXAMPLE 16 8-Methyl-1-naphthyl 4-piperidyl ketone hydrochloride A solution of 10.0 g (45 mmoles) of 1-bromo-8-methylnaphthalene in 5 ml of ethyl ether is added gradually to a stirred mixture of 1.2 g (50 mmoles) of magnesium in 30 ml of anhydrous ether. The mixture is stirred at reflux for 1 hour and a solution of 6.0 g (43 mmoles) of 1-acetyl-4-piperidinecarbonitrile in 10 ml of tetrahydrofuran slowly added. The mixture is allowed to stir for 16 hours, an excess of saturated aqueous ammonium chloride solution added and the mixture heated on a steam bath for 3 hours. After cooling, the mixtures is extracted with toluene and the organic phase dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in 20 ml of ethanol and made basic with sodium hydroxide and the solution extracted into toluene. Dry hydrogen chloride is bubbled through the organic phase to yield 8-methyl-1-naphthyl 4-piperidyl ketone hydrochloride.

Reference： [1]Current Patent Assignee: PROCTER & GAMBLE CO; SANOFI - US4246268, 1981, A

6
[ 14938-58-0 ]
[ 33295-37-3 ]

Reference： [1]Tetrahedron,2008,vol. 64,p. 6090 - 6102
[2]Journal of Organic Chemistry,2012,vol. 77,p. 1693 - 1700

7
[ 33295-37-3 ]
[ 19455-23-3 ]
[ 72681-59-5 ]

Reference： [1]Tetrahedron,2008,vol. 64,p. 6090 - 6102

8
[ 33295-37-3 ]
[ 1184-88-9 ]
[ 72681-59-5 ]

Reference： [1]Tetrahedron,2008,vol. 64,p. 6090 - 6102

9
[ 121-43-7 ]
[ 33295-37-3 ]
[ 948592-91-4 ]

Yield	Reaction Conditions	Operation in experiment
40%	Stage #1: 1-bromo-8-methylnaphthalene With n-butyllithium In diethyl ether; hexane for 0.0333333h; Inert atmosphere; Stage #2: Trimethyl borate In diethyl ether; hexane at -78 - 22℃; for 18h; Inert atmosphere; Stage #3: With hydrogenchloride In diethyl ether; hexane for 16h; Inert atmosphere;

Reference： [1]Miles, William H.; Robinson, Michael J.; Lessard, Samantha G.; Thamattoor, Dasan M. [Journal of Organic Chemistry, 2016, vol. 81, # 22, p. 10791 - 10801]

10
[ 17135-74-9 ]
[ 74-88-4 ]
[ 33295-37-3 ]

Yield	Reaction Conditions	Operation in experiment
61%	In tetrahydrofuran; at 25℃; for 3.5h;Inert atmosphere;	Step 1: Preparation of 1-bromo-8-methylnaphthalene To a solution of 1,8-dibromonaphthalene (21.2 g, 74.0 mmol, 1 eq) in THF (400 mL) at 0 C was added MeLi (1.6 M, 50.9 mL, 1.1 eq) dropwise, and the reaction mixture was stirred for 0.5 hour. CH3I (42.0 g, 296.1 mmol, 4 eq) was then added under N2, and the reaction mixture was stirred at 25 C for 3 hours. The reaction was quenched by addition of water (80 mL) at 0C, and the resulting mixture was extracted with EtOAc (2 x 300 mL). The combined organic extract was washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by prep-HPLC (55-95% CH3CN in water (0.225% formic acid)) to afford 1-bromo-8-methylnaphthalene (10.5 g, 45.1 mmol, 61% yield) as a yellow solid.1H- NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.76-7.70 (m, 1H), 7.40-7.35 (m, 2H), 7.23 (t, J = 8.0 Hz, 1H), 3.15 (s, 3H).
58%		Under the protection of nitrogen, compound 1a (2.00g, 6.99mmol) was dissolved in tetrahydrofuran (15mL), the temperature was lowered to -78C, 2.5M n-butyllithium in n-hexane solution (3.08mL, 7.70mmol) was added to it, and the reaction For 0.5 hour, iodomethane (4.00 g, 2.81 mmol) was added dropwise at -78C. The reaction system was naturally warmed to room temperature. After the reaction was continued for 2.5 hours, it was diluted by adding water (20mL) and ethyl acetate (10mL), and the liquids were separated. The aqueous phase was extracted with ethyl acetate (10mL x 1). After the organic phases were combined, there was no water. It was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was recrystallized from isopropanol (1 mL) to obtain 1b (903 mg), yield: 58%.
51%		Two separate reactions were run in parallel. For each reaction, to a solution of 1,8- dibromonaphthalene (75 g, 262 mmol, 1 equiv) in THF (1.5 L) at 0 C was added MeLi (1 M in 2- methyltetrahydrofuran, 420 mL, 1.6 equiv) dropwise, then the mixture was warmed to 13 C. After 0.5 h, MeI (253 g, 1.78 mol, 6.8 equiv) was added dropwise to the mixture. After 0.5 h, the two separate reaction mixtures were combined. H2O (2 L) was poured into the mixture and the aqueous phase was extracted with EtOAc (2 x 800 mL). The combined organic phase was washed with sat. aq. NaCl (800 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% petroleum ether) followed by reverse phase chromatography to afford 1-bromo-8-methyl-naphthalene (60 g, 51% yield) as a white solid. 1H NMR (400 MHz, Chloroform- d) δ 7.84 (dd, J = 1.2, 7.4 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.75 - 7.68 (m, 1H), 7.39 - 7.33 (m, 2H), 7.22 (t, J = 7.8 Hz, 1H), 3.14 (s, 3H).

