[ CAS No. 105806-13-1 ] {[proInfo.proName]}

Name: 105806-13-1|4,6-Dichloro-5-fluoro-2-methylpyrimidine|97%
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SKU: A116154
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Quality Control of [ 105806-13-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 105806-13-1 ]

SDS Specification

Alternatived Products of [ 105806-13-1 ]

Product Details of [ 105806-13-1 ]

CAS No. :	105806-13-1	MDL No. :	MFCD11520450
Formula :	C₅H₃Cl₂FN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IWPZWKNMDQSDQP-UHFFFAOYSA-N
M.W :	181.00	Pubchem ID :	13731033
Synonyms :

Calculated chemistry of [ 105806-13-1 ] Expand+

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	36.98
TPSA :	25.78 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) :	-5.54 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.05
Log Po/w (XLOGP3) :	2.63
Log Po/w (WLOGP) :	2.65
Log Po/w (MLOGP) :	1.6
Log Po/w (SILICOS-IT) :	3.1
Consensus Log Po/w :	2.41

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.06
Solubility :	0.157 mg/ml ; 0.000865 mol/l
Class :	Soluble
Log S (Ali) :	-2.82
Solubility :	0.273 mg/ml ; 0.00151 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.55
Solubility :	0.051 mg/ml ; 0.000282 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.74

Safety of [ 105806-13-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 105806-13-1 ]

* 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 [ 105806-13-1 ]
Downstream synthetic route of [ 105806-13-1 ]

[ 105806-13-1 ] Synthesis Path-Upstream 1~3

1
[ 1598-63-6 ]
[ 105806-13-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	at 120℃; for 3 h;	Part B: 4,6-Dichloro-5-fluoro-2-methylpyrimidine. 5-Fluoro-4,6-dihydroxy-2-methylpyrimidine (assumed 60 g, 0.42 mol) was treated with 300 ml. of POCI3 at 120 ⁰C for 3 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo until the rate of solvent removal slowed to a drop rate of less than 1 drop/second. The product is somewhat volatile and excessive concentration in vacuo will reduce the yield. The crude residue was poured over crushed ice, and the resulting slurry was stirred for 1 h, during which time the solution came to room temperature. A yellow solid formed which was filtered off, washed with water, and air dried briefly until free flowing. This solid was collected and placed in a dessicator over P₂O₅ until dry, providing pure 4,6-dichloro-5-fluoro-2-methylpyrimidine (59 g, 79percent). LCMS: (M+H)⁺: 181/183 .
79%	at 120℃; for 3 h; Inert atmosphere	Part B: 4,6-Dichloro-5-fluoro-2-methylpyrimidine 5-Fluoro-4,6-dihydroxy-2-methylpyrimidine (assumed 60 g, 0.42 mol) was treated with 300 mL of POCI₃ at 120 °C for 3 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo until the rate of solvent removal slowed to a drop rate of less than 1 drop/second. The product is somewhat volatile and excessive concentration in vacuo will reduce the yield. The crude residue was poured over crushed ice, and the resulting slurry was stirred for 1 h, during which time the solution came to room temperature. A yellow solid formed which was filtered off, washed with water, and air dried briefly until free flowing. This solid was collected and placed in a dessicator over P₂0₅ until dry, providing pure 4,6-dichloro-5-fluoro-2- methylpyrimidine (59 g, 79percent). LCMS: (M+H)⁺: 181/183 .
62%	With trichlorophosphate In <i>N</i>,<i>N</i>-dimethyl-aniline for 2 h; Heating / reflux	Part B: A mixture of 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.00 g, 13.9 mmol), phosphorous oxychloride (15.0 mL, 161 mmol), and JV,iV-diinethyIaniline (2.00 mL, 15.8 mmol) was heated at reflux for 2 h. The reaction mixture was cooled to RT and concentrated under reduced press. The residue was poured onto ice and allowed to warm to RT as a ppt formed. The solids were collected by suction filtration, washed with water, and air-dried at RT for Ih to give 4,6-dichloro-5-fluoro-2-methylpyrimidine (1.56 g, 62percent) as a tan solid. LCMS (m/z): 181,183 (M+H)⁺

