[ CAS No. 63234-80-0 ] {[proInfo.proName]}

Name: 63234-80-0|3-(2-Chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one|97%
Brand: Ambeed
SKU: A123984
Price: 15.0 USD
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Product Details of [ 63234-80-0 ]

CAS No. :	63234-80-0	MDL No. :	MFCD06200813
Formula :	C₁₁H₁₅ClN₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CMWCQQUYLPYOMY-UHFFFAOYSA-N
M.W :	226.70	Pubchem ID :	2763079
Synonyms :

Safety of [ 63234-80-0 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P501-P260-P270-P264-P280-P303+P361+P353-P301+P330+P331-P363-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P405	UN#:	3261
Hazard Statements:	H302-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 63234-80-0 ]

* 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 [ 63234-80-0 ]
Downstream synthetic route of [ 63234-80-0 ]

[ 63234-80-0 ] Synthesis Path-Upstream 1~8

1
[ 63234-80-0 ]
[ 84163-77-9 ]
[ 106266-06-2 ]

Yield	Reaction Conditions	Operation in experiment
92.8%	With sodium carbonate In methanol at 73 - 75℃; for 4 - 4.5 h;	Example 2; Preparation of risperidone of the formula (I) from 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [ 1,2-a]pyrirnidine-4-one and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole bases of the formulae (II) and (III).Starting from 11.45 g of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, 12.45 g of 3-(2-cWoroemyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one and 11.8 g of dry sodium carbonate the same method as described in Example 1 is followed, to give 19.8 g (92.8 percent) of risperidone.Mp: 171-172 °C; purity is at least 99 percent, determined by HPLC
77.8%	With N-ethyl-N,N-diisopropylamine In methanol at 45 - 50℃; for 70 - 100 h;	6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (20.0 grams), 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (22.6 grams) and diisopropyl ethylamine (14.1 grams) were dissolved in methanol (90.0 ml). The resulting reaction mixture was maintained at 45-50° C. for about 70-100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (20.0 ml) followed by water (120.0 ml). The wet product was dried at 70-80° C. to get 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-A]pyrimidin-4-one. (Yield: 29.0 g; 77.8percent; purity by HPLC is 99.93percent)6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10 Kg), 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (11.3 Kg) and diisopropyl ethylamine (7 Kg) were dissolved in methanol (45 Lt). The resulting reaction mixture was maintained at 45-50° C. for about 70 to 100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (10 Lt) followed by water (60 Lt). The wet product was dried at 70-80° C. to get 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-A]pyrimidin-4-one. (Yield: 18 Kg, purity by HPLC is 99.93percent).
73%	With sodium carbonate In water at 85 - 90℃; for 4 h;	[2.27G OF 4- (6-FLUORO-1, 2-BENZISOXAZOL-3-YL) -PIPERIDINE OBTAINED IN STEP A)] and 2.26g of 3- (2-chloroethyl)-6, 7,8, 9-tetrahydro-2-methyl-4H-pyrido [1, 2- [A] PYRIMIDIN-4-ONE] obtained in Preparation Example 2 were added to a solution of 2.25g of [NA2C03] in [12ML] of water. The resulting mixture was stirred at 85 to [90 °C] for 4 hours, cooled to room temperature, and filtered. The resulting solid was added to [16ML] of N, N- dimethylformamide. The resulting suspension was heated to [80 °C,] left at that temperature for 5 minutes, and then slowly cooled to room temperature. The crystal was filtered, washed with [5ML] of water and dried to obtain 3.02g of the title compound as a white crystal (yield: 73percent). The melting point [ANDAPOS;H-NMR] data were the same as in Example 1.

Reference： [1] Patent: WO2006/5974, 2006, A1, . Location in patent: Page/Page column 7
[2] Patent: US2006/4199, 2006, A1, . Location in patent: Page/Page column 2
[3] Patent: WO2004/35573, 2004, A1, . Location in patent: Page 11
[4] Patent: US2002/115672, 2002, A1,