43%		To a solution of 1,8-dibromonaphthalene (1 g, 3.50 mmol, 1 eq) in THF (20 mL) was added MeLi (1.6 M in diethyl ether, 2.62 mL, 1.2 eq) at 0° C. dropwise. After stirring for 30 minutes at 0° C., iodomethane (3.38 g, 23.8 mmol, 1.48 mL, 6.81 eq) was added dropwise. The mixture was warmed up to 25° C. and stirred for another 3 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL 3). The combined organic layers were washed with brine (20 mL), dried over Na 2SO 4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18 25050 mm10 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 45%-70%, 28 MIN; 40% min). Title compound 1-bromo-8-methyl-naphthalene (340 mg, 1.49 mmol, 43% yield, 97% purity) was obtained as a yellow solid after lyophilisation. 1H NMR (400 MHz, chloroform-d) δ=7.75 (dd, J=0.8, 7.2 Hz, 1H), 7.69 (dd, J=0.8, 8.0 Hz, 1H), 7.66-7.59 (m, 1H), 7.30-7.22 (m, 2H), 7.13 (t, J=8.0 Hz, 1H), 3.05 (s, 3H).
43%	With methyllithium; In tetrahydrofuran; at 0 - 25℃; for 3.5h;	To a solution of 1,8-dibromonaphthalene (1 g, 3.50 mmol, 1 eq ) in THF (20 ml.) was added MeLi (1.6 M in diethyl ether, 2.62 mL, 1.2 eg) at 0C dropwise. After stirring for 30 minutes at 0C, iodomethane (3.38 g, 23.8 mmol, 1.48 mL, 6.81 eq) was added dropwise. The mixture was warmed up to 25C and stirred for another 3 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini Cl 8 25050mm 10 um; mobile phase: [water (0.05% ammonium hydroxide v/v) - ACN]; B%: 45% - 70%, 28 MIN; 40% min). Ttitle compound l-bromo-8-methyl -naphthalene (340 mg, 1.49 mmol, 43% yield, 97% purity) was obtained as a yellow solid after lyophilisation.(0504) [0309] NMR (400MHz, chloroform-d) d = 7.75 (dd, J = 0.8, 7.2 Hz, 1H), 7.69 (dd, J = 0.8, 8.0 Hz, 1H), 7.66 - 7.59 (m, 1 H), 7.30 - 7.22 (m, 2H), 7.13 (t, j= 8.0 Hz, HI), 3.05 (s, 3H).
2.15 g		In an ice-salt bath at -10C, the 1.8-dibromonaphthalene(4.70g) dissolved in anhydrous THF (50mL), under the protection of nitrogen,The ether solution of methyl lithium (1.6M, 11.2mL)Use a syringe to slowly add to the above solution,Keep at 0C and stir for 1 hour, then drop to -10C,Add methyl iodide (9.30g) in THF(10mL) The solution was slowly added to the reaction solution and slowly returned to room temperature.Continue to stir for 5 hours,The reaction was quenched with saturated aqueous sodium chloride solution,Then it was extracted with ethyl acetate, the organic phases were combined,Dry with anhydrous sodium sulfate, filter,The filtrate was concentrated under reduced pressure,The residue was separated by column chromatography to obtain a yellow solid (4.10g),The yellow solid was recrystallized from tert-butanol to obtain white flake crystals (2.15 g).

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 10791 - 10801
[2]Patent: WO2021/207172,2021,A1 .Location in patent: Paragraph 00332
[3]Patent: CN112778302,2021,A .Location in patent: Paragraph 0069-0074
[4]Patent: CN113135924,2021,A .Location in patent: Paragraph 0706; 0721-0722
[5]Patent: WO2021/108683,2021,A1 .Location in patent: Page/Page column 190-191
[6]Patent: US2019/144444,2019,A1 .Location in patent: Paragraph 0484-0486
[7]Patent: WO2020/47192,2020,A1 .Location in patent: Paragraph 0307-0309
[8]Patent: CN113004269,2021,A .Location in patent: Paragraph 0198-0204