62%

for 2 h; Heating / reflux

Part B:
A mixture of 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.00 g, 13.9 mmol), phosphorous oxychloride (15.0 mL, 161 mmol), and N,N-dimethylaniline (2.00 mL, 15.8 mmol) was heated at reflux for 2 h.
The reaction mixture was cooled to RT and concentrated under reduced press.
The residue was poured onto ice and allowed to warm to RT as a ppt formed.
The solids were collected by suction filtration, washed with water, and air-dried at RT for 1 h to give 4,6-dichloro-5-fluoro-2-methylpyrimidine (1.56 g, 62percent) as a tan solid. LCMS (m/z): 181,183 (M+H)⁺

Reference： [1] Patent: WO2009/61879, 2009, A1, . Location in patent: Page/Page column 61
[2] Patent: WO2013/82388, 2013, A1, . Location in patent: Page/Page column 67
[3] Patent: WO2007/75852, 2007, A2, . Location in patent: Page/Page column 32
[4] Patent: US2007/197523, 2007, A1, . Location in patent: Page/Page column 7
[5] Patent: US4617393, 1986, A,

2
[ 105806-13-1 ]
[ 943006-45-9 ]

Yield	Reaction Conditions	Operation in experiment
61%	With ammonia In methanol; water at 70℃; for 2 h;	Part C: A mixture of 4,6-dichloro-5-fluoro-2-methylpyrimidine (1.55 g, 8.56 mmol), ammonium hydroxide (35percent, 10.0 mL, 257 mmol), and MeOH (1.00 mL) was heated, in a sealed tube, at 70 ⁰C for 2h. The reaction mixture was cooled to RT, and a precipitate was formed. The reaction mixture was diluted with water (ca. 10 mL) and was stirred 30 min. The solids were collected by suction filtration, washed with water and air-dried to give 4-amino-6-chloro-5-fluoro-2-methylpyrimidine (845 mg, 61percent) as a tan solid. LCMS (m/z): 162,164 (M+H)⁺
61%	With ammonia In methanol; water at 70℃; for 2 h;	Part C: A mixture of 4,6-dichloro-5-fluoro-2-methylpyrimidine (1.55 g, 8.56 mmol), ammonium hydroxide (35percent, 10.0 mL, 257 mmol), and MeOH (1.00 mL) was heated, in a sealed tube, at 70° C. for 2 h. The reaction mixture was cooled to RT, and a precipitate was formed. The reaction mixture was diluted with water (ca. 10 mL) and was stirred 30 min. The solids were collected by suction filtration, washed with water and air-dried to give 4-amino-6-chloro-5-fluoro-2-methylpyrimidine (845 mg, 61percent) as a tan solid. LCMS (m/z): 162,164 (M+H)⁺

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5188 - 5219
[2] Patent: WO2007/75852, 2007, A2, . Location in patent: Page/Page column 32
[3] Patent: US2007/197523, 2007, A1, . Location in patent: Page/Page column 7-8

3
[ 105806-13-1 ]
[ 124-41-4 ]
[ 1383976-40-6 ]

Yield	Reaction Conditions	Operation in experiment
9 g	at 5 - 20℃; for 3 h;	Step 1a 4-Chloro-5-fluoro-6-methoxy-2-methylpyrimidine 3.21 g of sodium methoxide are added to a solution of 9.8 g of 2-methyl-4,6-dichloro-5-fluoropyrimidine in 80 ml of THF cooled to 5° C. in an ice bath. The ice bath is removed. The suspension is stirred at ambient temperature for 3 hours. The reaction medium is cooled to 5° C. in an ice bath. 20 ml of water and 100 ml of ethyl acetate are added. After settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 9 g of 4-chloro-5-fluoro-6-methoxy-2-methylpyrimidine in the form of a colorless oil which crystallizes, the characteristics of which are the following: Mass spectrometry: method A Retention time Tr (min)=0.82; [M+H]+: m/z 177

Reference： [1] Patent: US2013/274253, 2013, A1, . Location in patent: Paragraph 0798-0802