2
[ 63234-80-0 ]
[ 106266-06-2 ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium hydroxide In water at 120 - 130℃; for 1.5 h;	2.77g of 2,4-difluorophenyl (4-piperidinyl) methanone oxime hydrochloride obtained in Preparation Example 1 and 2.26g of 3- (2-chloroethyl)- 6,7, 8,9-tetrahydro-2-methyl-4H-pyrido [1, 2-a] pyrimidin-4-one obtained in Preparation Example 2 were added to [27ML] of 30percent aqueous potassium hydroxide, and then the resulting mixture was stirred at 120 to 130°C for 90 minutes. The reaction mixture was cooled to room temperature, filtered, and the obtained solid was added to [16ML] of N, N-dimethylformamide. The resulting suspension was heated to [80 °C,] left at that temperature for 5 minutes, and then slowly cooled to room temperature. The resulting crystal was filtered, washed with 5ml of water and dried to obtain 3.39g of the title compound as a white crystal (yield: 82percent). Melting point: 167-169°C ; Purity: 99.7percent (by HPLC); [H-NMR] [(300MHZ,] [CDC13)] : [6] 7.65-7. 61 (m, 1H), 7.18-7. 14 (m, 1H), 7.00-6. 94 (m, 1H), 3.87-3. 83 (m, 2H), 3.12-3. 07 (m, 2H), 2.97-3. 02 (m, 1H), 2.81-2. 76 (m, 2H), 2.71-2. 66 (m, 2H), 2.48-2. 43 (m, 2H), 2.23 (s, 3H), 2.34-2. 19 (m, 2H), 2.05-2. 01 (m, 4H), 1.87-1. 79 (m, 4H).

Reference： [1] Patent: WO2004/35573, 2004, A1, . Location in patent: Page 9-11

3
[ 63234-80-0 ]
[ 84163-13-3 ]
[ 106266-06-2 ]

Yield	Reaction Conditions	Operation in experiment
93.2%	With sodium carbonate In water at 110 - 120℃; for 0.666667 h;	Example 9; Preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (risperidone)In a 50-ml reaction flask, 2.56 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride and 2.95 g of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one are placed, then a sodium carbonate solution or suspension (dissolved or suspended 8.5 g of sodium carbonate in 25 ml water) is added. The mixture is put into heating bath at 110-120° C. with stirring for 40 min, then cooled with continuous stirring to the room temperature and the precipitate solid is filtered, washed with pure water, and dried to give 3.82 g of the product in 93.2percent yield. The product is purified to obtain a purity of 99.5percent (determined by HPLC) with DMF and isopropanol.

Reference： [1] Patent: US2010/130740, 2010, A1, . Location in patent: Page/Page column 4

4
[ 63234-80-0 ]
[ 106266-06-2 ]

Reference： [1] Patent: WO2007/93870, 2007, A2, . Location in patent: Page/Page column 7-9

5
[ 41078-70-0 ]
[ 63234-80-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; hydrogen In water at 20℃; for 8 h;	28g of [3- (2-CHLOROETHYL)-2-METHYL-4H-PYRIDO [1,] 2-a] pyrimidin-4-one obtained in step A) was dissolved in [90ML] of 6N hydrochloric acid, 2.8g of 10percent- palladium was added thereto, and then the mixture was hydrogenated under a hydrogen pressure of 35psi at room temperature for 8 hours. The reaction mixture was filtered through Cellite and the filtrate was concentrated under a reduced pressure, [200ML] of isopropanol was added to the residue, and then the mixture was stirred. The solid was filtered and dried to obtain 25. 1g of the title compound as a white crystal (yield: 90percent).

Reference： [1] Patent: WO2004/35573, 2004, A1, . Location in patent: Page 9
[2] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276
[3] Letters in Drug Design and Discovery, 2011, vol. 8, # 10, p. 988 - 995
[4] Medicinal Chemistry, 2013, vol. 9, # 2, p. 240 - 248

6
[ 504-29-0 ]
[ 63234-80-0 ]

Reference： [1] Letters in Drug Design and Discovery, 2011, vol. 8, # 10, p. 988 - 995
[2] Medicinal Chemistry, 2013, vol. 9, # 2, p. 240 - 248
[3] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276

7
[ 517-23-7 ]
[ 63234-80-0 ]

8
[ 380634-63-9 ]
[ 63234-80-0 ]

Reference： [1] Letters in Drug Design and Discovery, 2011, vol. 8, # 10, p. 988 - 995
[2] Medicinal Chemistry, 2013, vol. 9, # 2, p. 240 - 248

[ 63234-80-0 ] Synthesis Path-Downstream 1~71

1
[ 63234-80-0 ]
[ 84163-77-9 ]
[ 106266-06-2 ]

