[ CAS No. 914612-23-0 ] {[proInfo.proName]}

Name: 914612-23-0|6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine|98%
Brand: Ambeed
SKU: A306081
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Quality Control of [ 914612-23-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 914612-23-0 ]

SDS Specification

Alternatived Products of [ 914612-23-0 ]

Product Details of [ 914612-23-0 ]

CAS No. :	914612-23-0	MDL No. :	MFCD08273929
Formula :	C₁₄H₁₄ClN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RPJAAZOTUXKSEV-UHFFFAOYSA-N
M.W :	259.73	Pubchem ID :	25324046
Synonyms :

Calculated chemistry of [ 914612-23-0 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.29
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	75.77
TPSA :	29.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.07 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.66
Log Po/w (XLOGP3) :	2.56
Log Po/w (WLOGP) :	2.0
Log Po/w (MLOGP) :	2.07
Log Po/w (SILICOS-IT) :	3.28
Consensus Log Po/w :	2.52

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.42
Solubility :	0.0977 mg/ml ; 0.000376 mol/l
Class :	Soluble
Log S (Ali) :	-2.82
Solubility :	0.396 mg/ml ; 0.00152 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.36
Solubility :	0.00113 mg/ml ; 0.00000437 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.18

Safety of [ 914612-23-0 ]

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 [ 914612-23-0 ]

* 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 [ 914612-23-0 ]
Downstream synthetic route of [ 914612-23-0 ]

[ 914612-23-0 ] Synthesis Path-Upstream 1~3

1
[ 109229-22-3 ]
[ 914612-23-0 ]

Yield	Reaction Conditions	Operation in experiment
57.8%	Stage #1: With N,N-dimethyl-formamide; trichlorophosphate In acetonitrile at 70℃; for 1 h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water at 0℃;	6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (5.0 g, 0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated to at 70° C. for 1 hour. The mixture was reduced in vacuo and the remaining black residue was taken up in dichloromethane (250 ml) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The layers were separated and the organic dried over sodium sulfate and reduced in vacuo. The mixture was chromatographed using an ethyl acetate:hexanes (0-100percent) gradient on an isco flash chromatography system. The combined pure fractions were reduced in vacuo to yield the title compound as a yellow oil (3 g, 57.8percent). MS: M+H=260. ¹H NMR (DMSO-d6): δ 8.80 (s, 1H). 7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H).
57.8%	Stage #1: With N,N-dimethyl-formamide; trichlorophosphate In acetonitrile at 70℃; for 1 h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water at 0℃;	Intermediate 26-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (5.0 g, 0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at 70° C. for 1 hour. The mixture was concentrated in vacuo and the remaining black residue was taken up in dichloromethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The organic layer was separated and dried over sodium sulfate and concentrated in vacuo. The mixture was purified by silica gel column with EtOAc/hexane (0-100percent) to yield the title compound as a yellow oil (3 g, 57.8percent). LC-MS: 260 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H).
57.8%	Stage #1: With trichlorophosphate In acetonitrile at 70℃; for 1 h; Stage #2: With sodium hydrogencarbonate In dichloromethaneCooling with ice	INTERMEDIATE 26-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine[00274] A mixture of 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (5.0 g,0.02 mol), phosphoryl chloride (3.30 mL, 0.035 mol) and acetonitrile (80 mL) and DMF (catalytic amount) was heated at 70 ⁰C for 1 hour. The mixture was concentrated in vacuo and the remaining black residue was taken up in dichloroniethane (250 mL) and poured over ice. The mixture was carefully neutralized with the addition of solid sodium bicarbonate. The organic layer was separated and dried over sodium sulfate and concentrated in vacuo. The mixture was purified by silica gel column with EtOAc/hexane (0-100percent) to yield the title compound as a yellow oil (3 g, 57.8percent). MS: 260 [M+l]⁺; ¹H NMR (400 MHz, DMSO-d6): 8.80 (s, IH), 7.40-7.24 (m, 5H), 3.76 (s, 2H), 3.57 (s, 2H), 2.92 (t, 2H), 2.80 (t, 2H).

Reference： [1] Patent: US2006/258689, 2006, A1, . Location in patent: Page/Page column 23; 28
[2] Patent: US2008/275037, 2008, A1, . Location in patent: Page/Page column 23
[3] Patent: WO2008/123963, 2008, A1, . Location in patent: Page/Page column 44
[4] Journal of Medicinal Chemistry, 2008, vol. 51, # 11, p. 3124 - 3132
[5] Patent: WO2011/103715, 2011, A1, . Location in patent: Page/Page column 40
[6] Patent: WO2011/106276, 2011, A1, . Location in patent: Page/Page column 40

2
[ 1454-53-1 ]
[ 914612-23-0 ]

Reference： [1] Patent: WO2011/103715, 2011, A1,
[2] Patent: WO2011/106276, 2011, A1,
[3] Patent: WO2008/123963, 2008, A1,

3
[ 57611-47-9 ]
[ 914612-23-0 ]

Reference： [1] Helvetica Chimica Acta, 2018, vol. 101, # 6,

[ 914612-23-0 ] Synthesis Path-Downstream 1~88

1
[ 914612-23-0 ]
[ 769-92-6 ]
C₂₄H₂₈N₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Various N-substituted-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine derivatives are prepared using a general procedure described below. Accordingly, ethyl 1-benzyl-4-oxopiperidine-3-carboxylate hydrochloride is reacted with formamidine acetate to yield 6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(4aH)-one, which, in turn, is reacted with POCl3 to afford the 4-chloro derivative. The intermediate chloro derivative is then condensed with substituted aniline or amine to give the desired N-substituted-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine. Debenzylation using standard procedures known in the art followed by nucleophilic displacement of an appropriate 2-halo-pyridine yields the appropriate N-substituted-6-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine. As a representative example, synthesis of N-(4-tert-butylphenyl)-6-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine is depicted in Scheme 1.