[ 105806-13-1 ] Synthesis Path-Downstream 1~47

2
[ 1598-63-6 ]
[ 105806-13-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	With trichlorophosphate; at 120℃; for 3h;	Part B: 4,6-Dichloro-5-fluoro-2-methylpyrimidine. 5-Fluoro-4,6-dihydroxy-2-methylpyrimidine (assumed 60 g, 0.42 mol) was treated with 300 ml. of POCI3 at 120 0C for 3 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo until the rate of solvent removal slowed to a drop rate of less than 1 drop/second. The product is somewhat volatile and excessive concentration in vacuo will reduce the yield. The crude residue was poured over crushed ice, and the resulting slurry was stirred for 1 h, during which time the solution came to room temperature. A yellow solid formed which was filtered off, washed with water, and air dried briefly until free flowing. This solid was collected and placed in a dessicator over P2O5 until dry, providing pure 4,6-dichloro-5-fluoro-2-methylpyrimidine (59 g, 79%). LCMS: (M+H)+: 181/183 .
79%	With trichlorophosphate; at 120℃; for 3h;Inert atmosphere;	Part B: 4,6-Dichloro-5-fluoro-2-methylpyrimidine 5-Fluoro-4,6-dihydroxy-2-methylpyrimidine (assumed 60 g, 0.42 mol) was treated with 300 mL of POCI3 at 120 C for 3 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo until the rate of solvent removal slowed to a drop rate of less than 1 drop/second. The product is somewhat volatile and excessive concentration in vacuo will reduce the yield. The crude residue was poured over crushed ice, and the resulting slurry was stirred for 1 h, during which time the solution came to room temperature. A yellow solid formed which was filtered off, washed with water, and air dried briefly until free flowing. This solid was collected and placed in a dessicator over P205 until dry, providing pure 4,6-dichloro-5-fluoro-2- methylpyrimidine (59 g, 79%). LCMS: (M+H)+: 181/183 .
62%	With trichlorophosphate; In N,N-dimethyl-aniline; for 2h;Heating / reflux;	Part B: A mixture of 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.00 g, 13.9 mmol), phosphorous oxychloride (15.0 mL, 161 mmol), and JV,iV-diinethyIaniline (2.00 mL, 15.8 mmol) was heated at reflux for 2 h. The reaction mixture was cooled to RT and concentrated under reduced press. The residue was poured onto ice and allowed to warm to RT as a ppt formed. The solids were collected by suction filtration, washed with water, and air-dried at RT for Ih to give 4,6-dichloro-5-fluoro-2-methylpyrimidine (1.56 g, 62%) as a tan solid. LCMS (m/z): 181,183 (M+H)+

62%	With N,N-dimethyl-aniline; trichlorophosphate; for 2h;Heating / reflux;	Part B: A mixture of 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.00 g, 13.9 mmol), phosphorous oxychloride (15.0 mL, 161 mmol), and N,N-dimethylaniline (2.00 mL, 15.8 mmol) was heated at reflux for 2 h. The reaction mixture was cooled to RT and concentrated under reduced press. The residue was poured onto ice and allowed to warm to RT as a ppt formed. The solids were collected by suction filtration, washed with water, and air-dried at RT for 1 h to give 4,6-dichloro-5-fluoro-2-methylpyrimidine (1.56 g, 62%) as a tan solid. LCMS (m/z): 181,183 (M+H)+
43%	In sodium hydroxide; trichlorophosphate;	(Step c) Preparation of 2-Methyl-4,6-dichloro-5-fluoropyrimidine A suspension of 1.44 g (10 mmol) of 2-methyl-4,6-dihydroxy-5-fluoropyrimidine in 7.5 mL (12 g, 80 mmol) of phosphorus oxychloride was heated to reflux for 4 hours. The mixture was cooled to 23 C., and poured into an ice/water slurry in which sodium hydroxide (15.0 g) had been dissolved. The mixture was stirred for 20 minutes and then extracted with chloroform. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to provide product (0.78 g, 43%), m.p. 49-50 C. This crude product was used in subsequent reactions without further purification. 1 H NMR (60 MHz, CDCl3) delta 2.7 (s, 3H); IR (CHCl3) 1520, 1415 cm-1; mass spectrum m/e 180 (M+, 29%), 145 (M+ -Cl, 68%).