Yield	Reaction Conditions	Operation in experiment
92.8%	With sodium carbonate; In methanol; at 73 - 75℃; for 4 - 4.5h;Product distribution / selectivity;	Example 2; Preparation of risperidone of the formula (I) from 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [ 1,2-a]pyrirnidine-4-one and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole bases of the formulae (II) and (III).Starting from 11.45 g of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, 12.45 g of 3-(2-cWoroemyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one and 11.8 g of dry sodium carbonate the same method as described in Example 1 is followed, to give 19.8 g (92.8 percent) of risperidone.Mp: 171-172 °C; purity is at least 99 percent, determined by HPLC
77.8%	With N-ethyl-N,N-diisopropylamine; In methanol; at 45 - 50℃; for 70 - 100h;Product distribution / selectivity;	6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (20.0 grams), <strong>[63234-80-0]3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one</strong> (22.6 grams) and diisopropyl ethylamine (14.1 grams) were dissolved in methanol (90.0 ml). The resulting reaction mixture was maintained at 45-50° C. for about 70-100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (20.0 ml) followed by water (120.0 ml). The wet product was dried at 70-80° C. to get 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-A]pyrimidin-4-one. (Yield: 29.0 g; 77.8percent; purity by HPLC is 99.93percent)6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (10 Kg), <strong>[63234-80-0]3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one</strong> (11.3 Kg) and diisopropyl ethylamine (7 Kg) were dissolved in methanol (45 Lt). The resulting reaction mixture was maintained at 45-50° C. for about 70 to 100 hours. The reaction mass was then cooled to 25-35° C. and then separate solid product. The solid mass was filtered and washed with methanol (10 Lt) followed by water (60 Lt). The wet product was dried at 70-80° C. to get 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-A]pyrimidin-4-one. (Yield: 18 Kg, purity by HPLC is 99.93percent).
73%	With sodium carbonate; In water; at 85 - 90℃; for 4h;	[2.27G OF 4- (6-FLUORO-1, 2-BENZISOXAZOL-3-YL) -PIPERIDINE OBTAINED IN STEP A)] and 2.26g of 3- (2-chloroethyl)-6, 7,8, 9-tetrahydro-2-methyl-4H-pyrido [1, 2- [A] PYRIMIDIN-4-ONE] obtained in Preparation Example 2 were added to a solution of 2.25g of [NA2C03] in [12ML] of water. The resulting mixture was stirred at 85 to [90 °C] for 4 hours, cooled to room temperature, and filtered. The resulting solid was added to [16ML] of N, N- dimethylformamide. The resulting suspension was heated to [80 °C,] left at that temperature for 5 minutes, and then slowly cooled to room temperature. The crystal was filtered, washed with [5ML] of water and dried to obtain 3.02g of the title compound as a white crystal (yield: 73percent). The melting point [ANDAPOS;H-NMR] data were the same as in Example 1.

With potassium iodide; sodium carbonate; In water; isopropyl alcohol;

Example 1 Synthesis of Risperidone Isopropanol (20 mL), 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one (Compound II)("the chlorine derivative")(2.63 g, 10 mmoles, 1 eq.), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I)("the piperidine derivative") (2.17 g, 10 mmoles, 1 eq.), sodium carbonate (3.18 g, 30 mmoles, 3 eq.), and potassium iodide (66 mg) were added to a 100 mL round bottom flask and stirred with a magnetic stir bar. The flask was placed in an oil bath at 80° C. and allowed to reflux for 9 hours. The flask was then cooled in an ice bath and the contents was filtered. The filter cake was washed in the filter with a small amount of isopropanol. The filter cake was then slurried 3 times in 20 mL of water and filtered. The resulting slurry was dried to give 3 g of material in 73percent yield. The slurry was recrystallized by dissolving in 37 mL of boiling isopropanol, filtered hot and allowed to cool and filtered to give material which had a purity of 99.7percent and an overall yield of 60percent.