11
[ 33295-37-3 ]
[ 62-53-3 ]
N-phenyl-8-methyl-1-naphthylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With tris-(dibenzylideneacetone)dipalladium(0); triphenylphosphine; sodium t-butanolate; In toluene; at 100 - 110℃; for 5h;Inert atmosphere;	1000 ml three-necked flask with magnetic stirring, argon replacement followed by sodium tert-butoxide 46.1 g (0.48 mol), aniline 27.9 g (purity 99%, 0.3 mol), 44.2 g <strong>[33295-37-3]1-bromo-8-methylnaphthalene</strong> (purity 99%, 0.2 mol) and 400 ml of toluene. After argon substitution again, 3 ml of tri-tert-butylphosphine and 0.46 g of tris(diphenylbenzylacetone)dipalladium were successively added. After the addition was completed, the mixture was heated to a temperature of 100 C by stirring, and the temperature was controlled at 100 to 110 C for 5 hours. After cooling to 30 C, the filtrate was filtered through a silica gel column. The filtrate was evaporated, dissolved in dichloromethane, washed twice with 4 mol/L hydrochloric acid solution, separated, dried over anhydrous sodium sulfate, filtered, and evaporated. The filtrate gave 41 g of a yellow product, purity 99%, yield 88%.

Reference： [1]Patent: CN108484417,2018,A .Location in patent: Paragraph 0076; 0077; 0084; 0086; 0090; 0093; 0095; 0096

12
[ 33295-37-3 ]
benzyl (S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate [ No CAS ]
benzyl (S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In toluene; at 100℃; for 18h;Inert atmosphere;	To a solution of benzyl (S)-2-(cyanomethyl)-4-(2-((((S)-1-methylpyrrolidin-2-yl)methyl)thio)-5,6,- 7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (61 mg, 0.12 mmol) in toluene (2 mL) was added <strong>[33295-37-3]1-bromo-8-methylnaphthalene</strong> (78 mg, 0.35 mmol) and the reaction degassed with argon for 15 minutes followed by addition of Cs 2CO 3 (190 mg, 0.58 mmol), Pd 2(dba) 3 (21 mg, 0.023 mmol) and Xantphos (27 mg, 0.047 mmol) and the reaction heated to 100° C. for 18 hr. The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was next purified by chromatography using 1 12% MeOH/DCM with 2% NH 4OH as additive to give benzyl (S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-((((S)-1-methylpyrro- lidin-2-yl)methyl)thio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)pipe- razine-1-carboxylate (54 mg, 0.082 mmol, 70% yield).

Reference： [1]Patent: US2019/144444,2019,A1 .Location in patent: Paragraph 3525

13
[ 33295-37-3 ]
(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepan-4-yl)piperazine-1-carboxylic acid benzyl ester [ No CAS ]
(S)-2-(cyanomethyl)-4-(8-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azepan-4-yl)piperazine-1-carboxylic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos; In toluene; at 110℃;Inert atmosphere; Reflux;	(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro -5H-Pyrimido[4,5-c]azeppan-4-yl)piperazine-1-carboxylic acid benzyl ester (Intermediate 12) (580mg, 1.12mmol) and 1-bromo-8-methyl Naphthalene (450mg, 2.05mmol, 1.2eq) was mixed uniformly in toluene (15mL), after nitrogen replacement, Cs2CO3 (1.1g, 3.37mmol), RuPhos (104mg, 0.23mmol) and Pd2dba3 (102mg, 0.11mmol) were added.Under the protection of N2, heat to reflux, stir and react overnight. Cool to room temperature and filter,After the filtrate is concentrated, it is purified by silica gel column chromatography (eluent: EtOH/EA(V/V): 0-15%),(S)-2-(cyanomethyl)-4-(8-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methan Oxy)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c]azeppan-4-yl)piperazine-1-carboxylic acid benzyl ester(Intermediate 13) (350 mg, 47% yield).
17%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In toluene; at 90℃; for 12h;Inert atmosphere;	A mixture of benzyl (25)-2-(cyanomethyl)-4-[2-[[(25r)-l- methylpyriOlidin-2-yl]methoxy]-6,7,8,9-tetrahydro-577-pyrimido[4,5-c]azepin-4-yl]piperazine-l- carboxylate (330 mg, 540 pmol, 1.0 eq ), l-bromo- 8 -methyl -naphthalene (239 mg, 1.08 mmol, (0533) 2.0 eq), Xantphos (93.7 mg, 162 pmol, 0.3 eq), Pd2(dba)3 (74.2 mg, 81.0 pmol, 0.15 eq) and CS2CO3 (528 mg, 1.62 mmol, 3.0 eq) in toluene (3.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 C for 12 hours under N2 atmosphere. After completion, the reaction was washed with HC1 (1 N, 2 x 5.0 mL). The aqueous phase was treated with solid NaHC03 to pH ~ 7 and extracted with ethyl acetate (3 x 5.0 mL). The organic layer was dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (basic A1203, Petroleum ether: Ethyl acetate = 3: 1 to Ethyl acetate : Methanol = 50:1) and then residue was purified by reverse phase flash [C18, 0.1% FA in water , 0-65% MeCN] and was treated with NallC'Ch solid to pH ~ 7, and extracted with ethyl acetate (2 c 50 mL). The organic layers were dried over Na2S04, filtered and concentrated under vacuum. (0534) Benzyl(2S)-2-(cyanomethyl)-4-[8-(8-methyl-l-naphthyl)-2-[[(25)-l-methylpyrrolidin-2- yl]methoxy]-5, 6, 7, 9-tetrahydropyrimido[4,5-c]azepin-4-yl]piperazine-l -carboxylate (60.0 mg, 91.0 pmol, 17% yield, 100% purity) was obtained as white solid. LCMS [ESI, M+l]: 660. (0535) [0321] NMR (400 MHz, chloroform-d) d 7.55 - 7.46 (m, 2LI), 7.31 - 7.27 (m, 2H), 7.27 - 7.10 (m, 6H), 7.06 (t , J= 5.8 Hz, 1H), 5.09 (s, 2H), 4.58 (br s, 1H), 4.28 - 4.20 (m, 2H), 4.19 - 4.1 1 (m, 1H), 3.99 - 3.92 (m, 1H), 3.71 - 3.59 (m, 1H), 3.49 (t, J= 12.6 Hz, 1H), 3.36 - 3.03 (m, 4H), 2.98 - 2.76 (m, 4H), 2.73 - 2.47 (m, 7H), 2.31 (d, J= 3.2 Hz, 3H), 2.18 - 2.10 (m, 1H), 1.92 - 1.79 (m, 3 FI), 1.73 - 1.54 (m, 3H).