Reference： [1]Patent: US2006/258689,2006,A1 .Location in patent: Page/Page column 22; 23

2
[ 914612-23-0 ]
[ 62-53-3 ]
[ 500889-14-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	In acetonitrile; at 180℃; for 0.166667h;microwave irradiation;	6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Intermediate 2, 1.0 g, 3.86 mmol) was dissolved in anhydrous acetonitrile (3 mL) and aniline was added (0.39 mL, 4.24 mmol). The mixture was heated at 180 C. for 600 s in a microwave (Emrys Optimizer model, Personal Chemistry). The solvents were removed under vacuum to give the desired product as a beige powder (1.5 g, quant.). The crude product was used as such for the subsequent step. MS: M+H=317.

Reference： [1]Patent: US2006/258689,2006,A1 .Location in patent: Page/Page column 29; 30

3
[ 914612-23-0 ]
[ 371-40-4 ]
[ 914612-27-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	In acetonitrile; at 200℃; for 0.166667h;microwave irradiation;	6-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (Intermediate 2, 0.25 g, 0.97 mmol) was dissolved in anhydrous acetonitrile (3 mL) and 4-fluorobenzenamine was added (0.10 mL, 1.06 mmol). The mixture was heated at 200 C. for 600 s in a microwave (Emrys Optimizer model, Personal Chemistry). The solvents were removed under vacuum to give the desired product as a beige powder (0.313 g, 97%.). MS: M+H=335

Reference： [1]Patent: US2006/258689,2006,A1 .Location in patent: Page/Page column 29; 30

4
[ 914612-23-0 ]
[ 455-14-1 ]
[ 914612-35-4 ]

Yield	Reaction Conditions	Operation in experiment
91%		6-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (0.6 g, 2.3 mmol) was dissolved in anhydrous dioxane (2 mL) and 4-(trifluoromethyl)aniline was added (0.43 mL, 3.45 mmol), followed by HI/H2O (0.2 ml, 47%). The mixture was heated at 130 C. in a sealed tube for 10 min in a microwave (Smith creator model, Personal Chemistry). The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the desired compound as a yellow solid (800 mg, 91%) which was used as such for the next step. M+H=385.

Reference： [1]Patent: US2006/258689,2006,A1 .Location in patent: Page/Page column 64

5
[ 914612-23-0 ]
[ 106877-33-2 ]
[ 914612-29-6 ]

Yield	Reaction Conditions	Operation in experiment
95%		6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.5 g, 1.93 mmol) was dissolved in anhydrous dioxane (3 mL) and 6-trifluoromethylpyridin-3-ylamine was added (469 mg, 2.9 mmol), followed by HI/H2O (0.3 mL, 47%). The mixture was heated at 130 C. for 600 s in a Personal Chemistry microwave. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the product as an orange solid (700 mg, 95% crude). The crude product was used for the subsequent step. MS: M+H=386.

Reference： [1]Patent: US2006/258689,2006,A1 .Location in patent: Page/Page column 31

6
[ 914612-23-0 ]
[ 22236-10-8 ]
[ 914612-24-1 ]

Yield	Reaction Conditions	Operation in experiment
94.2%	In acetonitrile; at 180℃; for 0.166667h;microwave irradiation;	6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.09 g, 4.21 mmol) prepared as described above (Intermediate 2, 1.0 g, 3.86mmol) was dissolved in anhydrous acetonitrile (3 mL) and 4-difluoromethoxyaniline was added (1.34 g, 8.42 mmol). The mixture was heated at 180 C. for 600 s in a microwave (Emrys Optimizer model, Personal Chemistry). The solvents were removed under vacuum to give the desired product as a beige powder (1.3 g, 94.2%). The crude product was used for the subsequent step.

Reference： [1]Patent: US2006/258689,2006,A1 .Location in patent: Page/Page column 29

7
[ 914612-23-0 ]
[ 124-41-4 ]
[ 1071435-57-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	In methanol; for 2h;Heating / reflux;	Intermediate 34-Methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine A) 6-Benzyl-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidineA 1 L flask was charged with <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine</strong> (39.6 g, 0.152 mol) and methanol (300 mL), and the mixture was heated to dissolve the chloropyrimidine. 4.37 M of sodium methoxide in methanol (105 mL) was added slowly to the warm mixture and the stirred mixture rapidly turned cloudy. The resultant suspension was heated under reflux for 2 h. After cooling, the mixture was concentrated in vacuo to ca 100 mL. The residue was poured into water (600 mL), and extracted with CH2Cl2 (200 mL×2). The combined organic layers were washed with brine (400 mL), dried (Na2SO4), filtered and concentrated in vacuo to yield a light brown oil (38.9 g, 100%).LC-MS: 256.1 M+H]+

Reference： [1]Patent: US2008/275037,2008,A1 .Location in patent: Page/Page column 23