Reference： [1]Patent: WO2006/5974,2006,A1 .Location in patent: Page/Page column 7
[2]Patent: US2006/4199,2006,A1 .Location in patent: Page/Page column 2
[3]Patent: WO2004/35573,2004,A1 .Location in patent: Page 11
[4]Patent: US2002/115672,2002,A1

2
[ 63234-80-0 ]
2,4-difluorophenyl-(4-piperidinyl)methanone oxime hydrochloride [ No CAS ]
[ 106266-06-2 ]

Yield	Reaction Conditions	Operation in experiment
40 - 91%	With potassium hydroxide; In water; at 120 - 130℃; for 1.5h;	2.77g of 2,4-difluorophenyl (4-piperidinyl) methanone oxime hydrochloride obtained in Preparation Example 1 and 2.26g of 3- (2-chloroethyl)- 6,7, 8,9-tetrahydro-2-methyl-4H-pyrido [1, 2-a] pyrimidin-4-one obtained in Preparation Example 2 were added to [27ML] of 30percent aqueous potassium hydroxide, and then the resulting mixture was stirred at 120 to 130°C for 90 minutes. The reaction mixture was cooled to room temperature, filtered, and the obtained solid was added to [16ML] of N, N-dimethylformamide. The resulting suspension was heated to [80 °C,] left at that temperature for 5 minutes, and then slowly cooled to room temperature. The resulting crystal was filtered, washed with 5ml of water and dried to obtain 3.39g of the title compound as a white crystal (yield: 82percent). Melting point: 167-169°C ; Purity: 99.7percent (by HPLC); [H-NMR] [(300MHZ,] [CDC13)] : [6] 7.65-7. 61 (m, 1H), 7.18-7. 14 (m, 1H), 7.00-6. 94 (m, 1H), 3.87-3. 83 (m, 2H), 3.12-3. 07 (m, 2H), 2.97-3. 02 (m, 1H), 2.81-2. 76 (m, 2H), 2.71-2. 66 (m, 2H), 2.48-2. 43 (m, 2H), 2.23 (s, 3H), 2.34-2. 19 (m, 2H), 2.05-2. 01 (m, 4H), 1.87-1. 79 (m, 4H).

Reference： [1]Patent: WO2004/35573,2004,A1 .Location in patent: Page 9-11

3
[ 41078-70-0 ]
[ 63234-80-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; hydrogen;palladium; In water; at 20℃; under 1810.07 Torr; for 8h;	28g of [3- (2-CHLOROETHYL)-2-METHYL-4H-PYRIDO [1,] 2-a] pyrimidin-4-one obtained in step A) was dissolved in [90ML] of 6N hydrochloric acid, 2.8g of 10%- palladium was added thereto, and then the mixture was hydrogenated under a hydrogen pressure of 35psi at room temperature for 8 hours. The reaction mixture was filtered through Cellite and the filtrate was concentrated under a reduced pressure, [200ML] of isopropanol was added to the residue, and then the mixture was stirred. The solid was filtered and dried to obtain 25. 1g of the title compound as a white crystal (yield: 90%).
90%	With hydrogenchloride; palladium on activated charcoal; hydrogen; In water; at 30 - 40℃; under 1500.15 Torr;	Adding 500 mL of drinking water and 100 g of hydrochloric acid to the obtained intermediate (III),Add 10g 7percent wet palladium carbon(50wtpercent), temperature control 30-40 ° C,Hydrogenation at a pressure of 0.20 ± 0.05 MPa.End of hydrogenation,Filtering palladium on carbon,The resulting hydrogenated solution was adjusted to pH = 8-9 with a saturated sodium carbonate solution.It was further extracted by adding 500 mL of ethyl acetate.The resulting ethyl acetate solution was evaporated to drynessObtained 78g of chlorinated compound (II) with a yield of 90percent.Purity ?99percent.
	With palladium 10% on activated carbon; hydrogen; In methanol;	Compound 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (4) (5 g, 22.45 mmol) was taken in methanol, added 0.5 g of 10 % Pd/C and maintained 3-4 kg pressure of H2 for 48 hr. The reaction was monitored by TLC. After completion, the reaction mixture was filtered through ceilite bed and filtrate was concentrated under reduced pressure. The residue was dissolved in water to get a white precipitate, which was filtered, washed with water anddried to get creamy white solid.