Reference： [1]Patent: CN112538084,2021,A .Location in patent: Paragraph 0485; 0511-0514
[2]Patent: WO2020/47192,2020,A1 .Location in patent: Paragraph 0314; 0320-0321

14
[ 55124-35-1 ]
[ 33295-37-3 ]
2-B-((N,N-diisopropylamino)-8-methylnaphth-1-yl)-borane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With magnesium In tetrahydrofuran at 20 - 40℃;

Reference： [1]Birepinte, Mélodie; Chabaud, Laurent; Pinet, Sandra; Pucheault, Mathieu; Robert, Frédéric [Organic and biomolecular chemistry, 2020, vol. 18, # 16, p. 3007 - 3011]

15
[ 33295-37-3 ]
[ 73183-34-3 ]
4,4,5,5-tetramethyl-2-(8-methyl-1-naphthyl)-1,3,2-dioxaborolane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 95℃; for 18h;Inert atmosphere;	To a solution of l-bromo-8-methylnaphthalene (1 g, 4.5 mmol) in dioxane (23 mL) were added potassium acetate (1.3 g, 14 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3.4 g, 14 mmol) and the reaction was sparged with N2 for 15 minutes, followed by addition of PdCl2(dppf) (330 mg, 0.45 mmol). The reaction was heated to 95C for 18 hrs. The reaction was concentrated in vacuo and taken up in DCM. The slurry was filtered through GF/F paper and the organics concentrated in vacuo. The crude material was chromatographed using 0- >30% ethyl acetate/hexane as eluent to give 4,4,5,5-tetramethyl-2-(8-methylnaphthalen-l-yl)-l,3,2- dioxaborolane (1.5 g, 4.5 mmol, 99 % yield). HPLC (5-95% ACN/H2O+0.1%TFA) 4.67 min.
68%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 95℃; for 18h;Inert atmosphere;	Step A. 4A5A-tetramethyl-2-(8-methylnaphthalen-l-yl)-E3,2-dioxaborolane. To a solution of l-bromo-8-methylnaphthalene (0.700 g, 3.17 mmol) in dioxane (15.8 ml) was added potassium acetate (0.932 g, 9.50 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (2.41 g, 9.50 mmol) and the reaction sparged with N2 for 15 minutes, followed by the addition of PdC12(dppf) (0.232 g, 0.317 mmol). The reaction was heated to 95C for 18 hrs. The reaction was concentrated in vacuo and taken up in DCM. The slurry was filtered through GF/F filter paper and the organics was concentrated in vacuo. The material was chromatographed twice using 10- >100% Ethyl acetate/hexane as eluent to give 4,4,5,5-tetramethyl-2-(8- methylnaphthalen-l-yl)-l,3,2-dioxaborolane (576 mg, 2.15 mmol, 68 % yield). HPLC (5-95% ACN/H2O+0.1%TFA) 3.701 min.
55%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 90℃; for 15h;Inert atmosphere;	To <strong>[33295-37-3]1-bromo-8-methylnaphthalene</strong> (2.00 g, 9.05 mmol, 1 eq) in DMF (30 mL) were added KOAc (2.66 g, 27.1 mmol, 3 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.59 g, 18.1 mmol, 2 eq), and Pd(dppf)Cl2 (662 mg, 0.905 mmol, 0.1 eq) under N2 atmosphere, and the reaction mixture was stirred at 90 C for 15 hours. The reaction mixture was cooled and diluted with EtOAc (100 mL). The resulting mixture was washed with water (3 x 20 mL), brine (3 x 20 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography (gradient: 0-4% EtOAc in petroleum ether) followed by prep-HPLC (25-90% CH3CN in water (10 mM NH4HCO3)) to give 4,4,5,5-tetramethyl-2-(8-methyl-1-naphthyl)-1,3,2-dioxaborolane (1.35 g, 5.01 mmol, 55% yield) as a yellow solid. LC/MS (ESI) m/z: 269.4 [M+H]+.