8
[ 914612-23-0 ]
[ 387350-39-2 ]
[ 1073428-54-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 200℃; for 3.5h;Microwave irradiation;	A) 6-Benzyl-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amineTwo 20 mL microwave vials were each charged with a half portion of <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine</strong> (5.62 g, 21.6 mmol), (6-(trifluoromethyl)pyridin-3-yl)methanamine (5.0 g, 28 mmol), N,N-diisopropylethylamine (7.6 mL, 44 mmol) and acetonitrile (10 mL), and the mixture was subjected to a microwave irradiation at 200 C. for 3.5 h. LC-MS analysis showed the reaction was complete for both samples. The samples were combined, and partitioned between CH2Cl2 (150 mL) and 0.5M NaH2PO4 (pH 4; 120 mL). The organic layer was extracted with 2M HCl (60 mL, 30 mL). The combined acid extracts were basified with 50% KOH (25 mL), extracted with CH2Cl2 (2×100 mL), dried (Na2SO4), filtered and concentrated to yield a light brown oil, which was absorbed on silica (40 g) and purified by column (120 g silica gel, 0-7.5% MeOH/CH2Cl2) to afford a light yellow foam (7.42 g, 86%).LC-MS: 400.4 [M+H]+ 1H NMR (400 MHz, CDCl3): delta 8.67 (d, 1H, J=1.8 Hz), 8.45 (s, 1H), 7.83 (dd, 1H, J=8.0, 1.8 Hz), 7.62 (d, 1H, J=7.9 Hz), 7.39-7.27 (m, 5H), 4.79 (s, 2H), 3.77 (s, 2H), 3.31 (s, 2H), 2.90-2.80 (m, 4H).

Reference： [1]Patent: US2008/275037,2008,A1 .Location in patent: Page/Page column 33; 34

9
[ 914612-23-0 ]
[ 97004-04-1 ]
[ 1073428-71-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 180℃; for 2h;Microwave irradiation;	Method J (Compound 13)5-Chloro-2-(4-((6-methoxypyridin-3-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile A) 6-Benzyl-N-((6-chloropyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amineA mixture of <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine</strong> (2.5 g, 9.6 mmol), 2-chloro-5-aminomethylpyridine (2.7 g, 19 mmol), acetonitrile (10 mL), and N,N-diisopropylethylamine (3.4 mL, 19 mmol) was subjected to microwave irradiation at 180 C. for 2 h. After standing at rt overnight, the precipitated solids were collected by filtration and washed with cold acetonitrile (5 mL×2), and dried to yield a yellow powder (2.8 g, 77%).LC-MS: 366.3 [M+H]+ 1H NMR (400 MHz, d6-DMSO): delta 8.34 (d, 1H, J=2.8 Hz), 8.23 (s, 1H), 7.74 (dd, 1H, J=8.4, 2.8 Hz), 7.45-7.25 (m, 7H), 4.56 (d, 2H, J=6.0 Hz), 3.72 (s, 2H), 3.36 (s, 2H), 2.72-2.62 (m, 4H).

Reference： [1]Patent: US2008/275037,2008,A1 .Location in patent: Page/Page column 39

10
[ 914612-23-0 ]
[ 1071435-61-4 ]
[ 1073428-64-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 200℃; for 3.5h;Microwave irradiation;	A) (R)-6-Benzyl-N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (5.00 g, 19.2 mmol), (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethanamine (4.76 g, 25.0 mmol), N,N-diisopropylethylamine (6.71 mL, 38.5 mmol), and acetonitrile (15 mL) were divided evenly between two 20 mL microwave vials. The reactions were subjected to microwave irradiation at 200 C. for 3.5 h. The two reactions were mixed together and evaporated the acetonitrile off. The residue was redissolved in CH2Cl2 (150 mL) and washed with 1M NaH2PO4 (2×50 mL). The product was extracted with 1M HCl (2×50 mL). The aqueous extracts were basified to pH 14 and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried with Na2SO4, filtered and evaporated to produce a yellow to orange solid (7.21 g). The crude product was washed with ether (25 mL) by stirring the solids for about 30 minutes. The solids were filtered from the ether and washed with ether (2×5 mL) to obtain a pale yellow powder (3.55 g, 45% yield). The ether filtrate was absorbed onto silica and purified by column with MeOH/CH2Cl2 (0-10%) to yield more product (2.38 g, 30% yield; 75% combined yield).LC-MS: 414.5 [M+H]+ 1H NMR (400 MHz, CDCl3): delta 8.72 (d, 1H, J=1.6 Hz), 8.37 (s, 1H), 7.80 (dd, 1H, J=8.4, 1.6 Hz), 7.62 (d, 1H, J=8.0 Hz), 7.42-7.28 (m, 5H), 5.47 (m, 1H), 4.43 (d, 1H, J=6.4 Hz), 3.79 and 3.75 (AB, 2H, J=13.2 Hz), 3.37 (t, 2H, J=14.8 Hz), 2.88-2.76 (m, 4H), 1.62 (d, 3H, J=6.8 Hz).

Reference： [1]Patent: US2008/275037,2008,A1 .Location in patent: Page/Page column 36; 37

11
[ 914612-23-0 ]
[ 108-44-1 ]
[ 1032184-60-3 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 3124 - 3132

12
[ 914612-23-0 ]
[ 57260-71-6 ]
[ 1032184-62-5 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 3124 - 3132

13
[ 1126-09-6 ]
[ 914612-23-0 ]
[ 1332455-18-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethanol; for 4h;Reflux;	Step B:To the solution of compound 2 (5.4g, 20.8mmol) and ethyl isonipecotate (3.92 g. 24.95 mmol) in 100 mL of ethanol was added DIEA (4.02g, 31.2mmol) and the mixture was heated to reflux for 4 hours. TLC (DCM: MeOH=15: 1) indicated that the reaction completed. The reaction mixture was then concentrated and purified by chromatography over silica gel to give compound 3 as pale brown solid (7.2 g) MS (ESEI): 381.4 [M+l]+
	With N-ethyl-N,N-diisopropylamine; In ethanol; for 4h;Reflux;	To the solution of compound 2 (5.4g, 20.8mmol) and ethyl isonipecotate (3.92 g, 24.95 mmol) in 100 mL of ethanol was added DIEA (4.02g, 3 i.2mmol) and the mixture was heated to reflux for 4 hours. TLC (DCM: MeOH=T5: 1) indicated that the reaction completed. The reaction mixture was then concentrated and purified by chromatography over silica gel to give compound 3 as pale brown solid (7.2 g) MS (ESEI): 381.4 [M+l]+