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 61
[2]Patent: WO2013/82388,2013,A1 .Location in patent: Page/Page column 67
[3]Patent: WO2007/75852,2007,A2 .Location in patent: Page/Page column 32
[4]Patent: US2007/197523,2007,A1 .Location in patent: Page/Page column 7
[5]Patent: US4617393,1986,A

3
[ 105806-13-1 ]
2-methyl-4-hydroxy-5-fluoro-6-chloropyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With sodium chloride; sulfuric acid; In water;	(Step d) Preparation of 2-Methyl-4-hydroxy-5-fluoro-6-chloropyrimidine To a mixture of water (3 mL) and concentrated sulfuric acid (7 mL) was added 1.81 g (10 mmol) of <strong>[105806-13-1]2-methyl-4,6-dichloro-5-fluoropyrimidine</strong>. The reaction mixture was stirred for 3 hours and then poured onto ice. The mixture was saturated with sodium chloride and extracted with ethyl acetate. The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo to give crude product (1.4 g, 86%), m.p. 214-216 C. This product was used in subsequent reactions without further purification. 1 H NMR (60 MHz, CDCl3) delta 2.42 (s, 3H); IR (Nujol) 1650, 1585, 1450 cm-1.

Reference： [1]Patent: US4617393,1986,A

4
[ 105806-13-1 ]
[ 943006-45-9 ]

Yield	Reaction Conditions	Operation in experiment
61%	With ammonia; In methanol; water; at 70℃; for 2h;	Part C: A mixture of <strong>[105806-13-1]4,6-dichloro-5-fluoro-2-methylpyrimidine</strong> (1.55 g, 8.56 mmol), ammonium hydroxide (35%, 10.0 mL, 257 mmol), and MeOH (1.00 mL) was heated, in a sealed tube, at 70 0C for 2h. The reaction mixture was cooled to RT, and a precipitate was formed. The reaction mixture was diluted with water (ca. 10 mL) and was stirred 30 min. The solids were collected by suction filtration, washed with water and air-dried to give 4-amino-6-chloro-5-fluoro-2-methylpyrimidine (845 mg, 61%) as a tan solid. LCMS (m/z): 162,164 (M+H)+
61%	With ammonia; In methanol; water; at 70℃; for 2h;	Part C: A mixture of <strong>[105806-13-1]4,6-dichloro-5-fluoro-2-methylpyrimidine</strong> (1.55 g, 8.56 mmol), ammonium hydroxide (35%, 10.0 mL, 257 mmol), and MeOH (1.00 mL) was heated, in a sealed tube, at 70 C. for 2 h. The reaction mixture was cooled to RT, and a precipitate was formed. The reaction mixture was diluted with water (ca. 10 mL) and was stirred 30 min. The solids were collected by suction filtration, washed with water and air-dried to give 4-amino-6-chloro-5-fluoro-2-methylpyrimidine (845 mg, 61%) as a tan solid. LCMS (m/z): 162,164 (M+H)+

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5188 - 5219
[2]Patent: WO2007/75852,2007,A2 .Location in patent: Page/Page column 32
[3]Patent: US2007/197523,2007,A1 .Location in patent: Page/Page column 7-8

5
[ 123-75-1 ]
[ 105806-13-1 ]
[ 1152110-00-3 ]

Yield	Reaction Conditions	Operation in experiment
59%		Part A: 5-Fluoro-4-hydrazino-2-methyl-6-(1-pyrrolidinyl)pyrimidine. 4,6-Dichloro-5-fluoro-2-methylpyrimidine (100 mg, 0.55 mmol) was dissolved in 2 ml. of DMSO and stirred at room temperature. Pyrrolidine (50 mul_, 0.61 mmol) was added, followed by DIPEA (210 mul_, 1.21 mmol). The resulting reaction mixture was stirred for 2 h, and then hydrazine was added (1.0 ml.) and the contents were heated to 80 0C for 1 h. The reaction mixture was then cooled to room temperature and purified by RP- HPLC to provide 5-fluoro-4-hydrazino-2-methyl-6-(1-pyrrolidinyl)pyrimidine (69 mg, 59%).