52.2%

With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In 1,4-dioxane; at 90℃; for 3h;Inert atmosphere;

Dissolve <strong>[33295-37-3]1-bromo-8-methylnaphthalene</strong> (660.0mg, 3.0mmol) in dioxane (20.0mL),It was added with boronic acid ester (914.4g, 3.6mmol),Pd(PPh3)2Cl2(63.0mg, 0.09mmol)And potassium acetate (882.0mg, 9.0mmol),The system reacts at 90C for 3 hours in a nitrogen environment,After the reaction is complete, concentrate,Column chromatography (petroleum ether: ethyl acetate = 50:1) was purified to obtain the product (420.0 mg, yield: 52.2%).

Reference： [1]Patent: WO2021/41671,2021,A1 .Location in patent: Paragraph 0249; 0318; 0479
[2]Patent: WO2022/31678,2022,A1 .Location in patent: Paragraph 0199
[3]Patent: WO2022/31678,2022,A1 .Location in patent: Paragraph 0199
[4]Patent: WO2021/207172,2021,A1 .Location in patent: Paragraph 00332
[5]Patent: CN112047948,2020,A .Location in patent: Paragraph 0186-0189

16
[ 33295-37-3 ]
tert-butyl 2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate [ No CAS ]
tert-butyl 2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With caesium carbonate; In 1,4-dioxane; at 72℃; for 16h;Inert atmosphere;	The tert-butyl 2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate(2g, 4.94mmol),<strong>[33295-37-3]1-bromo-8-methylnaphthalene</strong> (2.73g, 12.35mmol),Cesium carbonate (4.83 g, 14.82 mmol) and dioxane (80 mL) were added to the reaction flask, and then replaced with nitrogen three times, followed by Ruphos PdG3 (1.24 g, 1.48 mmol).The resulting mixture was replaced with nitrogen three times and then heated to 72C and stirred for 16 h. The resulting mixture was added with water (100 mL), and then extracted with ethyl acetate (3×100 mL).After all the organic phases were combined, washed once with saturated sodium chloride, then dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE/EA=1/0 to 5/1) to obtain the target product (863 mg, yield 32%).

Reference： [1]Patent: CN112694475,2021,A .Location in patent: Paragraph 0246; 0259-0261
[2]Patent: WO2021/23247,2021,A1 .Location in patent: Page/Page column 50-51

17
[ 33295-37-3 ]
ethyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxylate [ No CAS ]
ethyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-7-(8-methylnaphthalen-1-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1‘-biphenyl)[2-(2’-methylamino-1,1’-biphenyl)]palladium(II) methanesulfonate; caesium carbonate; In 1,4-dioxane; at 100℃; under 760.051 Torr; for 3.5h;Inert atmosphere; Sealed tube;	To a 40 mL glass vial was added ethyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)- 5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxylate (Int-1) (1.00 g, 2.36 mmol), 1-bromo-8- methylnaphthalene (0.781 g, 3.53 mmol), methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i- propoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (0.200 g, 0.236 mmol), cesium carbonate (2.69 g, 8.24 mmol), and a teflon-coated magnetic stir bar. Then anhydrous 1,4-dioxane (11.8 mL) was added, and the mixture was degassed by subsurface sparging with nitrogen for 4 min, and the vial was then sealed under 1 atm of nitrogen. The mixture was stirred at 100 C for 3.5 h, then filtered through CELITE. The CELITE was rinsed with dichloromethane, and the combined filtrate was concentrated to a residue that was purified by column chromatography on silica gel (10% to 20% (3:1 ethyl acetate:ethanol v/v) in hexane), followed by a second purification by column chromatography on silica gel (15% to 40% ethyl acetate in hexane) to afford ethyl 4-(4-((benzyloxy)carbonyl)piperazin-1-yl)-7-(8- methylnaphthalen-1-yl)-5,6,7,8-tetrahydro-1,7-naphthyridine-2-carboxylate (Int-12a).1H NMR (500 MHz, Methanol-d4) Diagnostic signals: d 7.69 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.62 (s, 1H), 7.44 - 7.28 (m, 8H), 7.23 (d, J = 7.0 Hz, 1H), 5.17 (s, 2H), 4.47 - 4.34 (m, 3H), 3.89 (d, J = 17.1 Hz, 1H), 3.82 - 3.62 (m, 4H), 3.62 - 3.54 (m, 1H), 3.05 - 2.94 (m, 3H), 2.89 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). Mass Calc'd: 564.3, found 565.3 (M+H)+.

