[ CAS No. 871254-61-4 ] {[proInfo.proName]}

Name: 871254-61-4|2,4-Dichloropyrimidine-5-carbaldehyde|98%
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SKU: A241363
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Quality Control of [ 871254-61-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 871254-61-4 ]

CAS No. :	871254-61-4	MDL No. :	MFCD11112096
Formula :	C₅H₂Cl₂N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MTIXQNKVUJSOQH-UHFFFAOYSA-N
M.W :	176.99	Pubchem ID :	18983168
Synonyms :

Calculated chemistry of [ 871254-61-4 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	37.44
TPSA :	42.85 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.25 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.36
Log Po/w (XLOGP3) :	1.59
Log Po/w (WLOGP) :	1.6
Log Po/w (MLOGP) :	0.19
Log Po/w (SILICOS-IT) :	2.37
Consensus Log Po/w :	1.42

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.32
Solubility :	0.853 mg/ml ; 0.00482 mol/l
Class :	Soluble
Log S (Ali) :	-2.1
Solubility :	1.4 mg/ml ; 0.00793 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.83
Solubility :	0.261 mg/ml ; 0.00148 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.51

Safety of [ 871254-61-4 ]

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 [ 871254-61-4 ]

* 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 [ 871254-61-4 ]
Downstream synthetic route of [ 871254-61-4 ]

[ 871254-61-4 ] Synthesis Path-Upstream 1~8

1
[ 68-12-2 ]
[ 66-22-8 ]
[ 3934-20-1 ]
[ 871254-61-4 ]

Reference： [1] Patent: CN108467368, 2018, A, . Location in patent: Paragraph 0014; 0015

2
[ 871254-61-4 ]
[ 23002-51-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With hydrazine In tetrahydrofuran at 20℃; for 0.5 h;	Example 18 6-Chloro-1H-pyrazolo[3,4-d]pyrimidine To a stirred solution of hydrazine (Aldrich, 64 mg, 2 mmol) in THF (5 mL), 2,4-Dichloro-pyrimidine-5-carbaldehyde (Example 17, 176 mg, 1 mmol) was added and the mixture was stirred at room temperature for 30 min. The mixture was poured into water and extracted with EtOAc. The extract was dried with sodium sulfate and the solvent was removed to give an orange solid. 128 mg, 82percent. MS (M+H)+, 155.
57%	With hydrazine hydrate In tetrahydrofuran at 0 - 20℃; for 0.5 h;	Compound 75 (2.0g, 11.3mmol) dissolved in THF (10mL), and at 0 was added hydrazine hydrate (1.33g, 22.6mmol) in THF (20mL) added and the reaction was stirred at room temperature for half hour and purified by silica gel column to give compound 76 as a yellow solid (1.0g, 57percent).
34%	With hydrazine In tetrahydrofuran at 20℃; for 1 h;	Preparation No.2: 6-Chloro-l/ -pyrazolo[3,4-i/\|pyrimidine; A solution of 2,4-dichloropyrimidine-5-carbaldehyde (7.75 g, 43.8 mmol, Preparation No.1) in THF (100 mL) was added to a 500 mL round-bottomed flask charged with anhydrous hydrazine (3.0 mL, 96 mmol) in THF (250 mL). The reaction mixture was allowed to stir at ambient temperature for about 1 h after which the reaction mixture was concentrated under reduced pressure. The crude product was suspended in DCM (100 mL) and filtered through a silica gel pad. The silica gel pad was washed with additional DCM (2 x 20 mL) and the combined organic layers were concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 30percent EtOAc in heptane to provide 6-chloro-lH-pyrazolo[3,4- djpyrimidine (2.3 g, 34percent) as a white solid. LC/MS (Table 2, Method a) R, = 1.29 min; MS m/z: 155 (M+H)⁺.

Reference： [1] Patent: US2005/277655, 2005, A1, . Location in patent: Page/Page column 15
[2] Patent: CN105524048, 2016, A, . Location in patent: Paragraph 0427; 0428
[3] Patent: WO2011/156698, 2011, A2, . Location in patent: Page/Page column 52-53

3
[ 4394-85-8 ]
[ 36082-50-5 ]
[ 871254-61-4 ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: With TurboGrignard In tetrahydrofuran at 78℃; for 1 h; Stage #2: at -78 - -35℃; for 1.5 h; Stage #3: With hydrogenchloride; water In tetrahydrofuran at -35℃;	Preparation No.1: 2,4-Dichloropyrimidine-5-carbaldehyde; A solution of isopropyl magnesium chloride lithium chloride complex in THF (2M, 184 mL, 368 mmol) was added drop-wise over about 30 min to a 2 L round-bottomed flask charged with a solution of 5-bromo-2,4-dichloropyrimidine (49.6 g, 218 mmol) in THF (1000 mL) at about -78 °C. The reaction was allowed to stir at about -78 °C for about 30 min. Morpholine-4- carbaldehyde (75.0 g, 653 mmol) was then added drop-wise at about -78 °C over about 30 min. The reaction was allowed to stir for about 30 min at about -78 °C then allowed to warm to about - 35 °C and stirred for about 30 min. Aqueous HCl (IN, 250 mL) and Et₂0 (500 mL) were added and the reaction mixture was allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was further extracted with Et₂0 (200 mL). The combined organic layers were dried over anhydrous MgS0₄, filtered through a silica gel pad on a fritted funnel, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using DCM (100percent) as the eluent to provide 2,4-dichloropyrimidine-5- carbaldehyde (27.3 g, 71percent ) as a light yellow solid. ^.H NMR (400 MHz, CDC1₃ ) δ 10.34 (s, 1H), 9.30 (s, 1H).