Reference： [1]Patent: WO2011/103715,2011,A1 .Location in patent: Page/Page column 40-41
[2]Patent: WO2011/106276,2011,A1 .Location in patent: Page/Page column 40-41

14
[ 1454-53-1 ]
[ 914612-23-0 ]

Reference： [1]Patent: WO2011/103715,2011,A1
[2]Patent: WO2011/106276,2011,A1
[3]Patent: WO2008/123963,2008,A1

15
[ 914612-23-0 ]
[ 1332455-28-3 ]

Reference： [1]Patent: WO2011/103715,2011,A1

16
[ 914612-23-0 ]
[ 1332454-53-1 ]

Reference： [1]Patent: WO2011/103715,2011,A1

17
[ 914612-23-0 ]
[ 1332453-13-0 ]

Reference： [1]Patent: WO2011/103715,2011,A1

18
[ 914612-23-0 ]
[ 1332453-16-3 ]

Reference： [1]Patent: WO2011/103715,2011,A1

19
[ 914612-23-0 ]
[ 1332455-19-2 ]

Reference： [1]Patent: WO2011/103715,2011,A1

20
[ 914612-23-0 ]
[ 1332455-37-4 ]

Reference： [1]Patent: WO2011/103715,2011,A1

21
[ 914612-23-0 ]
[ 1332455-46-5 ]

Reference： [1]Patent: WO2011/103715,2011,A1

22
[ 914612-23-0 ]
[ 1332455-30-7 ]

Reference： [1]Patent: WO2011/103715,2011,A1

23
[ 914612-23-0 ]
[ 1332455-35-2 ]
[ 1332455-36-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethanol; at 80℃; for 3h;	Step ETo a solution of <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine</strong> (3.9 g, 15.0 mmol) in EtOH (50 mL) was added compound 5 (2.3 g, 15.0 mmol) and DIEA (3.87 g, 30 mmol). The mixture was stirred at 80 C for 3 hours then the mixture was evaporated to dryness. The crude product was purified by silica gel chromatography eluted with PE: EA = (5: 1) to give the desired product (4.08 g)
	With N-ethyl-N,N-diisopropylamine; In ethanol; at 80℃; for 3h;	To a solution of 6-benzyl-4-chloro-5,6,7,8-tetraliydro-pyrido[4,3-d]pyrimidine (3.9 g, 15.0 mmol) in EtOH (50 mL) was added compound 5 (2.3 g, 15.0 mmol) and D3EA (3.87 g, 30 mmol). The mixture was stirred at 80 C for 3 hours then the mixture was evaporated to dryness. The crude product was purified by silica gel chromatography eluted with PE: EA = (5:1) to give the desired product (4.08 g)

Reference： [1]Patent: WO2011/103715,2011,A1 .Location in patent: Page/Page column 47
[2]Patent: WO2011/106276,2011,A1 .Location in patent: Page/Page column 47

24
[ 914612-23-0 ]
[ 141699-55-0 ]
[ 1354691-91-0 ]

Yield	Reaction Conditions	Operation in experiment
		3-( 6-Benzyl-5, 6, 7, 8-tetrahydro-pyrido[4, 3-d]pyrimidin-4-yloxy)-azetidine-1-carboxylic acid tert-butyl ester; 3-Hydroxy-azetidine-1-carboxylic acid tert-butyl ester (217 mg, 1.25 mmol) was dissolved under argon in THF (10 ml.) and NaH (58 mg, 1 .44 mmol) was added. The resulting suspension was stirred at rt under argon for 15 min following by the addtion of a solution of 6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3d]pyrimidine (250 mg, 0.963 mmol). The reaction mixture was stirred at rt for 18h, quenched with water (20 ml.) and diluted withCH2CI2. The organic layer was filtered through a phase separation tube and concentrated in vacuo. Purification by flash chromatography on silica gel with heptane / CH2CI2, 50/50 to 0/100 then EtOAc to give 3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)- azetidine-1 -carboxylic acid tert-butyl ester as a yellow gum (425 mg, 1 1 1 % yield) LCMS: [M+H]+= 397.4, Rt (4)= 0.98 min.
		3-Hydroxy-azetidine-1 -carboxylic acid tert-butyl ester (217 mg, 1.25 mmol) was dissolved under argon in THF (10 ml_) and NaH (58 mg, 1.44 mmol) was added. The resulting suspension was stirred at rt under argon for 15 min following by the addtion of a solution of 6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3d]pyrimidine (250 mg, 0.963 mmol). The reaction mixture was stirred at rt for 18h, quenched with water (20 ml_) and diluted withCH2CI2. The organic layer was filtered through a phase separation tube and concentrated in vacuo. Purification by flash chromatography on silica gel with heptane / CH2CI2, 50/50 to 0/100 then EtOAc to give 3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-azetidine-1 -carboxylic acid tert-butyl ester as a yellow gum (425 mg, 1 11 % yield) LCMS: [M+H]+= 397.4, Rt (4)= 0.98 min.
		3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-azetidine-1-carboxylic acid tert-butyl ester 3-Hydroxy-azetidine-1-carboxylic acid tert-butyl ester (217 mg, 1.25 mmol) was dissolved under argon in THF (10 mL) and NaH (58 mg, 1.44 mmol) was added. The resulting suspension was stirred at rt under argon for 15 min following by the addition of a solution of 6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3d]pyrimidine (250 mg, 0.963 mmol). The reaction mixture was stirred at rt for 18 h, quenched with water (20 mL) and diluted with CH2Cl2. The organic layer was filtered through a phase separation tube and concentrated in vacuo. Purification by flash chromatography on silica gel with heptane/CH2Cl2, 50/50 to 0/100 then EtOAc to give 3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-azetidine-1-carboxylic acid tert-butyl ester as a yellow gum (425 mg, 111% yield) LCMS: [M+H]+=397.4, Rt(4)=0.98 min.