Reference： [1]Patent: WO2021/55728,2021,A1 .Location in patent: Page/Page column 50-51

18
[ 33295-37-3 ]
(S)-4-(3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester [ No CAS ]
tert-butyl (S)-4-(3-cyano-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With methanesulfonato(2-dicyclohexylphosphino-2’-6’-di-i-propoxy-1,1‘-biphenyl)(2-amino-1,1‘-biphenyl-2-yl)palladium(II); caesium carbonate; In 1,4-dioxane; at 90℃; for 4h;Inert atmosphere; Sealed tube;	Into a 20-mL sealed tube, purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (S)-4-(3-cyano-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate (251 mg, 0.55 mmol), <strong>[33295-37-3]1-bromo-8-methylnaphthalene</strong> (336 mg, 1.52 mmol), RuPhos Pd G3 (217 mg, 0.26 mmol), Cs2CO3 (472 mg, 1.45 mmol), 1,4-dioxane (8 m L). The reaction mixture was stirred at 90 C. for 4 hrs. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by C18 column eluted with ACN/H2O (v/v=1/1). This resulted in 142 mg (74%) of tert-butyl (S)-4-(3-cyano-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazine-1-carboxylate as yellow oil. LCMS: m/z=597[M+1]+

Reference： [1]Patent: US2021/94919,2021,A1 .Location in patent: Paragraph 0213; 0217

19
[ 33295-37-3 ]
benzyl (2S)-2-(cyanomethyl)-4-(2-methylsulfanyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate [ No CAS ]
benzyl (S)-2-(cyanomethyl)-4-(7-(8-methylnaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 12h;Inert atmosphere;	Compound 1h (408mg, 0.93mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (290mg, 0.46mmol), sodium tert-butoxide (224mg, 2.33mmol), tris(dibenzylidene) Base acetone) two palladium (136 mg, 0.15 mmol) and 1b (408 mg, 1.86 mmol) were dissolved in anhydrous toluene (10 mL), replaced with nitrogen three times, and heated to 100 C. to react for 12 hours. The filter was filtered with celite at room temperature, and the filter residue was washed with ethyl acetate (20 mL x 1). After the organic phases were combined, concentrated under reduced pressure to obtain a residue. The residue was subjected to column chromatography (ethyl acetate: petroleum ether = 0-100). %) to obtain the crude product (460 mg), which was then purified by thin layer chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain 1i (247 mg). Yield: 41%.
6.63 g	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos; In toluene; at 105℃; for 12h;	A solution of benzyl (S)-2-(cyanomethyl)-4-(2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-yl)piperazine-1-carboxylate (15.7 g, 35.9 mmol, 1 equiv), 1-bromo-8-methyl-naphthalene (15.9 g, 71.7 mmol, 2 equiv), Cs2CO3 (29.2 g, 89.6 mmol, 2.5 equiv), RuPhos (3.35 g, 7.17 mmol, 0.2 equiv), and Pd2(dba)3 (3.28 g, 3.58 mmol, 0.1 equiv) in toluene (160 mL) was heated to 105 C. After 12 h the mixture was filtered to remove solids, added to H2O (300 mL), and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with sat. aq. NaCl (3 x 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (0→50% EtOAc/petroleum ether) to afford benzyl (S)-2-(cyanomethyl)-4-(7- (8-methylnaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)piperazine-1- carboxylate (6.63 g, 32% yield) as yellow solid. LCMS (ESI) m/z: [M + H] calcd for C33H35N6O2S: 579.25; found 579.3; 1H NMR (400 MHz, CDCl3) δ 7.72 - 7.62 (m, 2H), 7.42 - 7.34 (m, 7H), 7.25 - 7.14 (m, 2H), 5.21 (s, 2H), 4.69 (s, 1H), 4.31 - 4.19 (m, 1H), 4.00 - 3.74 (m, 3H), 3.56 - 3.39 (m, 2H), 3.25 - 3.09 (m, 3H), 3.07 - 2.94 (m, 2H), 2.91 (s, 3H), 2.80 - 2.58 (m, 3H), 2.50 (d, J = 4.77 Hz, 3H).

Reference： [1]Patent: CN112778302,2021,A .Location in patent: Paragraph 0069; 0071; 0089-0091
[2]Patent: WO2021/108683,2021,A1 .Location in patent: Page/Page column 267; 269

20
[ 33295-37-3 ]
[ 72758-17-9 ]

Yield	Reaction Conditions	Operation in experiment
96%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 16h;Inert atmosphere;	9a (5.00 g, 22.80 mmol) was dissolved in carbon tetrachloride (80 mL), and N-bromosuccinimide (4.50 g, 25.10 mmol) and azobisisobutyronitrile (375 mg, 23.00 mmol) were added. After nitrogen replacement for three times and stirring at 80C for 16 hours, water (50 mL) and ethyl acetate (50 mL) were added to quench the reaction, filtered, and separated. The organic phase was concentrated under reduced pressure to obtain a residue. The residue was subjected to column chromatography (petroleum ether: (Ethyl acetate=0-100%) purification to obtain compound 9b (5.00 g), yield: 96%.