Reference： [1] Patent: WO2011/156698, 2011, A2, . Location in patent: Page/Page column 52

4
[ 36082-50-5 ]
[ 68-12-2 ]
[ 871254-61-4 ]

Yield	Reaction Conditions	Operation in experiment
31%	Stage #1: With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78 - -35℃; for 4 h;	Under nitrogen in a dry 250mL three flask was added 74 (10.00g, 43.9mmol) and tetrahydrofuran (100.0mL), - 78 slowly added dropwise isopropylmagnesium chloride lithium chloride complex solution (2M) (24.2mL, 48.3mmol), - for half hour at 78 --35 , DMF is then slowly added dropwise at -78 (9.6g, 131.6mmol), followed by stirring at -35 4 hours. The reaction with saturated ammonium chloride solution was quenched at -78 deg.] C, the reaction solution was diluted with 100.0mL of water, extracted twice with 200 mL of ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, the solvent was spin-dried compound 75 (2.1g , 31percent) as a white solid.
28%	Stage #1: With hydrogenchloride In tetrahydrofuran at -78 - 35℃; for 0.5 h; Stage #2: at -78℃; for 2 h;	Example 17 2,4-Dichloro-pyrimidine-5-carbaldehyde To a stirred solution of 5-bromo-2,4-dichloropyrimidine (Aldrich, 454 mg, 2 mmol) in THF at -78° C., diisopropyl magnesium chloride (2M solution in THF, 2.1 mmol, 1.05 mL) was added and the mixture was stirred for 30 minutes at -35° C. Next, the solution was cooled to 31 78° C. and 1 mL of dry DMF was added. The mixture was stirred for 120 minutes at -78° C. and the reaction was quenched with 1 N HCl. The mixture was extracted with EtOAc and dried with sodium sulfate. The solvent was removed and the residue was chromatographed to give a brown solid. 102 mg, 28percent. H1NMR (CDCl3), (ppm), 9.0 (s, 1 H), 10.4 (s, 1 H).

Reference： [1] Patent: CN105524048, 2016, A, . Location in patent: Paragraph 0424; 0425; 0426
[2] Patent: US2005/277655, 2005, A1, . Location in patent: Page/Page column 15

5
[ 68-12-2 ]
[ 58-96-8 ]
[ 871254-61-4 ]

Yield	Reaction Conditions	Operation in experiment
96.6%	Stage #1: at 5℃; for 0.5 h; Stage #2: at 5℃; for 2 h;	In the reaction flask, the solvent DMF (560 mL) was added, the temperature was lowered to 5 ° C, and phosphorus oxychloride (153 g) was slowly added dropwise, and the reaction temperature of the mixed system was controlled not to exceed 5 ° C, and the phosphorus oxychloride was added dropwise. Add boric acid (30.9g), stir for 30min, then add uridine 112g (1mol) in solid form to the above mixed system, control the reaction temperature not to exceed 5 ° C, stir for 2h, slowly warm to room temperature and continue to stir the reaction until The raw materials disappeared. Then, 560 mL of phosphorus oxychloride was added to the reaction system and the temperature was raised to reflux for 6 hours, then phosphorus oxychloride was recovered, and the residue was poured into a rapidly stirred ice water mixture to precipitate 2,4-dichloro-5-pyrimidine formaldehyde solid. 170 g, yield 96.6percent, purity 99.4percent.

Reference： [1] Patent: CN108467368, 2018, A, . Location in patent: Paragraph 0010; 0011; 0012; 0013

6
[ 68-12-2 ]
[ 66-22-8 ]
[ 3934-20-1 ]
[ 871254-61-4 ]

Reference： [1] Patent: CN108467368, 2018, A, . Location in patent: Paragraph 0014; 0015

7
[ 107-31-3 ]
[ 13544-44-0 ]
[ 871254-61-4 ]

Reference： [1] Organic Letters, 2014, vol. 16, # 19, p. 4972 - 4975

8
[ 871254-61-4 ]
[ 1211443-58-1 ]

Reference： [1] Patent: CN108586356, 2018, A,

[ 871254-61-4 ] Synthesis Path-Downstream 1~87

1
[ 871254-61-4 ]
[ 75-16-1 ]
[ 130825-17-1 ]

Yield	Reaction Conditions	Operation in experiment
97%		Example 20 1-(2,4-Dichloro-pyrimidin-5-yl)-ethanol To a stirred solution of <strong>[871254-61-4]2,4-dichloro-pyrimidine-5-carbaldehyde</strong> (Example 17, 1.01 g, 5.7 mmol) in THF (10 mL), methyl magnesium bromide (Aldrich, 3 M in ether, 6.27 mmol, 2.1 mL) was added slowly at -78 C. The mixture was stirred for an additional 2 hours at -78 C. and the reaction was quenched with 1N HCl (10 mL). The resulting mixture was extracted with EtOAc and the extract was dried with sodium sulfate. Removal of solvent gave a brown solid. 1.07 g, 97%. MS (M+H)+, 193.