Reference： [1]Patent: WO2012/4299,2012,A1 .Location in patent: Page/Page column 136
[2]Patent: WO2013/88404,2013,A1 .Location in patent: Page/Page column 151
[3]Patent: US2015/342951,2015,A1 .Location in patent: Paragraph 0921

25
[ 914612-23-0 ]
[ 147081-44-5 ]
[ 1354691-71-6 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 20h;	Alternative synthesis for intermediate 22: (S)-tert-Butyl-3-aminopyrrolidine-1 -carboxylate (50 g, 192.5 mmol) was added to 6-benzyl-4- chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (39.440 g, 21 1.8 mmol) in NMP (200 mL) solution followed by the addition of K2C03 (39.9 g, 288.8 mmol). The mixture was heated to 120C for 20h. The mixture was allowed to cool, partitioned between water (300 mL) and ethylacetate (500 mL). the bottom aqueous phase was discarded and the upper organic phase was washed with brine (150 mL) and concentrated in vacuo to provide crude (S)-3-(6- benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert- butyl ester as a pale yellow foam (76.44 g, 97% yield).
97%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 20h;Sealed tube;	Intermediate 22: (S)-3-(6-Benzyl-5,6J,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester6-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (5.0 g, 19.06 mmol), (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (4.1 1 g, 20.96 g) and triethylamine (3.98 mL, 28.6 mmol) were heated in a sealed vial at 120C for 42h. The mixture was allowed to cool, diluted with tert-butyl methyl ether (100 mL) and the resulting suspension stirred for 10 min. The mixture was diluted with water (50 mL) and the organic layer separated. The organic layer was washed with brine (20 mL), dried (Na2S04) and evaporated in vacuo to give a brown gum. The residue was purified by column chromatography on silica gel with EtOAc / MeOH, 98/2 to 82/18 to give (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1 -carboxylic acid tert-butyl ester as a pale yellow foam (7.36 g, 93% yield). 1 H-NMR (400 MHz, CDCI3, 298 K): delta ppm 1.48 (s, 9H) 2.10-2.31 (m, 2H) 2.80-2.96 (m, 4H) 3.15-3.87 (m, 8H) 4.44-4.77 (m, 1 H) 5.62-5.73 (m, 1 H) 7.29-7.45 (m, 5H) 8.50 (s, 1 H). LCMS: [M+H]+=410.0, Rt (6)= 1.39 min. Alternative synthesis for intermediate 22: (S)-tert-Butyl-3-aminopyrrolidine-1 -carboxylate (50 g, 192.5 mmol) was added to <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine</strong> (39.440 g, 21 1.8 mmol) in NMP (200 mL) solution followed by the addition of K2C03 (39.9 g, 288.8 mmol). The mixture was heated to 120C for 20h. The mixture was allowed to cool, partitioned between water (300 mL) and ethylacetate (500 mL). the bottom aqueous phase was discarded and the upper organic phase was washed with brine (150 mL) and concentrated in vacuo to provide crude (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1 -carboxylic acid tert-butyl ester as a pale yellow foam (76.44 g, 97% yield).
97%	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 20h;	Alternative synthesis for intermediate 22 (S)-tert-Butyl-3-aminopyrrolidine-1-carboxylate (50 g, 192.5 mmol) was added to <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine</strong> (39.440 g, 211.8 mmol) in NMP (200 mL) solution followed by the addition of K2CO3 (39.9 g, 288.8 mmol). The mixture was heated to 120 C. for 20 h. The mixture was allowed to cool, partitioned between water (300 mL) and ethylacetate (500 mL). the bottom aqueous phase was discarded and the upper organic phase was washed with brine (150 mL) and concentrated in vacuo to provide crude (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow foam (76.44 g, 97% yield).

93%

With triethylamine; at 120℃; for 42h;Sealed vial;Mechanism;

Intermediate 22: (S)-3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino)- pyrrolidine-1 -carboxylic acid tert-butyl ester; 6-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (5.0 g, 19.06 mmol), (S)-tert- butyl 3-aminopyrrolidine-1 -carboxylate (4.1 1 g, 20.96 g) and triethylamine (3.98 mL, 28.6 mmol) were heated in a sealed vial at 120C for 42h. The mixture was allowed to cool, diluted with tert-butyl methyl ether (100 mL) and the resulting suspension stirred for 10 min. The mixture was diluted with water (50 mL) and the organic layer separated. The organic layer was washed with brine (20 mL), dried (Na2S04) and evaporated in vacuo to give a brown gum. The residue was purified by column chromatography on silica gel with EtOAc / MeOH, 98/2 to 82/18 to give (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4- ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester as a pale yellow foam (7.36 g, 93% yield). 1H-NMR (400 MHz, CDCI3, 298 K): delta ppm 1.48 (s, 9H) 2.10-2.31 (m, 2H) 2.80-2.96 (m, 4H) 3.15-3.87 (m, 8H) 4.44-4.77 (m, 1 H) 5.62-5.73 (m, 1 H) 7.29-7.45 (m, 5H) 8.50 (s, 1 H). LCMS: [M+H]+=410.0, Rt (6)= 1 .39 min.