Reference： [1]Patent: WO2004/35573,2004,A1 .Location in patent: Page 9
[2]Patent: CN109705119,2019,A .Location in patent: Paragraph 0033; 0035; 0036; 0038; 0039; 0041; 0046; 0048
[3]Journal of the American Chemical Society,2017,vol. 139,p. 8267 - 8276
[4]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995
[5]Medicinal Chemistry,2013,vol. 9,p. 240 - 248

4
[ 63234-80-0 ]
[ 104-15-4 ]
(E)-3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-(phenylmethylene)-4H-pyrido[1,2-a]pyrimidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzaldehyde; In 5,5-dimethyl-1,3-cyclohexadiene;	a) To a solution of 5.67 parts of <strong>[63234-80-0]3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one</strong> in 43 parts of xylene there were added 2.65 parts of benzaldehyde and 0.7 parts of 4-methylbenzenesulfonic acid. The whole was refluxed for 8 hours using a water separator. After cooling, the precipitate was filtered off and crystallized from 2-propanol, yielding 2.4 parts (30.5percent) of product. The mother liquor was evaporated and the residue was purified by column chromatography (silica gel; CHCl3 /CH3 OH 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from 2-propanol, yielding an additional 2 parts (25.4percent) of product. Total yield: 4.4 parts (55.9percent) of (E)-3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-(phenylmethylene)-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 130.8° C. (interm. 7).

Reference： [1]Patent: US5482943,1996,A

5
3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride [ No CAS ]
[ 63234-80-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;potassium iodide; In water; 4-methyl-2-pentanone;Product distribution / selectivity;	Example 1: Preparation of Risperidone; Water (300 mL), methyl isobutyl ketone (400 mL) and 6-fluoro-3-(4- piperidinyl)-l, 2-benzisoxazole monohydrochloride (97.5 g) were taken in a reaction vessel and NaOH solution (30.40 g in 300 mL water) was slowly added, stirred the reaction mass for 5 to 10 min. the organic layer separated and washed with water (150 mL). Water (300 mL), methyl isobutyl ketone (200 mL) were taken in another reaction vessel and 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride (100 g) and KI (5.0 g) were added to the reaction vessel. Sodium carbonate (100.70 g) was slowly added to the reaction mass and then methyl isobutyl ketone layer of 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole base was added to the reaction mass and then the contents were heated up to 85 to 900C and maintained up to 8 hrs. Cooled the reaction mass to room temperature and stirred at room temperature for 4 hrs. Water (300 mL) was added and stirred for 10 min., filtered <n="9"/>the solid and washed with water (200 mL) followed by methyl isobutyl ketone (200 mL) to get the Crude Risperidone, which was taken in another reaction vessel and isopropyl alcohol (1800 mL) was added and the solution was heated to 70 to 8O0C to get a clear solution. Carbon (10 g) was added to the solution and stirred for 20 to30 min., filtered the carbon through highflo. washed the bed with isopropyl alcohol (300 mL) and distilled the filtrate up to residual volume 7 times the 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyriniidin-4-one monohydrochloride quantity. Heated the suspension to 70 to 8O0C to get the clear solution and dimethylformamide (70 mL) was added. Cooled the reaction mass to room temperature' and stirred at room temperature for 3 to 6 hrs., filtered the solid, washed with isopropyl alcohol (100 mL) and dried the solid at 60 to70°C for 2 hrs. Micronized the material and dried at 80 to 850C for 12 hrs to get Risperidone. (80 g) having HPLC Purity more than 99.70 percent.; Example 3: Preparation of Risperidone Water (300 mL), methyl isobutyf ketone (400 mL) and 6-fluoro-3-(4- piperidinyl)-l, 2-benzisoxazole monohydrochloride (97.5 g) were taken in a reaction vessel and NaOH solution (30.40 g in 300 mL water) was slowly added, stirred the reaction mass for 5 to 10 min., the organic layer was separated and washed with water (150 mL). Water (300 mL), methyl isobutyl ketone (200 mL) were taken in another reaction vessel and 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride (100 g), potassium iodide (5.0 g) were added to the reaction vessel. Sodium carbonate (100.70 g) slowly added in to the reaction mass and then methyl isobutyl ketone layer of 6-fluoro-3-(4-pirhoeridinyl)-l, 2-benzisoxazole <n="10"/>base was added to the reaction mass and then heated the contents up to 85 to 900C and maintained up to 8 hrs. Cooled the reaction mass to room temperature and stirred at room temperature for 4 hrs. Water (300 mL) was added and stirred for 10 min. filtered the solid and washed with water (200 mL) followed by methyl isobutyl ketone (200 mL) to get the solid which is dried at 60 to70°C under vacuum for 2 hrs to get crude Risperidone 80g.