Reference： [1]Patent: US2005/277655,2005,A1 .Location in patent: Page/Page column 16

2
[ 871254-61-4 ]
[ 23002-51-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With hydrazine; In tetrahydrofuran; at 20℃; for 0.5h;	Example 18 6-Chloro-1H-pyrazolo[3,4-d]pyrimidine To a stirred solution of hydrazine (Aldrich, 64 mg, 2 mmol) in THF (5 mL), 2,4-Dichloro-pyrimidine-5-carbaldehyde (Example 17, 176 mg, 1 mmol) was added and the mixture was stirred at room temperature for 30 min. The mixture was poured into water and extracted with EtOAc. The extract was dried with sodium sulfate and the solvent was removed to give an orange solid. 128 mg, 82%. MS (M+H)+, 155.
57%	With hydrazine hydrate; In tetrahydrofuran; at 0 - 20℃; for 0.5h;	Compound 75 (2.0g, 11.3mmol) dissolved in THF (10mL), and at 0 was added hydrazine hydrate (1.33g, 22.6mmol) in THF (20mL) added and the reaction was stirred at room temperature for half hour and purified by silica gel column to give compound 76 as a yellow solid (1.0g, 57%).
50%	With hydrazine hydrate; In tetrahydrofuran; at 0 - 20℃; for 1.25h;	To a solution of 2,4-dichloropyrimidine-5-carbaldehyde (20.2 g, 114 mmol) in THF (530 mL) at 0 C was added a chilled solution of hydrazine hydrate (11.5 g, 2 eq) in THF (230 mL) over 5 minutes. The reaction mixture was stirred 10 minutes at 0 C and 1 hour at room temperature. It was then diluted with EtOAc and H20 and the layers were separated. The aqueous layer was extracted with EtOAc then the combined organic phase was dried over Na2S04, filtered, and concentrated. The crude product was purified by normal-phase column chromatography on silica gel (50% EtO Ac/hexanes) to afford 6-chloro-lH- pyrazolo[3,4-d]pyrimidine as a light-yellow solid (8.8 g, 50% yield). 1HNMR (400 MHz, CD3OD) d (ppm): 9.17 (s, 1H), 8.30 (s, 1H).

34%

With hydrazine; In tetrahydrofuran; at 20℃; for 1h;

Preparation No.2: 6-Chloro-l/ -pyrazolo[3,4-i/|pyrimidine; A solution of 2,4-dichloropyrimidine-5-carbaldehyde (7.75 g, 43.8 mmol, Preparation No.1) in THF (100 mL) was added to a 500 mL round-bottomed flask charged with anhydrous hydrazine (3.0 mL, 96 mmol) in THF (250 mL). The reaction mixture was allowed to stir at ambient temperature for about 1 h after which the reaction mixture was concentrated under reduced pressure. The crude product was suspended in DCM (100 mL) and filtered through a silica gel pad. The silica gel pad was washed with additional DCM (2 x 20 mL) and the combined organic layers were concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 30% EtOAc in heptane to provide 6-chloro-lH-pyrazolo[3,4- djpyrimidine (2.3 g, 34%) as a white solid. LC/MS (Table 2, Method a) R, = 1.29 min; MS m/z: 155 (M+H)+.

Reference： [1]Patent: US2005/277655,2005,A1 .Location in patent: Page/Page column 15
[2]Patent: CN105524048,2016,A .Location in patent: Paragraph 0427; 0428
[3]Patent: WO2019/236631,2019,A1 .Location in patent: Paragraph 0523
[4]Patent: WO2011/156698,2011,A2 .Location in patent: Page/Page column 52-53

3
[ 36082-50-5 ]
[ 68-12-2 ]
[ 871254-61-4 ]

Yield	Reaction Conditions	Operation in experiment
31%		Under nitrogen in a dry 250mL three flask was added 74 (10.00g, 43.9mmol) and tetrahydrofuran (100.0mL), - 78 slowly added dropwise isopropylmagnesium chloride lithium chloride complex solution (2M) (24.2mL, 48.3mmol), - for half hour at 78 --35 , DMF is then slowly added dropwise at -78 (9.6g, 131.6mmol), followed by stirring at -35 4 hours. The reaction with saturated ammonium chloride solution was quenched at -78 deg.] C, the reaction solution was diluted with 100.0mL of water, extracted twice with 200 mL of ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, the solvent was spin-dried compound 75 (2.1g , 31%) as a white solid.
28%		Example 17 2,4-Dichloro-pyrimidine-5-carbaldehyde To a stirred solution of 5-bromo-2,4-dichloropyrimidine (Aldrich, 454 mg, 2 mmol) in THF at -78 C., diisopropyl magnesium chloride (2M solution in THF, 2.1 mmol, 1.05 mL) was added and the mixture was stirred for 30 minutes at -35 C. Next, the solution was cooled to 31 78 C. and 1 mL of dry DMF was added. The mixture was stirred for 120 minutes at -78 C. and the reaction was quenched with 1 N HCl. The mixture was extracted with EtOAc and dried with sodium sulfate. The solvent was removed and the residue was chromatographed to give a brown solid. 102 mg, 28%. H1NMR (CDCl3), (ppm), 9.0 (s, 1 H), 10.4 (s, 1 H).