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 68

6
[ 105806-13-1 ]
[ 78797-58-7 ]
[ 1152110-15-0 ]

Yield	Reaction Conditions	Operation in experiment
55%		Part A: 4-Azetidino-6-hydrazino-5-fluoro-2-methylpyrimidine. 4,6-Dichloro-5-fluoro-2-methylpyrimidine (6 g, 33 mmol) was dissolved in 50 ml. of iPrOH and stirred at room temperature. Azetidine-HCI (3.25 g, 35 mmol) was added, followed by 14.4 ml. of DIPEA. The resulting reaction mixture was stirred for 3 h, and then hydrazine monohydrate was added (4.0 ml_, 82.5 mmol) and the contents were heated to 80 0C overnight. The reaction mixture was then cooled to room temperature and a precipitate formed. The precipitate was filtered, washed with iPrOH, and dried. The remaining filtrate was poured into 250 ml. of water and extracted (5 x 100 ml.) with EtOAc. The combined organic fractions were washed with water (2 x 100 ml.) and brine (2 x 100 ml_). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. This crude product was purified by flash chromatography on silica gel using 97.5/2.5/0.25 DCM/MeOH/NH4OH as the eluent. The overall combined yield of 4- azetidino-6-hydrazino-5-fluoro-2-methylpyrimidine (precipitate + chromatographed product) was 3.6 g (55%). LCMS: (M+H)+: 198.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 78

7
[ 109-96-6 ]
[ 105806-13-1 ]
[ 1152110-10-5 ]

Yield	Reaction Conditions	Operation in experiment
68%		Part A: 4-(2,5-Dihydro-1H-pyrrol-1-yl)-5-fluoro-6-hydrazino-2-methylpyrimidine. 4,6-Dichloro-5-fluoro-2-methylpyrimidine (181 mg, 1.0 mmol) was dissolved in 4 ml. of DMSO and stirred at room temperature. 3-Pyrroline (71 mg, 1.05 mmol) was added, followed by DIPEA (244 mul_, 1.4 mmol). The resulting reaction mixture was stirred until displacement of the first chloride was complete, and then hydrazine (350 mul_) and MeOH (~2 ml.) were added to the reaction mixture. The contents were then heated to 70 0C for ~2 h, until displacement of the second chloride was complete. The reaction mixture was then cooled to room temperature and purified by RP-HPLC to provide 4-(2,5-dihydro-1H- pyrrol-1-yl)-5-fluoro-6-hydrazino-2-methylpyrimidine (142 mg, 68%).

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 74

8
[ 4597-87-9 ]
[ 105806-13-1 ]
[ 1152110-51-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In tetrahydrofuran; for 4h;	Part A: 6-Chloro-5-fluoro-2-methyl-N-(2-pyridinylmethyl)-4-pyrimidinamine. 4,6-Dichloro-5-fluoro-2-methylpyrimidine (0.2 g, 1.1 11 mmol) was dissolved in THF (1 ml_). To this solution was added triethylamine (0.17 ml_, 1.22 mmol), followed by commercially available (2-pyridinylmethyl)amine (0.11 ml_, 1.067 mmol), which was dissolved in THF (1 ml_). The reaction was left to stir for 4 hours. The reaction mixture was diluted with water and extracted with ether. The organics were dried (MgSO4) and concentrated to provide 6-chloro-5-fluoro-2-methyl-N-(2-pyridinylmethyl)-4- pyrimidinamine as a yellow wax (0.2517 g, 90%). LCMS: (M+H)+ = 253.3.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 140

9
[ 55661-33-1 ]
[ 105806-13-1 ]
[ 1152110-56-9 ]

Yield	Reaction Conditions	Operation in experiment
38%		Part A: 5-Fluoro-4-hydrazino-2-methyl-6-[(1,3-thiazol-2-ylmethyl)amino]pyrimidine. 4,6-Dichloro-5-fluoro-2-methylpyiotamidine (180 mg, 1 mmol) was dissolved in 1 ml. of DMSO and stirred at room temperature. (1 ,3-Thiazol-2-ylmethyl)amine (124 mg, 1.1 mmol) was added, followed by triethylamine (150 mul_, 1.1 mmol). The resulting reaction mixture was stirred for 3 h, then hydrazine was added (1.0 ml_), and the contents were heated to 60 0C for 1.5 h. The reaction mixture was then cooled to room temperature and purified by RP-HPLC to provide 5-fluoro-4-hydrazino-2-methyl-6-[(1 ,3-thiazol-2- ylmethyl)amino]pyrimidine (97 mg, 38%). LCMS: (M+H)+: 255.2.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 144