Reference： [1]Patent: CN112778302,2021,A .Location in patent: Paragraph 0240-0244

21
[ 33295-37-3 ]
(S)-4-(benzyloxy)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine [ No CAS ]
(S)-4-(benzyloxy)-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; ruphos; In 1,4-dioxane; at 100℃; for 13h;	To a solution of (S)-4-(benzyloxy)-2-((1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidine (20 g, 56.4 mmol, 1 equiv) in dioxane (400 mL) was added 1-bromo-8- methylnaphthalene (18.7 g, 84.6 mmol, 1.5 equiv), Cs2CO3 (46.0 g, 141 mmol, 2.5 equiv), RuPhos (5.27 g, 11.3 mmol, 0.2 equiv) and Pd2(dba)3 (5.17 g, 5.64 mmol, 0.1 equiv). The resulting mixture was heated to 100 C for 13 h then cooled to room temperature. The mixture was filtered, and the solid cake was washed with DCM (3 x 80 mL), then the filtrate was concentrated under reduced pressure. The mixture was suspended in EtOAc (90 mL) and H2O (90 mL). The aqueous phase was extracted into EtOAc (3 x 60 mL), the combined organic phase was washed with sat. aq. NaCl (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% EtOAc) to afford (S)-4-(benzyloxy)-7-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2- yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (16 g, 44% yield) as a brown oil.1H NMR (400 MHz, Chloroform-d) δ 7.72 - 7.61 (m, 2H), 7.50 - 7.45 (m, 2H), 7.44 - 7.30 (m, 5H), 7.26 - 7.21 (m, 1H), 5.58 - 5.40 (m, 2H), 4.49 - 4.27 (m, 1H), 4.25 - 4.05 (m, 2H), 3.84 (d, J = 17.4 Hz, 1H), 3.52 (dd, J = 5.4, 11.9 Hz, 1H), 3.28 - 3.04 (m, 2H), 2.98 - 2.83 (s, 3H), 2.73 (d, J = 16.6 Hz, 2H), 2.49 (s, 3H), 2.36 - 2.23 (m, 1H), 2.15 - 1.99 (m, 1H), 1.89 - 1.55 (m, 5H).

Reference： [1]Patent: WO2021/108683,2021,A1 .Location in patent: Page/Page column 190; 193

22
[ 33295-37-3 ]
(S)-2-((1-methylpyrrolidin-2-yl)methoxy)-8-(naphthalen-1-yl)-4-(piperazin-1-yl)-6,7,8,9-tetrahydropyrimido[4,5-f][1,4]oxazepine [ No CAS ]
(S)-4-(8-(8-methylnaphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydropyrimido[4,5-f][1,4]oxazepin-4-yl)piperazine-1-carboxylic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In toluene; at 100℃;Inert atmosphere;	Add (S)-4-(2-((1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydropyrimido[4,5-f][1,4]oxazepin-4-yl)piperazine-1-carboxylic acid benzyl ester (934mg, 1.9mmol),1-Bromo-8-methylnaphthalene (771mg, 2.9mmol), Pd2(dba)3 (181mg, 0.19mmol),XantPhos (231mg, 0.39mmol), cesium carbonate (1.93g, 5.8mmol) and toluene (10mL),Reacted overnight at 100C under the protection of nitrogen, and then cooled to room temperature. The reaction solution was concentrated to dryness.Then it was purified by column chromatography (DCM/MeOH(v/v)=100/1) to obtain the title compound as a yellow solid (0.84g, 70%).

Reference： [1]Patent: CN113135924,2021,A .Location in patent: Paragraph 0457-0461

23
[ 33295-37-3 ]
(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydropyrimido[4,5-f][1,4]oxazepin-4-yl)piperazine-1-carboxylic acid benzyl ester [ No CAS ]
(S)-2-(cyanomethyl)-4-(8-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydropyrimido[4,5-f][1,4]oxazepin-4-yl)piperazine-1-carboxylic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In toluene; at 100℃;Inert atmosphere;	Add to the bottle(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydropyrimido[4,5-f][1,4]oxazepin-4-yl)piperazine-1-benzyl carboxylate (740mg, 1.4mmol),1-Bromo-8-methylnaphthalene (480mg, 2.1mmol), Pd2(dba)3 (133mg, 0.14mmol), XantPhos (169mg, 0.28mmol),Cesium carbonate (1.42g, 4.3mmol) and toluene (10mL), under nitrogen protection, react overnight at 100C,After cooling to room temperature, the reaction solution was concentrated to dryness, and then purified by column chromatography (DCM/MeOH(v/v)=100/1) to obtain the title compound as a yellow solid (670.0 mg, 71%).

Reference： [1]Patent: CN113135924,2021,A .Location in patent: Paragraph 0468; 0483-0485

24
[ 33295-37-3 ]
(S)-2-(cyanomethyl)-4-((6S,9S)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-6,9-methanopyrimidino[4,5-c]azepin-4-yl)piperazine-1-carboxylic acid benzyl ester [ No CAS ]
(S)-2-(cyanomethyl)-4-((6S,9S)-8-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-6,9-methanopyrimidino[4,5-c]azepin-4-yl)piperazine-1-carboxylic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In toluene; at 90℃;Inert atmosphere;	Add to the reaction flask one by one(S)-2-(cyanomethyl)-4-((6S,9S)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,7,8,9-tetrahydro-5H-6,9-methanopyrimido[4,5-c]azepin-4-yl)piperazine-1-carboxylic acid benzyl ester (180.0mg, 0.34mmol),1-bromo-8-methyl-naphthalene (150.0mg, 0.68mmol), tris(dibenzylideneacetone) two palladium (16.0mg, 0.02mmol),4,5-bisdiphenylphosphine-9,9-dimethylxanthene (25.0mg, 0.04mmol), cesium carbonate (220.0mg, 0.67mmol) and toluene (4mL),Under nitrogen protection, the temperature was raised to 90C and the reaction was stirred overnight, then cooled to room temperature, filtered, and concentrated.Then it was purified by column chromatography (DCM/MeOH(v/v)=9/1) to obtain the title compound (97.5 mg, 43%).