Reference： [1]Patent: CN105524048,2016,A .Location in patent: Paragraph 0424; 0425; 0426
[2]Patent: US2005/277655,2005,A1 .Location in patent: Page/Page column 15

4
[ 871254-61-4 ]
1H-pyrazolo[3,4-d]pyrimidin-6-amine [ No CAS ]

Reference： [1]Patent: WO2011/156698,2011,A2

5
[ 871254-61-4 ]
tert-butyl (trans-4-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexyl)methylcarbamate [ No CAS ]

Reference： [1]Patent: WO2011/156698,2011,A2

6
[ 4394-85-8 ]
[ 36082-50-5 ]
[ 871254-61-4 ]

Yield	Reaction Conditions	Operation in experiment
87%		To a solution of 5-bromo-2,4-dichloropyrimidine (30.0 g, 132 mmol) in THF (310 mL) was added zPrMgCl-LiCl complex (1.3 M in THF, 112 mL, 1.1 eq) dropwise, over 30 minutes, at -78 C. The reaction mixture was stirred for 15 minutes at -78 C after addition completed and then warmed to -42 C for 30 minutes. The reaction mixture was cooled to -78 C again and a solution of N-formylmorpholine (46.2 g, 3 eq) in THF (180 mL) was added dropwise, over 45 minutes, at -78 C. The reaction was stirred at -78 C for 10 minutes, warmed to -42 C, and stirred for 3 hours, monitoring by NMR. When most of the starting material was consumed, the reaction was poured into a flask containing 1N aq HC1 (750 mL) at 0 C, 500 mL of Et20 was added and the layers were separated. The aqueous phase was extracted with Et20 (500 mL) then the combined organic phase was dried over Na2S04, filtered, and concentrated via rotary evaporation. The crude product was purified by normal- phase column chromatography on silica gel (dichloromethane) to afford 2,4- dichloropyrimidine-5-carbaldehyde as a white solid (20.2 g, 87% yield). 1HNMR (400 MHz, CDCh) d (ppm): 10.38 (s, 1H), 9.03 (s, 1H).
71%		Preparation No.1: 2,4-Dichloropyrimidine-5-carbaldehyde; A solution of isopropyl magnesium chloride lithium chloride complex in THF (2M, 184 mL, 368 mmol) was added drop-wise over about 30 min to a 2 L round-bottomed flask charged with a solution of 5-bromo-2,4-dichloropyrimidine (49.6 g, 218 mmol) in THF (1000 mL) at about -78 C. The reaction was allowed to stir at about -78 C for about 30 min. Morpholine-4- carbaldehyde (75.0 g, 653 mmol) was then added drop-wise at about -78 C over about 30 min. The reaction was allowed to stir for about 30 min at about -78 C then allowed to warm to about - 35 C and stirred for about 30 min. Aqueous HCl (IN, 250 mL) and Et20 (500 mL) were added and the reaction mixture was allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was further extracted with Et20 (200 mL). The combined organic layers were dried over anhydrous MgS04, filtered through a silica gel pad on a fritted funnel, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using DCM (100%) as the eluent to provide 2,4-dichloropyrimidine-5- carbaldehyde (27.3 g, 71% ) as a light yellow solid. .H NMR (400 MHz, CDC13 ) delta 10.34 (s, 1H), 9.30 (s, 1H).

Reference： [1]Patent: WO2019/236631,2019,A1 .Location in patent: Paragraph 0522
[2]Patent: WO2011/156698,2011,A2 .Location in patent: Page/Page column 52

7
[ 871254-61-4 ]
[ 106-95-6 ]
1-(2,4-dichloropyrimidin-5-yl)but-3-en-1-ol [ No CAS ]

Reference： [1]Organic Letters,2014,vol. 16,p. 4972 - 4975

8
[ 871254-61-4 ]
(Z)-methyl 5-(2,4-dichloropyrimidin-5-yl)-5-hydroxypent-2-enoate [ No CAS ]
(E)-methyl 5-(2,4-dichloropyrimidin-5-yl)-5-hydroxypent-2-enoate [ No CAS ]

Reference： [1]Organic Letters,2014,vol. 16,p. 4972 - 4975

9
[ 107-31-3 ]
[ 13544-44-0 ]
[ 871254-61-4 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 4972 - 4975

10
[ 871254-61-4 ]
methyl 2-((2-methoxy-2-oxoethyl)sulfonyl)thieno[2,3-d]pyrimidine-6-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/100184,2016,A1

11
[ 871254-61-4 ]
methyl 2-aminothieno[2,3-d]pyrimidine-6-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/100184,2016,A1

12
[ 871254-61-4 ]
2-aminothieno[2,3-d]pyrimidine-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2016/100184,2016,A1