Reference： [1]Patent: WO2013/1445,2013,A1 .Location in patent: Page/Page column 40-41
[2]Patent: WO2013/88404,2013,A1 .Location in patent: Page/Page column 88
[3]Patent: US2015/342951,2015,A1 .Location in patent: Paragraph 0832
[4]Patent: WO2012/4299,2012,A1 .Location in patent: Page/Page column 81
[5]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 975 - 980

26
[ 914612-23-0 ]
[ 101469-92-5 ]
[ 1354691-53-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium tert-butylate; In 2-methyltetrahydrofuran; at 20℃; for 0.416667h;Inert atmosphere;Product distribution / selectivity;	Alternative synthesis for (S)-3-(6-Benzyl-5,6, 7,8-tetrahvdro-Dyrido[4,3-dlDyrimidin-4-yloxy)- Dyrrolidine-1 -carboxylic acid tert-butyl ester; To a solution of (S)-3-hydroxypyrrolidine-1 - carboxylic acid tert-butyl ester (6.21 g, 33.16 mmol) and <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine</strong> (9 g, 34.65 mmol) in 2-Me-THF (100 ml.) was added under nitrogen tBuOK (8.17 g, 72.95 mmol). The mixture was stirred at rt for 25 min. The mixture was quenched with H20. The organic layer was washed with brine. The resulting organic solution was concentrated in vacuo to provide (S)- 3-(6-benzyl-5, 6, 7, 8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester (12.6 g, 89% yield) as a yellow gum.
89%	With potassium tert-butylate; In 2-methyltetrahydrofuran; at 20℃; for 0.416667h;Inert atmosphere;	Alternative synthesis for (S)-3-(6-Benzyl-5,6, 7,8-tetrahvdro-Dyridof4,3-dlDyrimidin-4-yloxy)- pyrrolidine-1-carboxylic acid tert-butyl esterTo a solution of (S)-3-hydroxypyrrolidine-1- carboxylic acid tert-butyl ester (6.21 g, 33.16 mmol) and <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine</strong> (9 g, 34.65 mmol) in 2-Me-THF (100 ml.) was added under nitrogen tBuOK (8.17 g, 72.95 mmol). The mixture was stirred at rt for 25 min. The mixture was quenched with H20. The organic layer was washed with brine. The resulting organic solution was concentrated in vacuo to provide (S)- 3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester (12.6 g, 89% yield) as a yellow gum.
89%	With potassium tert-butylate; In 2-methyltetrahydrofuran; at 20℃; for 0.416667h;Inert atmosphere;	To a solution of (S)-3-hydroxypyrrolidine-1 - carboxylic acid tert-butyl ester (6.21 g, 33.16 mmol) and <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine</strong> (9 g, 34.65 mmol) in 2-Me-THF (100 mL) was added under nitrogen tBuOK (8.17 g, 72.95 mmol). The mixture was stirred at rt for 25 min. The mixture was quenched with H20. The organic layer was washed with brine. The resulting organic solution was concentrated in vacuo to provide (S)-3-(6-benzyl-5, 6, 7, 8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester (12.6 g, 89% yield) as a yellow gum.

89%

With potassium tert-butylate; In 2-methyltetrahydrofuran; at 20℃; for 0.416667h;Inert atmosphere;

Alternative synthesis for (S)-3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester To a solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (6.21 g, 33.16 mmol) and <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine</strong> (9 g, 34.65 mmol) in 2-Me-THF (100 mL) was added under nitrogen tBuOK (8.17 g, 72.95 mmol). The mixture was stirred at rt for 25 min. The mixture was quenched with H2O. The organic layer was washed with brine. The resulting organic solution was concentrated in vacuo to provide (S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (12.6 g, 89% yield) as a yellow gum.

Reference： [1]Patent: WO2012/4299,2012,A1 .Location in patent: Page/Page column 71
[2]Patent: WO2013/1445,2013,A1 .Location in patent: Page/Page column 40
[3]Patent: WO2013/88404,2013,A1 .Location in patent: Page/Page column 78
[4]Patent: US2015/342951,2015,A1 .Location in patent: Paragraph 0815
[5]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 975 - 980

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[ 914612-23-0 ]
{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone citrate [ No CAS ]

Reference： [1]Patent: WO2013/1445,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone fumarate [ No CAS ]

Reference： [1]Patent: WO2013/1445,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354689-69-2 ]

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[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-84-1 ]

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[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-83-0 ]

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[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354690-13-3 ]

Reference： [1]Patent: US2015/342951,2015,A1
[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
(S)-tert-butyl 3-(6-(6-(bis(tert-butoxycarbonyl)amino)-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylate trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2012/4299,2012,A1

34
[ 914612-23-0 ]
[ 1354691-90-9 ]

Reference： [1]Patent: WO2013/88404,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-89-6 ]

Reference： [1]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
4-(azetidin-3-yloxy)-(6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5, 6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine) ditrifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
{3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-azetidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone [ No CAS ]

Reference： [1]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-94-3 ]

Reference： [1]Patent: WO2013/88404,2013,A1
[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-93-2 ]

Reference： [1]Patent: WO2013/88404,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-92-1 ]

Reference： [1]Patent: WO2013/88404,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354690-16-6 ]

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[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354690-24-6 ]