Reference： [1]Patent: WO2007/93870,2007,A2 .Location in patent: Page/Page column 7-9

6
[ 63234-80-0 ]
3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride [ No CAS ]
[ 106266-06-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;potassium iodide; In water; 4-methyl-2-pentanone; at 20 - 90℃; for 12h;Product distribution / selectivity;	Example 1: Preparation of Risperidone; Water (300 mL), methyl isobutyl ketone (400 mL) and 6-fluoro-3-(4- piperidinyl)-l, 2-benzisoxazole monohydrochloride (97.5 g) were taken in a reaction vessel and NaOH solution (30.40 g in 300 mL water) was slowly added, stirred the reaction mass for 5 to 10 min. the organic layer separated and washed with water (150 mL). Water (300 mL), methyl isobutyl ketone (200 mL) were taken in another reaction vessel and 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride (100 g) and KI (5.0 g) were added to the reaction vessel. Sodium carbonate (100.70 g) was slowly added to the reaction mass and then methyl isobutyl ketone layer of 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole base was added to the reaction mass and then the contents were heated up to 85 to 900C and maintained up to 8 hrs. Cooled the reaction mass to room temperature and stirred at room temperature for 4 hrs. Water (300 mL) was added and stirred for 10 min., filtered <n="9"/>the solid and washed with water (200 mL) followed by methyl isobutyl ketone (200 mL) to get the Crude Risperidone, which was taken in another reaction vessel and isopropyl alcohol (1800 mL) was added and the solution was heated to 70 to 8O0C to get a clear solution. Carbon (10 g) was added to the solution and stirred for 20 to30 min., filtered the carbon through highflo. washed the bed with isopropyl alcohol (300 mL) and distilled the filtrate up to residual volume 7 times the 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyriniidin-4-one monohydrochloride quantity. Heated the suspension to 70 to 8O0C to get the clear solution and dimethylformamide (70 mL) was added. Cooled the reaction mass to room temperature' and stirred at room temperature for 3 to 6 hrs., filtered the solid, washed with isopropyl alcohol (100 mL) and dried the solid at 60 to70°C for 2 hrs. Micronized the material and dried at 80 to 850C for 12 hrs to get Risperidone. (80 g) having HPLC Purity more than 99.70 percent.; Example 3: Preparation of Risperidone Water (300 mL), methyl isobutyf ketone (400 mL) and 6-fluoro-3-(4- piperidinyl)-l, 2-benzisoxazole monohydrochloride (97.5 g) were taken in a reaction vessel and NaOH solution (30.40 g in 300 mL water) was slowly added, stirred the reaction mass for 5 to 10 min., the organic layer was separated and washed with water (150 mL). Water (300 mL), methyl isobutyl ketone (200 mL) were taken in another reaction vessel and 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one monohydrochloride (100 g), potassium iodide (5.0 g) were added to the reaction vessel. Sodium carbonate (100.70 g) slowly added in to the reaction mass and then methyl isobutyl ketone layer of 6-fluoro-3-(4-pirhoeridinyl)-l, 2-benzisoxazole <n="10"/>base was added to the reaction mass and then heated the contents up to 85 to 900C and maintained up to 8 hrs. Cooled the reaction mass to room temperature and stirred at room temperature for 4 hrs. Water (300 mL) was added and stirred for 10 min. filtered the solid and washed with water (200 mL) followed by methyl isobutyl ketone (200 mL) to get the solid which is dried at 60 to70°C under vacuum for 2 hrs to get crude Risperidone 80g.

Reference： [1]Patent: WO2007/93870,2007,A2 .Location in patent: Page/Page column 7-9

7
[ 63234-80-0 ]
[ 1204248-71-4 ]

Yield	Reaction Conditions	Operation in experiment
86.0%	With isopentyl nitrite; In butan-1-ol; at 85 - 90℃; for 1.5h;	Examples; Example ;1Compound (6a); 20.0 g of <strong>[63234-80-0]3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one</strong> was suspended in 20.0 ml of n-butanol and the suspension was heated to 85-90° C. Then 30.0 ml of isoamyl nitrite was dropped during 1.5 h. Reaction mixture was diluted with 50 ml of ethyl acetate and the suspension was cooled to 20° C. Product was filtered off after 1 h of stirring and washed with 2*15 ml of ethyl acetate. Yield: 19.39 g (86.0percent of the theoretical yield), 98percent purity (HPLC).