13
[ 871254-61-4 ]
[ 2365-48-2 ]
methyl 2-((2-methoxy-2-oxoethyl)thio)thieno[2,3-d]pyrimidine-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%		To a solution of <strong>[871254-61-4]2,4-dichloropyrimidine-5-carbaldehyde</strong> (0.22 g, 1.2 mmol) in dichloromethane (30 mL) under nitrogen was added diisopropylethylamine (0.16 g, 1.2 mmol). Then a solution of methyl 2-sulfanylacetate (0.26 g, 2.5 mmol) in dichloromethane (15 mL) was added dropwise over 10 min. The resulting solution was stirred at room temperature for 2 hours. On completion, the mixture was diluted with water (20 mL) and extracted with dichloromethane (3 chi 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was dissolved in N, N-dimethylformamide (40 mL), and diisopropylethylamine (0.16 g, 1.2 mmol) was added. The resulting solution was heated to 120 C for 1.5 hours. On completion, the mixture was concentrated, and the residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 5: 1] to give compound B-176 (0.12 g, 32% yield) as a white solid.

Reference： [1]Patent: WO2016/100184,2016,A1 .Location in patent: Paragraph 00415-00416

14
[ 871254-61-4 ]
[ 1614233-64-5 ]

Reference： [1]Patent: CN105524048,2016,A

15
[ 871254-61-4 ]
[ 1614233-65-6 ]

Reference： [1]Patent: CN105524048,2016,A

16
[ 871254-61-4 ]
[ 1614233-66-7 ]

Reference： [1]Patent: CN105524048,2016,A

17
[ 871254-61-4 ]
[ 1614233-67-8 ]

Reference： [1]Patent: CN105524048,2016,A

18
[ 871254-61-4 ]
C₁₈H₁₇Cl₂IN₄O₃ [ No CAS ]

Reference： [1]Patent: CN105524048,2016,A

19
[ 871254-61-4 ]
C₃₀H₃₃Cl₂N₇O₄ [ No CAS ]

Reference： [1]Patent: CN105524048,2016,A

20
[ 871254-61-4 ]
C₂₅H₂₅Cl₂N₇O₃ [ No CAS ]

Reference： [1]Patent: CN105524048,2016,A

21
[ 871254-61-4 ]
[ 20342-65-8 ]
2-(2,4-dichloropyrimidin-5-yl)-2-hydroxyacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With dmap; ammonium chloride; In acetonitrile; at 10℃; for 1.33333h;	2, 4-dichloropyrimidin-5-carboxaldehyde (177 mg, 1mmol, 4-dimethylaminopyridine (DMAP) (244 mg, 2 mmol) and ammonium chloride (64 mg, 1.2mmol) was dissolved in 2 mL of acetonitrile, 2-hydroxymalononitrile was added in acetic acid solution (2 mL, 3mol / L), stirred for 80 minutes at 10 C. The reaction mixture was concentrated by column chromatography to give 2-(2,4-dichloropyrimidin-5-yl)-2-hydroxyacetamide (188 mg, 85%)

Reference： [1]Patent: CN103086818,2016,B .Location in patent: Paragraph 0035; 0036; 0037

22
[ 871254-61-4 ]
[ 64-17-5 ]
[ 20342-65-8 ]
ethyl 2,4-dichloro-(α-hydroxy)-5-pyrimidineacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With dmap; acetic acid; at 10℃; for 0.666667h;	2,4-dichloro-5-carbaldehyde pyrimidine(177 mg, 1 mmol) was dissolved in 2 mL of ethanol, and 2-hydroxypropionaldehyde was added Acetic acid solution (0.4 mL, 5 mol / L) followed by rapid addition of 4-dimethylaminopyridine (12 mg) and stirring at 10 C for 40 min The reaction mixture was concentrated and separated by column chromatography to give ethyl 2,4-dichloro-5-(alpha-hydroxy)pyrimidineacetate (193mg,77%)

Reference： [1]Patent: CN103086881,2016,B .Location in patent: Paragraph 0050-0052

23
[ 67-56-1 ]
[ 871254-61-4 ]
[ 20342-65-8 ]
2,4-dichloro-(α-hydroxy)-5-pyrimidineacetic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With dmap; acetic acid; at 50℃; for 0.666667h;	General procedure: 4-methoxybenzaldehyde(136 mg, 1 mmol) was dissolved in 2 mL of methanol,The acetic acid 2,4-dichloro-5-formaldehyde pyrimidine (177 mg, 1mmol) dissolved in 2 ml methanol, by adding of 2-hydroxypropanedinitrile acetic acid solution (0.4 ml, 5mol/L), then rapidly added to 4-dimethyl aminopyridine (12 mg), 50 C stirring under 40 minutes. After concentrating the reaction solution through the column chromatography separation to obtain 2,4-dichloro-5 - (hydroxy-a)-acetic acid methyl ester pyrimidine (190 mg, 80%).