Reference： [1]Patent: WO2013/1445,2013,A1
[2]Patent: WO2013/88404,2013,A1
[3]Patent: US2015/342951,2015,A1
[4]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 975 - 980
[5]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354692-00-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 975 - 980
[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-97-6 ]

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[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-98-7 ]

Reference： [1]Patent: WO2013/1445,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-99-8 ]

Reference： [1]Patent: WO2013/1445,2013,A1
[2]Patent: WO2013/88404,2013,A1
[3]Patent: US2015/342951,2015,A1
[4]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354690-27-9 ]

Reference： [1]Patent: WO2013/88404,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(S)-pyrrolidin-3-yl-amine ditrifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2013/88404,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-51-2 ]

Reference： [1]Patent: WO2013/1445,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-54-5 ]

Reference： [1]Patent: US2015/342951,2015,A1
[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-55-6 ]

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[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-56-7 ]

Reference： [1]Patent: US2015/342951,2015,A1
[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-57-8 ]

Reference： [1]Patent: US2015/342951,2015,A1
[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-59-0 ]

Reference： [1]Patent: US2015/342951,2015,A1
[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-60-3 ]

Reference： [1]Patent: US2015/342951,2015,A1
[2]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
(S)-3-[6-(5-fluoro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2012/4299,2012,A1

58
[ 914612-23-0 ]
[ 1354691-72-7 ]

59
[ 914612-23-0 ]
[ 1354691-73-8 ]

60
[ 914612-23-0 ]
[ 1354691-74-9 ]

Reference： [1]Patent: WO2013/88404,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354689-60-3 ]

Reference： [1]Patent: WO2013/1445,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-79-4 ]

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[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-78-3 ]

Reference： [1]Patent: WO2013/1445,2013,A1
[2]Patent: US2015/342951,2015,A1
[3]Patent: WO2012/4299,2012,A1

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[ 914612-23-0 ]
[ 1354691-46-5 ]
[ 1354691-96-5 ]

Yield	Reaction Conditions	Operation in experiment
78%		1-[(S)-3-(6-Benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-propan-1-one Step 1 To a solution of 1-((S)-3-hydroxy-pyrrolidin-1-yl)-propan-1-one (intermediate 2) (358 mg, 2.503 mmol) in 5 mL of THF was added NaH (108 mg, 2.70 mmol) under Ar. The mixture was stirred at rt for 15 min, then <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine</strong> (500 mg, 1.925 mmol) and 5 mL of THF were added and stirred at rt for 5 h. The reaction was quenched with H2O and extracted with ethylacetate, the org. layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The residue was purified by flash-chromatography using Isco Companion system (12 g of SiO2) CH2Cl2/MeOH (95/5). The collected fractions were combined, evaporated and dried over high vacuum to give 1-[(S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-propan-1-one. (m=560 mg, yield 78%) MS: [M+H]+=367.6, Rt(7)=0.64 min.
		1-[(S)-3-(6-Benzyl-5fi ,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidinone; Step 1; To a solution of 1 -((S)-3-hydroxy-pyrrolidin-1-yl)-propan-1-one (intermediate 2) (358 mg,2.503 mmol) in 5ml_ of THF was added NaH (108 mg, 2.70 mmol) under Ar. The mixture was stirred at rt for 15min, then <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine</strong> (500 mg, 1.925 mmol) and 5 ml. of THF were added and stirred at rt for 5h. The reaction was quenched with H20 and extracted with ethylacetate, the org. layer was washed with brine, dried over MgS04, filtered and evaporated to dryness. The residue was purified by flash- chromatography using Isco Companion system (12g of Si02) CH2CI2 /MeOH(95/5). The collected fractions were combined, evaporated and dried over high vacuum to give 1-[(S)-3- (6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1 -yl]-propan-1-one. (m= 560 mg, yield 78%) MS: [M+H]+= 367.6, Rt(7) = 0.64 min.
		Step 1 To a solution of 1-((S)-3-hydroxy-pyrrolidin-1 -yl)-propan-1-one (intermediate 2) (358 mg,2.503 mmol) in 5mL of THF was added NaH (108 mg, 2.70 mmol) under Ar. The mixture was stirred at rt for 15min, then <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine</strong> (500 mg, 1 .925 mmol) and 5 ml_ of THF were added and stirred at rt for 5h. The reaction was quenched with H20 and extracted with ethylacetate, the org. layer was washed with brine, dried over MgS04, filtered and evaporated to dryness. The residue was purified by flash-chromatography using Isco Companion system (12g of S1O2) CH2CI2 /MeOH(95/5). The collected fractions were combined, evaporated and dried over high vacuum to give 1-[(S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-propan-1 -one. (m= 560 mg, yield 78%) MS: [M+H]+= 367.6, Rt(7) = 0.64 min.

Reference： [1]Patent: US2015/342951,2015,A1 .Location in patent: Paragraph 0931
[2]Patent: WO2012/4299,2012,A1 .Location in patent: Page/Page column 142
[3]Patent: WO2013/88404,2013,A1 .Location in patent: Page/Page column 157

65
[ 914612-23-0 ]
{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone napadisylate [ No CAS ]

Reference： [1]Patent: WO2012/4299,2012,A1

66
[ 67-56-1 ]
[ 914612-23-0 ]
[ 124-41-4 ]
[ 1071435-57-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	for 2h;Reflux;	A) 6-Benzyl-4-methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine[00278] A l L flask was charged with 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidine (39.6 g, 0.152 mol) and methanol (300 mL), and the mixture was heated to dissolve the chloropyrimidine. 4.37 M of sodium methoxide in methanol (105 mL) was added slowly to the warm mixture and the stirred mixture rapidly turned cloudy. The resultant suspension was heated under reflux for 2h. After cooling, the mixture was concentrated in vacuo to ca 100 mL. The residue was poured into water (600 mL), and extracted with CH2Cl2 (200 mL x 2). The combined organic layers were washed with brine (400 mL), dried (Na2SO^, filtered and concentrated in vacuo to a light brown oil (38.9 g, 100%). MS: 256.1 [M+l]+.