Reference： [1]Patent: CN113135924,2021,A .Location in patent: Paragraph 0251; 0281-0283

25
[ 33295-37-3 ]
(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester [ No CAS ]
(S)-2-(cyanomethyl)-4-(6-(8-methylnaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In toluene; at 110℃;Inert atmosphere;	Add to the reaction flask one by one(S)-2-(cyanomethyl)-4-(2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyridine[4,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid benzyl ester (700.0mg, 1.38mmol),1-Bromo-8-methyl-naphthalene (460.0mg, 2.08mmol), tris(dibenzylideneacetone) two palladium (63.0mg, 0.07mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (60.0mg, 0.10mmol),Cesium carbonate (902.0mg, 2.77mmol) and toluene (10.0mL), protected by nitrogen, heated to 110C and stirred overnight,After cooling to room temperature, ethyl acetate (20 mL) was added, and the resulting mixture was filtered and concentrated.Then it was purified by column chromatography (DCM/MeOH(v/v)=30/1) to obtain the title compound as a light brown solid (809.0 mg, 90%).

Reference： [1]Patent: CN113135924,2021,A .Location in patent: Paragraph 0290; 0308-0311

26
[ 33295-37-3 ]
[ 205-12-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate; bis-triphenylphosphine-palladium(II) chloride / water; tetrahydrofuran / 24 h / Inert atmosphere; Reflux 2: alumina / 190 °C / Sealed tube

Reference： [1]Akhmetov, Vladimir; Amsharov, Konstantin; Förtsch, Andreas; Feofanov, Mikhail [Chemical Communications, 2021, vol. 57, # 92, p. 12325 - 12328]

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Isomers

Technical Information

• Acid-Catalyzed α -Halogenation of Ketones • Addition of a Hydrogen Halide to an Internal Alkyne • Alcohols from Haloalkanes by Acetate Substitution-Hydrolysis • Alcohols React with PX3 • Alkyl Halide Occurrence • Alkylation of an Alkynyl Anion • An Alkane are Prepared from an Haloalkane • Benzylic Oxidation • Birch Reduction • Birch Reduction of Benzene • Blanc Chloromethylation • Complete Benzylic Oxidations of Alkyl Chains • Complete Benzylic Oxidations of Alkyl Chains • Conversion of Amino with Nitro • Convert Haloalkanes into Alcohols by SN2 • Deprotonation of Methylbenzene • Directing Electron-Donating Effects of Alkyl • Electrophilic Chloromethylation of Polystyrene • Friedel-Crafts Alkylation of Benzene with Acyl Chlorides • Friedel-Crafts Alkylation of Benzene with Carboxylic Anhydrides • Friedel-Crafts Alkylation of Benzene with Haloalkanes • Friedel-Crafts Alkylation Using Alkenes • Friedel-Crafts Alkylations of Benzene Using Alkenes • Friedel-Crafts Alkylations Using Alcohols • Friedel-Crafts Reaction • General Reactivity • Grignard Reaction • Groups that Withdraw Electrons Inductively Are Deactivating and Meta Directing • Halogenation of Alkenes • Halogenation of Benzene • Hiyama Cross-Coupling Reaction • Hydrogenation to Cyclohexane • Hydrogenolysis of Benzyl Ether • Kinetics of Alkyl Halides • Kumada Cross-Coupling Reaction • Methylation of Ammonia • Methylation of Ammonia • Nitration of Benzene • Nucleophilic Aromatic Substitution • Nucleophilic Aromatic Substitution with Amine • Oxidation of Alkyl-substituted Benzenes Gives Aromatic Ketones • Preparation of Alkylbenzene • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reactions of Dihalides • Reductive Removal of a Diazonium Group • Reverse Sulfonation——Hydrolysis • Stille Coupling • Substitution and Elimination Reactions of Alkyl Halides • Sulfonation of Benzene • Suzuki Coupling • The Acylium Ion Attack Benzene to Form Phenyl Ketones • The Claisen Rearrangement • The Nitro Group Conver to the Amino Function • Vilsmeier-Haack Reaction • Williamson Ether Syntheses

Historical Records

Related Functional Groups of
[ 33295-37-3 ]

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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

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. 33295-37-3 ] {[proInfo.proName]}

Quality Control of [ 33295-37-3 ]

Related Doc. of [ 33295-37-3 ]

Product Details of [ 33295-37-3 ]

Calculated chemistry of [ 33295-37-3 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 33295-37-3 ]

Application In Synthesis of [ 33295-37-3 ]

[ 33295-37-3 ] Synthesis Path-Downstream 1~26

Technical Information

Related Functional Groups of [ 33295-37-3 ]

Aryls

Bromides

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 33295-37-3 ]