Reference： [1]Patent: US2010/10218,2010,A1 .Location in patent: Page/Page column 10-11

8
[ 63234-80-0 ]
[ 68-12-2 ]
[ 1160611-32-4 ]

Yield	Reaction Conditions	Operation in experiment
75%		Example 1Compound (6a)Into 390 ml of N,N-dimethylformamide, 50 ml of POCl3 was added dropwise in 25 minutes, wherein the internal temperature was maintained at a temperature between -2 and 0° C. The mixture was stirred at a temperature between -1 and 0° C. for 80 min. Then a solution of 111.8 g of Compound (5a) in 150 ml of N,N-dimethylformamide was added dropwise at a temperature between -1 and +1° C. in 35 min. Then the reaction mixture was stirred at temperature 0° C. for 30 min and the temperature was gradually increased to 25° C. in 40 min. The reaction mixture was then warmed to 80° C. The reaction progress was monitored by HPLC.After 90 min, the reaction mixture was cooled down to 20° C. and poured onto 800 g of crushed ice. The mixture was stirred and neutralized with Na2CO3 (70 g) to pH 7-7.5. During the neutralization, a precipitate was formed.The heterogenic mixture was stirred with 500 ml of dichloromethane. The layers were separated and aqueous layer washed with 5.x.200 ml of ethyl acetate. The combined organic layers were washed with 7.x.200 ml of water, dried by anhydrous sodium sulphate and filtered with charcoal over celite.The solvent was evaporated (50° C.), yielding 115.5 g (91.8percent) of a solid. HPLC purity: 97.52percent (IN)Purification:115.5 g of raw compound (6a) from the preceded step was dissolved in 300 ml of dichloromethane. The solution was filtered over 50 g of silica gel layer (10 cm). The silica gel was washed with 200 ml of dichloromethane. The combined filtrate was mixed with 150 ml of ethyl acetate at 50° C. The dichloromethane was evaporated and ethyl acetate solution cooled down to temperature 5° C. The formations of fine crystals were observed. The heterogenic mixture was stirred for 1 h at 5° C. and the solid filtered by suction. The filtration cake was washed with 2.x.50 ml of cold ethyl acetate (0° C.) and dried at room temperature.Yield: 87 g (75percent) of off white fine crystalline material. HPLC: 99.86percent (IN)

Reference： [1]Patent: US2009/156810,2009,A1 .Location in patent: Page/Page column 10

9
[ 63234-80-0 ]
[ 84163-13-3 ]
[ 106266-06-2 ]

Yield	Reaction Conditions	Operation in experiment
93.2%	With sodium carbonate; In water; at 110 - 120℃; for 0.666667h;Product distribution / selectivity;	Example 9; Preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (risperidone)In a 50-ml reaction flask, 2.56 g of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride and 2.95 g of <strong>[63234-80-0]3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one</strong> are placed, then a sodium carbonate solution or suspension (dissolved or suspended 8.5 g of sodium carbonate in 25 ml water) is added. The mixture is put into heating bath at 110-120° C. with stirring for 40 min, then cooled with continuous stirring to the room temperature and the precipitate solid is filtered, washed with pure water, and dried to give 3.82 g of the product in 93.2percent yield. The product is purified to obtain a purity of 99.5percent (determined by HPLC) with DMF and isopropanol.
76.9%	With sodium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 10h;	In a 1000 mL sealed four-mouth reaction bottle,Add 6-fluoro-3-(4-piperidinyl)-1,2-benzisazole hydrochloride (IV 51.3 g,<strong>[63234-80-0]3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one</strong> (V) 45.3 g,Potassium iodide 6.6 g,Anhydrous sodium carbonate 42.4 g andN,N-dimethylformamide 250mL,Stir and heat to 80 ° C for 10 h.The reaction solution is cooled to 5 to 10 ° C,Add 250 grams of ice water mixture,A large amount of white solid precipitated,Stop stirring,Filtration of a pale yellow solid risperidone (I) 63.1 g,The yield was 76.9percent.