Reference： [1]Patent: CN103086881,2016,B .Location in patent: Paragraph 0047-0049

24
[ 871254-61-4 ]
[ 67-63-0 ]
[ 20342-65-8 ]
isopropyl 2,4-dichloro-(α-hydroxy)-5-pyrimidineacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With dmap; acetic acid; at 10℃; for 0.666667h;	General procedure: 2,4-dichloro-5-carbaldehyde pyrimidine(177 mg, 1 mmol) was dissolved in 2 mL of ethanol, and 2-hydroxypropionaldehyde was added Acetic acid solution (0.4 mL, 5 mol / L) followed by rapid addition of 4-dimethylaminopyridine (12 mg) and stirring at 10 C for 40 min The reaction mixture was concentrated and separated by column chromatography to give ethyl 2,4-dichloro-5-(alpha-hydroxy)pyrimidineacetate (193mg,77%)

Reference： [1]Patent: CN103086881,2016,B .Location in patent: Paragraph 0052; 0053-0055

25
[ 871254-61-4 ]
[ 1251333-53-5 ]
1-cyclopropyl-2-(2,4-dichloropyrimidin-5-yl)-6-fluoro-1H-benzo[d]imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
180 mg	With Oxone; In water; N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere;	To a stirred solution of <strong>[871254-61-4]2,4-dichloropyrimidine-5-carbaldehyde</strong> (200 mg, 1.20 mmol) in DMF (4 mL) under an inert atmosphere was added N1-cyclopropyl-5-fluorobenzene-1,2-diamine Int-1 (320 mg, 1.80 mmol) and oxone (738 mg, 2.40 mmol) followed by water (0.4 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. After consumption of starting material (by TLC), the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2*20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 30% EtOAc/hexane) to afford 1-cyclopropyl-2-(2,4-dichloropyrimidin-5-yl)-6-fluoro-1H-benzo[d]imidazole Ex. 35 (180 mg, 0.55 mmol, 46%) as brown solid. ?H NMR (400 MHz, CDC13): oe 8.80 (s, 1H),7.78-7.74 (m, 1H), 7.32 (dd, J=8.5, 2.4 Hz, 1H), 7.14-7.10(m, 1H), 3.55-3.36 (m, 1H), 1.12-1.07 (m, 2H), 0.79-0.68(m, 2H) EC-MS: mlz 324.9 [M+2H] at 2.53 RT (97.74% purity). HPEC: 95.01%.

Reference： [1]Patent: US2018/186773,2018,A1 .Location in patent: Paragraph 0649; 0650; 0651; 0652; 0653

26
[ 871254-61-4 ]
[ 1356483-73-2 ]
1-cyclopropyl-2-(2,4-dichloropyrimidin-5-yl)-1H-benzo[d]imidazole-6-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With Oxone; In water; N,N-dimethyl-formamide; at 20℃; for 5h;	To a stirred solution of 4-amino-3-(cyclopropy- lamino)benzonitrile Int-4 (500 mg, 2.89 mmol) in DMF (10 mE) and water (2 mE) was added 2,4-dichioropyrimidine- 5-carbaldehyde (613 mg, 3.46 mmol) and Oxone (1.77 g,5.78 mmol) at room temperature and the mixture was stirred for 5 h. Afier consumption of starting material (by TEC), the reaction mixture was diluted with water (50 mE) and extracted with EtOAc (2x60 mE). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel colunm chromatography (eluent: 15% EtOAc/Hexane) to afford 1 -cyclopropyl-2-(2,4-dichloropy- rimidin-5-yl)- 1 H-benzo[d]imidazole-6-carbonitrile (300 mg, 0.91 mmol, 31%) as an off white solid. ?H NMR (400 MHz, DMSO-d5): oe 9.19 (s, 1H),8.33 (dd, J=1.5, 0.6 Hz, 1H), 7.94 (dd, J=8.4, 0.6 Hz, 1H),7.73 (dd, J=8.5, 1.6 Hz, 1H), 3.634-3.59 (m, 1H), 1.09-1.03 (m, 2H), 0.78-0.73 (m, 2H)

Reference： [1]Patent: US2018/186773,2018,A1 .Location in patent: Paragraph 0673; 0674; 0675; 0851; 0852; 0853

27
[ 871254-61-4 ]
[ 1356483-58-3 ]
1-cyclopropyl-2-(2,4-dichloropyrimidin-5-yl)-5,6-difluoro-1H-benzo[d]imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With Oxone; In water; N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;	To a stirred solution of Int-6 (2.2 g, 11.95 mmol) in N,N-dimethylformamide (DMF) (22 mL) under an inert atmosphere was added <strong>[871254-61-4]2,4-dichloropyrimidine-5-carbaldehyde</strong> (2.53 g, 14.34 mmol), oxone (5.49 g, 23.91 mmol) and water (2.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After consumption of starting material (by TLC), the reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2 (2*100 mL). The combined organic extracts were washed with water (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 20% EtOAc/hexane) to afford 1-cyclopropyl-2-(2,4-dichloropyrimidin-5-yl)-5,6-difluoro-1H-benzo[d]imidazole Int-13 (1.5 g, 4.41 mmol, 38%) as an off-white solid. 1H NMR (500 MHz, CDCl3): delta 8.80 (s, 1H), 7.62-7.59 (m, 1H), 7.46-7.42 (m, 1H), 3.53-3.48 (m, 1H), 1.22-1.02 (m, 2H), 0.74-0.66 (m, 2H)

Reference： [1]Patent: US2018/186773,2018,A1 .Location in patent: Paragraph 0359; 0360; 0361