10
[ 6971-44-4 ]
[ 105806-13-1 ]
5-fluoro-6-hydrazino-N,2-dimethyl-N-(4-pyridinylmethyl)-4-pyrimidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		Part A: 5-Fluoro-6-hydrazino-N,2-dimethyl-N-(4-pyridinylmethyl)-4-pyrimidinamine. 4,6-Dichloro-5-fluoro-2-methylpyrimidine (0.18 g, 0.99 mmol) was dissolved in DMSO (1 ml_). To this solution was added triethylamine (0.15 ml_, 1.08 mmol), followed by commercially available N-methyl-1-(4-pyridinyl)methanamine (0.122 g, 1.0 mmol). The reaction was left to stir for 3 hours. Then hydrazine monohydrate was added, and the resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was heated to 6O0C for 90 minutes. After cooling, the reaction mixture was purified by RP-HPLC to provide 5-fluoro-6-hydrazino-N,2-dimethyl-N-(4-pyridinylmethyl)- 4-pyrimidinamine (0.130 g, 49%). LCMS: (M+H)+ = 263.0.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 142

11
[ 105806-13-1 ]
(9aS)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride [ No CAS ]
[ 1152110-18-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 2h;	Part I: (9aS)-(-(6-Chloro-5-fluoro-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine. To a mixture of (9aS)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (23.28 g, 108.2 mmol) in DCM (360 mL) was added <strong>[105806-13-1]4,6-dichloro-5-fluoro-2-methylpyrimidine</strong> (19.59 g, 108.2 mmol) and N,N-diisopropylethylamine (68 mL, 390.4 mmol). The mixture was stirred for 2 h, and the resulting solution was diluted with DCM (100 mL) and washed with saturated aq. NaHCO3 (200 mL). The aqueous phase was extracted with a fresh portion of DCM (100 mL), and this organic phase was washed with saturated aq. NaHCO3 (50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (9aS)-8-(6-chloro-5-fluoro-2-methyl-4- pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine as a light yellow oil that was used without further purification. LCMS: (M+H)+: 287.1.
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;Inert atmosphere;	Part I: (9aS)-8-(6-Chloro-5-fluoro-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1 - c][1 ,4]oxazine To a mixture of (9aS)-octahydropyrazino[2,1 -c][1 ,4]oxazine dihydrochloride (23.28 g, 108.2 mmol) in DCM (360 mL) was added 4,6-dichloro-5-fluoro-2- methylpyrimidine (19.59 g, 108.2 mmol) and N,N-diisopropylethylamine (68 mL, 390.4 mmol). The mixture was stirred for 2 h, and the resulting solution was diluted with DCM (100 mL) and washed with saturated aq. NaHC03 (200 mL). The aqueous phase was extracted with a fresh portion of DCM (100 mL), and this organic phase was washed with saturated aq. NaHC03 (50 mL). The combined organic phase was dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give (9aS)-8-(6-chloro-5- fluoro-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1 -c][1 ,4]oxazine as a light yellow oil that was used without further purification. LCMS: (M+H)+: 287.1.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 88
[2]Patent: WO2013/82388,2013,A1 .Location in patent: Page/Page column 78

12
[ 105806-13-1 ]
(R)-1,2-dimethylpiperazine dihydrochloride [ No CAS ]
[ 1152110-46-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; In tetrahydrofuran; methanol;	Part C: 4-Chloro-6-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine. To a solution of <strong>[105806-13-1]4,6-dichloro-5-fluoro-2-methylpyrimidine</strong> (0.181 g, 1.0 mmol) and (2R)- 1 ,2-dimethylpiperazine dihydrochloride (0.189 g, 1.0 mmol) in THF (10 mL) was added triethylamine (0.42 mL, 3.0 mmol). MeOH (1 mL) was added to improve solubility. Reaction left to stir overnight. The solvent was removed in vacuo, and THF and ether were added to the resulting residue, which was washed with water. The organics were dried (Na2SO4) and concentrated in vacuo to provide 4-chloro-6-[(3R)-3,4-dimethyl-1- piperazinyl]-5-fluoro-2-methylpyrimidine as a yellow oil (0.242 g, 94%). LCMS: (M+H)+ = 259.3.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 134