Reference： [1]Patent: WO2008/123963,2008,A1 .Location in patent: Page/Page column 46

67
[ 914612-23-0 ]
[ 27298-99-3 ]
[ 1071436-19-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 200℃; for 2.5h;Microwave irradiation;	) (R)-6-Benzyl-N-(l-(4-chlorophenyl)ethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine [00314] Two 20 mL microwave vials were charged with a half portion of <strong>[914612-23-0]6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine</strong> (3.50 g, 13.5 mmol), (R)-I -(4-chloro-phenyl)-ethylamine (4.20 g, 27.0 mmol), NN-diisopropylethylamine (4.7 mL, 27 mmol) and acetonitrile (20 mL); and the mixture was heated in a micrwave at 200 0C for 2.5 h. The mixture was concentrated in vacuo, and the residue was taken up in CH2Cl2 (100 mL) and ethyl acetate (20 mL), washed with 0.5 M aq. NaH2PO4 (pH 4, 100 mL), dried (Na2SO4), and concentrated. The residue was purified on silica gel column (0-5% MeOH/CH2Cl2) to give a pale yellow foam (4.46 g). LC-MS:, 379.5 [M+H]+;1H NMR (400 MHz, CDCl3): 8.41 (s, IH), 7.40-7.24 (m, 9H), 5.40 (p, IH, J= 7.0 Hz), 4.38 (d, IH, J = 7.2 Hz), 3.78 and 3.73 (AB, 2H, J= 13.2 Hz), 3.36 and 3.32 (AB, 2H, J = 14.8 Hz), 2.85-2.75 (m, 4H), 1.54 (d, 3H, J= 6.9 Hz).

Reference： [1]Patent: WO2008/123963,2008,A1 .Location in patent: Page/Page column 64

68
[ 914612-23-0 ]
[ 944902-70-9 ]

Reference： [1]Patent: WO2008/123963,2008,A1

69
[ 914612-23-0 ]
[ 1071436-20-8 ]

Reference： [1]Patent: WO2008/123963,2008,A1

70
[ 914612-23-0 ]
[ 1071436-17-3 ]

Reference： [1]Patent: WO2008/123963,2008,A1

71
[ 914612-23-0 ]
[ 1071436-22-0 ]

Reference： [1]Patent: WO2008/123963,2008,A1

72
[ 914612-23-0 ]
[ 1071436-23-1 ]

Reference： [1]Patent: WO2008/123963,2008,A1

73
[ 914612-23-0 ]
[ 1071436-24-2 ]

Reference： [1]Patent: WO2008/123963,2008,A1

74
[ 914612-23-0 ]
[ 1071436-27-5 ]

Reference： [1]Patent: WO2008/123963,2008,A1

75
[ 914612-23-0 ]
[ 1348426-98-1 ]

Reference： [1]Patent: WO2008/123963,2008,A1

76
[ 914612-23-0 ]
[ 1071435-59-0 ]

Reference： [1]Patent: WO2008/123963,2008,A1

77
[ 914612-23-0 ]
[ 1071435-60-3 ]

Reference： [1]Patent: WO2008/123963,2008,A1

78
[ 914612-23-0 ]
{(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone napadisylate [ No CAS ]

Reference： [1]Patent: WO2013/1445,2013,A1

79
[ 914612-23-0 ]
3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-azetidine-1-carboxylic acid tert-butyl ester trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2013/88404,2013,A1

80
[ 914612-23-0 ]
1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one phosphate [ No CAS ]

Reference： [1]Patent: WO2013/88404,2013,A1

81
[ 914612-23-0 ]
1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/88404,2013,A1

82
[ 914612-23-0 ]
(S)-tert-butyl 3-(6-(6-(bis(tert-butoxycarbonyl)amino)-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylate trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2015/342951,2015,A1

83
[ 914612-23-0 ]
3-[6-(6-methoxy-5-trifluoromethylpyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy]azetidine-1-carboxylic acid tert-butyl ester trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2015/342951,2015,A1

84
[ 914612-23-0 ]
[ 1354690-31-5 ]
[ 1354690-30-4 ]

Reference： [1]Patent: US2015/342951,2015,A1

85
[ 914612-23-0 ]
(S)-3-[6-(5-fluoro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2015/342951,2015,A1

86
[ 914612-23-0 ]
(S)-tert-butyl 3-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylate trifluoroacetate [ No CAS ]

Reference： [1]Patent: US2015/342951,2015,A1

87
[ 914612-23-0 ]
1-(4-(3-(6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)benzoyl)piperazin-1-yl)ethanone [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 975 - 980

88
[ 914612-23-0 ]
3-(6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)benzoic acid [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2017,vol. 8,p. 975 - 980

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Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
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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. 914612-23-0 ] {[proInfo.proName]}

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Application In Synthesis of [ 914612-23-0 ]

[ 914612-23-0 ] Synthesis Path-Upstream 1~3

[ 914612-23-0 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 914612-23-0 ]

Aryls

Chlorides

Related Parent Nucleus of [ 914612-23-0 ]

Other Aromatic Heterocycles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 914612-23-0 ]

Related Parent Nucleus of
[ 914612-23-0 ]