28
[ 68-12-2 ]
[ 58-96-8 ]
[ 871254-61-4 ]

Yield	Reaction Conditions	Operation in experiment
96.6%		In the reaction flask, the solvent DMF (560 mL) was added, the temperature was lowered to 5 C, and phosphorus oxychloride (153 g) was slowly added dropwise, and the reaction temperature of the mixed system was controlled not to exceed 5 C, and the phosphorus oxychloride was added dropwise. Add boric acid (30.9g), stir for 30min, then add uridine 112g (1mol) in solid form to the above mixed system, control the reaction temperature not to exceed 5 C, stir for 2h, slowly warm to room temperature and continue to stir the reaction until The raw materials disappeared. Then, 560 mL of phosphorus oxychloride was added to the reaction system and the temperature was raised to reflux for 6 hours, then phosphorus oxychloride was recovered, and the residue was poured into a rapidly stirred ice water mixture to precipitate 2,4-dichloro-5-pyrimidine formaldehyde solid. 170 g, yield 96.6%, purity 99.4%.

Reference： [1]Patent: CN108467368,2018,A .Location in patent: Paragraph 0010; 0011; 0012; 0013

29
[ 68-12-2 ]
[ 66-22-8 ]
[ 3934-20-1 ]
[ 871254-61-4 ]

Yield	Reaction Conditions	Operation in experiment
		In the reaction flask, add solvent DMF (560mL), reduce the temperature to -5 C, slowly add phosphorus oxychloride (230g), the reaction temperature of the mixed system is controlled to not exceed 5 C, and the phosphorus oxychloride is added dropwise. After stirring for 30 min, 11 g of uracil (1 mol) was added in a solid form to the above mixed system, and the reaction temperature was controlled to not exceed 5 C. After stirring for 2 h, the temperature was slowly raised to room temperature and the reaction was stirred until the starting material disappeared. Then, 560 mL of phosphorus oxychloride was added to the reaction system and the temperature was raised to reflux for 6 hours, then phosphorus oxychloride was recovered, and the residue was poured into a rapidly stirred ice water mixture to precipitate 2,4-dichloro-5-pyrimidinecarboxaldehyde and A mixture of 2,4-dichloro-uracils is difficult to purify.

Reference： [1]Patent: CN108467368,2018,A .Location in patent: Paragraph 0014; 0015

30
[ 871254-61-4 ]
[ 1211443-61-6 ]

Reference： [1]Patent: CN108586356,2018,A
[2]Patent: CN108586356,2018,A

31
[ 871254-61-4 ]
ethyl 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate [ No CAS ]

Reference： [1]Patent: CN108586356,2018,A

32
[ 871254-61-4 ]
[ 1211443-58-1 ]

Reference： [1]Patent: CN108586356,2018,A

33
[ 871254-61-4 ]
ethyl 2-((5-(4-(tert-butoxycarbonyl) piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate [ No CAS ]

Reference： [1]Patent: CN108586356,2018,A

34
[ 871254-61-4 ]
2-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid [ No CAS ]

Reference： [1]Patent: CN108586356,2018,A

35
[ 871254-61-4 ]
[ 1374639-78-7 ]

Reference： [1]Patent: CN108586356,2018,A
[2]Patent: CN108586356,2018,A
[3]Patent: CN108586356,2018,A

36
[ 871254-61-4 ]
[ 1211441-98-3 ]

Reference： [1]Patent: CN108586356,2018,A
[2]Patent: CN108586356,2018,A
[3]Patent: CN108586356,2018,A

37
[ 871254-61-4 ]
N,N-dimethyl(2-cyclopentylamino)acetamide [ No CAS ]
2-((2-chloro-5-formylpyrimidin-4-yl)(cyclopentylamino))-N,N-dimethylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium carbonate; In N,N-dimethyl-formamide; at 20℃;	2,4-Dichloro-5-pyrimidinecarboxaldehyde (17.70 g, 100 mmol) was added to a three-necked flask. N,N-dimethylformamide (88 mL), stirred and dissolved, added sodium carbonate (26.50 g, 250 mmol), and then stirred and then added 2-cyclopentylamino-N,N-dimethylformamide (17.03 g, 100 mmol) ), react at room temperature for 6-8 hours. At the end of the reaction, water (177 mL), ethyl acetate (177 mL) was added, and the mixture was separated, and the aqueous phase was further extracted with ethyl acetate (88 mL), and the organic phase brine (88 mL) the sodium salt is dried, filtered, concentrated, and then a small amount of isopropyl ether and petroleum ether is added, and the solid is separated by filtration and dried in vacuo to give 2-((2-chloro-5-formylpyrimidin-4-yl)(cyclopentylamino)-N,N-dimethylacetamide (25.48 g, 82%).