13
[ 105806-13-1 ]
(3R)-1,3-dimethylpiperazine dihydrochloride [ No CAS ]
[ 1152110-61-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 35℃; for 72h;	Part A: 4-Chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine. To a solution of (3R)-1 ,3-dimethylpiperazine dihydrochloride (Example 63) (5.88 g, 31.4 mmol) in dichloromethane (126 mL) was added N,N-diisopropylethylamine (18.1 1 mL, 104 mmol), and <strong>[105806-13-1]4,6-dichloro-5-fluoro-2-methylpyrimidine</strong> (5.69 g, 31.4 mmol). The solution was heated at 35 0C and stirred for 3 days. The solution was cooled to room temperature, diluted with DCM (100 mL), and washed with sat. aq. NaHCOs (100 mL). The aqueous phase was extracted with a fresh portion of DCM (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude 4-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2- methylpyrimidine (9.60 g, >100 % yield) as a brown oil that was used without further purification. LCMS: (M+H)+: 258.9.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 146

14
[ 105806-13-1 ]
(2S)-1,2-dimethylpiperazine dihydrochloride [ No CAS ]
[ 1152110-43-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine; In tetrahydrofuran; methanol; at 20℃;	Part C: 4-Chloro-6-[(3S)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine To a solution of <strong>[105806-13-1]4,6-dichloro-5-fluoro-2-methylpyrimidine</strong> (0.181 g, 1.0 mmol) and (2S)- 1 ,2-dimethylpiperazine dihydrochloride (0.189 g, 1.0 mmol) in THF (10 mL) was added triethylamine (0.42 mL, 3.0 mmol) at room temperature. MeOH (1 mL) was added to improve solubility. The reaction mixture was stirred overnight, and then the solvent was removed in vacuo. Ether, THF and water were added to the resulting residue. The organics were separated, dried (Na2SO4) and evaporated to provide 4-chloro-6-[(3S)- 3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine as a yellow solid (0.254 g, 98%). LCMS: (M+H)+ = 259.3.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 132

15
[ 105806-13-1 ]
(3S)-1,3-dimethylpiperazine dihydrochloride [ No CAS ]
[ 1152110-58-1 ]

Yield	Reaction Conditions	Operation in experiment
63%	With triethylamine; In tetrahydrofuran; methanol; at 20℃; for 96h;	Part A: 4-Chloro-6-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine. To 4,6-dichloro-5-fluoro-2-methylpyiotamidine (0.309 g, 1.71 mmol) and triethylamine (0.83 ml_, 5.98 mmol) in THF (6.0 ml.) was added (3S)-1 ,3-dimethylpiperazine dihydrochloride (Example 64) (0.320 g, 1.71 mmol). MeOH (3 ml.) was added to improve solubility and the reaction was stirred for 4 days at room temperature. The solvent was removed in vacuo, and ether, THF and water were added to the resulting residue. The organics were dried (Na2SO4) and concentrated in vacuo to provide 4-chloro-6-[(2S)-2,4-dimethyl- 1-piperazinyl]-5-fluoro-2-methylpyrimidine as an orange solid (0.277 g, 63%). LCMS: (M+H)+ = 259.3.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 145

16
[ 105806-13-1 ]
[ 511268-37-4 ]
[ 1152110-73-0 ]

Yield	Reaction Conditions	Operation in experiment
67%		Part A: (3S)-1-(5-Fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-4,4-dimethyl-3-pyrrolidinol. To a solution of (3S)-4,4-dimethyl-3-pyrrolidinol hydrochloride (Example 115) (0.1370 g, 0.916 mmol) in MeOH (3 mL) was added <strong>[105806-13-1]4,6-dichloro-5-fluoro-2-methylpyrimidine</strong>(0.1646 g, 0.909 mmol) and N,N-diisopropylethylamine (0.350 mL, 2.009 mmol). The solution was heated at 120 0C under microwave irradiation for 30 min, and then concentrated in vacuo. To a solution of the residue in DMSO (3 mL) was added hydrazine hydrate (0.5 mL), and the solution was heated at 50 0C and stirred for 24 h. The solution was then purified directly by Gilson RPLC to provide (3S)-1-(5-fluoro-6- hydrazino-2-methyl-4-pyrimidinyl)-4,4-dimethyl-3-pyrrolidinol (0.1560 g, 67% yield) as a light yellow foam. LCMS: (M+H)+: 256.2.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 155