Reference： [1]Patent: CN108586356,2018,A .Location in patent: Paragraph 0084; 0085

38
[ 871254-61-4 ]
[ 89479-61-8 ]
ethyl 2-((2-chloro-5-formylpyrimidin-4-yl)(cyclopentylamino))acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium carbonate; In N,N-dimethyl-formamide; at 20℃;	2,4-Dichloro-5-pyrimidinecarboxaldehyde (17.70 g, 100 mmol) was added to a three-necked flask. N,N-dimethylformamide (88 mL), stirred and dissolved, added sodium carbonate (26.50 g, 250 mmol), and then stirred and then added ethyl 2-(cyclopentylamino)acetate (17.12 g, 100 mmol), and reacted at room temperature 6- 8 hours. At the end of the reaction, water (177 mL) was added, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (88 mL), and the organic phase brine (88 mL) was washed once, dried over anhydrous sodium sulfate, filtered, concentrated. The petroleum ether is beaten and the solid is separated by filtration. drying in vacuo gave ethyl 2-((2-chloro-5-formylpyrimidin-4-yl)(cyclopentylamino))acetate (26.19 g, 84%).

Reference： [1]Patent: CN108586356,2018,A .Location in patent: Paragraph 0086; 0087

39
[ 871254-61-4 ]
ethyl 1-benzyl-3-(2-chloro-5-(dimethoxymethyl)pyrimidin-4-yl)pyrrolidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/191470,2019,A1

40
[ 871254-61-4 ]
ethyl 1-benzyl-3-(2-((cyclopropylmethyl)amino)-5-(dimethoxymethyl)pyrimidin-4-yl)pyrrolidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/191470,2019,A1

41
[ 871254-61-4 ]
ethyl 1-benzyl-3-(2-((cyclopropylmethyl)amino)-5-formylpyrimidin-4-yl)pyrrolidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/191470,2019,A1

42
[ 871254-61-4 ]
1‘-benzyl-2-((cyclopropylmethyl)amino)-6-(4-methoxybenzyl)-5,6-dihydro-7H-spiro[pyrido[4,3-d]pyrimidine-8,3‘-pyrrolidin]-7-one [ No CAS ]

Reference： [1]Patent: WO2019/191470,2019,A1

43
[ 871254-61-4 ]
ethyl 3-(2-chloro-5-(dimethoxymethyl)pyrimidin-4-yl)-1-(2-fluorobenzyl)pyrrolidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/191470,2019,A1

44
[ 871254-61-4 ]
ethyl 3-(2-((cyclopropylmethyl)amino)-5-(dimethoxymethyl)pyrimidin-4-yl)-1-(2-fluorobenzyl)pyrrolidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/191470,2019,A1

45
[ 871254-61-4 ]
ethyl 3-(2-((cyclopropylmethyl)amino)-5-formylpyrimidin-4-yl)-1-(2-fluorobenzyl)pyrrolidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2019/191470,2019,A1

46
[ 871254-61-4 ]
2-((cyclopropylmethyl)amino)-1‘-(2-fluorobenzyl)-6-((2-methoxypyridin-4-yl)methyl)-5,6-dihydro-7H-spiro[pyrido[4,3-d]pyrimidine-8,3‘-pyrrolidin]-7-one [ No CAS ]

Reference： [1]Patent: WO2019/191470,2019,A1

47
[ 871254-61-4 ]
6-((1H-pyrazol-5-yl)methyl)-2-((cyclopropylmethyl)amino)-1‘-(2-fluorobenzyl)-5,6-dihydro-7H-spiro[pyrido[4,3-d]pyrimidine-8,3‘-pyrrolidin]-7-one [ No CAS ]

Reference： [1]Patent: WO2019/191470,2019,A1

48
[ 871254-61-4 ]
2-((cyclopropylmethyl)amino)-1’-(2-fluorobenzyl)-6-(isoxazol-4-yl)-5,6-dihydro-7H-spiro[pyrido[4,3-d]pyrimidine-8,3‘-pyrrolidin]-7-one [ No CAS ]

Reference： [1]Patent: WO2019/191470,2019,A1

49
[ 871254-61-4 ]
2-((cyclopropylmethyl)amino)-1’-(2-fluorobenzyl)-6-(1H-pyrazol-4-yl)-5,6-dihydro-7H-spiro[pyrido[4,3-d]pyrimidine-8,3‘-pyrrolidin]-7-one [ No CAS ]

Reference： [1]Patent: WO2019/191470,2019,A1

50
[ 67-56-1 ]
[ 871254-61-4 ]
[ 149-73-5 ]
2,4-dichloro-5-(dimethoxymethyl)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With pyridinium p-toluenesulfonate; at 65℃; for 14h;	To a flask containing MeOH (24.0 mL), was added 2,4- dichloropyrimidine-5-carbaldehyde (1.5159 g, 1.0 equiv.), PPTS (215.0 mg, 0.1 equiv.) and trimethyl orthoformate (6.0 mL). The reaction mixture was stirred at 65 C for 14 h, cooled to rt and concentrated. The resulting residue was purified via column chromatography to yield the title compound as an oil (1.4361 g, 75% yield). NMR (400 MHz, Chloroform-^ d 8.73 (s, 1H), 5.54 (s, 1H), 3.38 (s, 7H). LC-MS: m/z 223, 225 [M+H]+.

Reference： [1]Patent: WO2019/191470,2019,A1 .Location in patent: Paragraph 00243; 00244; 00245

51
[ 871254-61-4 ]
3-bromo-6-chloro-1H-pyrazolo[3,4-d]pyrimidine [ No CAS ]