17
[ 105806-13-1 ]
[ 144163-74-6 ]
N-((2-amino-1,3-thiazol-4-yl)methyl)-6-chloro-5-fluoro-2-methyl-4-pyrimidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With triethylamine; In tetrahydrofuran; at 20℃;	Part B; N-((2-Amino-1,3-thiazol-4-yl)methyl]-6-chloro-5-fluoro-2-methyl-4-pyrimidinamine. 4,6-Dichloro-5-fluoro-2-methylpyrimidine (480 mg, 2.65 mmol) was dissolved in 20 ml. of THF and stirred at room temperature. (4-[(Methylamino)methyl]-1 ,3-thiazol-2-amine (2.65 mmol, theoretical) was added, followed by triethylamine (400 mul_, 2.92 mmol). The resulting reaction mixture was stirred overnight and evaporated. The residue was stirred in water and the solid precipitate was collected by filtration and was dried in vacuo to provide N-[(2-amino-1 ,3-thiazol-4-yl)methyl]-6-chloro-5-fluoro-2-methyl-4-pyrimidinamine (450 mg, 59%) that was used without further purification. LCMS: (M+H)+: 288.1.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 158

18
[ 105806-13-1 ]
[ 1152110-85-4 ]
[ 1152110-86-5 ]

Yield	Reaction Conditions	Operation in experiment
51%		Part E: 5-(5-Fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-5-azaspiro[2.4]heptan-7-ol. 4,6-Dichloro-5-fluoro-2-methylpyrimidine (110 mg, 0.636 mmol) was dissolved in 3 ml. of MeOH then added 5-azaspiro[2.4]heptan-7-ol hydrochloride (685 mg, 0.668 mmol) was added, followed by DIPEA (243 mul_, 1.4 mmol). The resulting reaction mixture was microwaved at 120 0C for 30 min, the voliailes were concentrated in vacuo, and the residue was dissolved in a mixture of DMSO (4 ml.) and MeOH (1 ml_). Then hydrazine monohydrate was added (600 mul_), and the contents were heated to 60 0C overnight. The reaction mixture was then cooled to room temperature and purified by RP-HPLC to provide 5-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-5-azaspiro[2.4]heptan-7-ol (82 mg, 51%). LCMS: (M+H)+: 254.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 167

19
[ 105806-13-1 ]
[ 1152110-94-5 ]
[ 1152110-95-6 ]

Yield	Reaction Conditions	Operation in experiment
36%		Part H:1-(5-Fluoro-6-hydrazino-2 -methyl -4-pyrimidinyl)-N,N,4,4-tetra methyl -3- pyrrolidinamine. To a solution of N,N,4,4-tetramethyl-3-pyrrolidinamine (0.0918 g, 0.645 mmol) in MeOH (3 mL) was added <strong>[105806-13-1]4,6-dichloro-5-fluoro-2-methylpyrimidine</strong> (0.1088 g, 0.601 mmol) and N,N-diisopropylethylamine (0.130 mL, 0.746 mmol). The solution was heated at 120 0C under microwave irradiation and stirred for 30 min. The solution was then cooled to room temperature and concentrated in vacuo. To a solution of the residue in 4:1 DMSO- MeOH (5 mL) was added hydrazine hydrate (0.5 mL). The solution was heated at 65 0C and stirred overnight. The solution was then cooled to room temperature and diluted with DCM (50 mL). The mixture was washed with sat. aq. NaHCOs (20 mL), and the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Gilson RPLC to afford racemic 1-(5-fluoro-6-hydrazino-2- methyl-4-pyrimidinyl)-N,N,4,4-tetramethyl-3-pyrrolidinamine (0.0617 g, 36%) as a light yellow solid. LCMS: (M+H)+: 283.2.

Reference： [1]Patent: WO2009/61879,2009,A1 .Location in patent: Page/Page column 170-171

20
[ 105806-13-1 ]
[ 1253568-87-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5188 - 5219

21
[ 105806-13-1 ]
[ 1253568-88-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5188 - 5219

22
[ 105806-13-1 ]
[ 1383976-50-8 ]