Reference： [1]Patent: US2010/130740,2010,A1 .Location in patent: Page/Page column 4
[2]Patent: CN109438443,2019,A .Location in patent: Paragraph 0038-0043

10
(4-bromo-1-methyl-1H-pyrazol-3-yl)piperazin-1-ylmethanone hydrochloride [ No CAS ]
[ 63234-80-0 ]
[ 1235992-87-6 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 5696 - 5706

11
[ 110-85-0 ]
[ 63234-80-0 ]
[ 63234-88-8 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

12
[ 504-29-0 ]
[ 63234-80-0 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995
[2]Medicinal Chemistry,2013,vol. 9,p. 240 - 248
[3]Journal of the American Chemical Society,2017,vol. 139,p. 8267 - 8276

13
[ 517-23-7 ]
[ 63234-80-0 ]

14
[ 63234-80-0 ]
[ 1345732-45-7 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

15
[ 63234-80-0 ]
[ 1345732-46-8 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

16
[ 63234-80-0 ]
[ 1345732-47-9 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

17
[ 63234-80-0 ]
[ 1345732-48-0 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

18
[ 63234-80-0 ]
[ 1345732-49-1 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

19
[ 63234-80-0 ]
[ 1345732-50-4 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

20
[ 63234-80-0 ]
[ 1345732-51-5 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

21
[ 63234-80-0 ]
[ 1345732-52-6 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

22
[ 63234-80-0 ]
[ 1345732-53-7 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

23
[ 63234-80-0 ]
[ 1345732-54-8 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

24
[ 63234-80-0 ]
[ 1345732-42-4 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

25
[ 63234-80-0 ]
[ 1345732-43-5 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

26
[ 63234-80-0 ]
[ 1345732-44-6 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995

27
[ 380634-63-9 ]
[ 63234-80-0 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 988 - 995
[2]Medicinal Chemistry,2013,vol. 9,p. 240 - 248

28
[ 63234-80-0 ]
[ 1569268-46-7 ]

Reference： [1]Patent: US2014/57301,2014,A1
[2]Patent: WO2014/31601,2014,A1
[3]Patent: US9751953,2017,B2

29
[ 63234-80-0 ]
[ 1569268-47-8 ]

Reference： [1]Patent: US2014/57301,2014,A1
[2]Patent: US9751953,2017,B2

30
[ 63234-80-0 ]
[ 1569268-45-6 ]
[ 106266-11-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In water; N,N-dimethyl-formamide;	Step A 3-(2-(4-(6-hydroxybenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one A solution of <strong>[63234-80-0]3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one</strong> (14.4 g, 0.05 mmol), 3-(piperidin-4-yl)benzo[d]isoxazol-6-ol (14.0 g, 0.05 mmol), sodium carbonate (16.0 g, 0.15 mmol) and potassium iodide (spatula point) in DMF (150 mL) was stirred for 5 h at 80° C. The mixture was allowed to cool down to room temperature and water was added. The precipitate was removed by filtration, and the filtrate was extracted with chloroform (3*100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was crystallized with isopropyl alcohol (70 mL), filtered, and washed with isopropanol/diisopropyl ether 50/50 mixture (10 mL). The residue was dried overnight at 100° C. yielding the title compound and was used without further purification in the next step.
	With sodium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 5h;	A solution of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[ 1 ,2-ajpyrimidin- 4-one (14.4 g, 0.05 mmol), 3-(piperidin-4-yl)benzo[d]isoxazol-6-ol (14.0 g, 0.05 mmol), sodium carbonate (16.0 g, 0.15 mmol) and potassium iodide (spatula point) in DMF (150 mL) was stirred for 5h at 80 °C. The mixture was allowed to cool down to room temperature and water was added. The precipitate was removed by filtration, and the filtrate was extracted with chloroform (3 x 100 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was crystallized with isopropyl alcohol (70 mL), filtered, and washed with isopropanol/diisopropyl ether 50/50mixture (10 mL). The residue was dried overnight at 100 °C yielding the title compound and was used without further purification in the next step.
	With sodium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 5h;	Step A 3-(2-(4-(6-hydroxybenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one A solution of <strong>[63234-80-0]3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one</strong> (14.4 g, 0.05 mmol), 3-(piperidin-4-yl)benzo[d]isoxazol-6-ol (14.0 g, 0.05 mmol), sodium carbonate (16.0 g, 0.15 mmol) and potassium iodide (spatula point) in DMF (150 mL) was stirred for 5 h at 80° C. The mixture was allowed to cool down to room temperature and water was added. The precipitate was removed by filtration, and the filtrate was extracted with chloroform (3*100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was crystallized with isopropyl alcohol (70 mL), filtered, and washed with isopropanol/diisopropyl ether 50/50 mixture (10 mL). The residue was dried overnight at 100° C. yielding the title compound and was used without further purification in the next step.

Reference： [1]Patent: US2014/57301,2014,A1 .Location in patent: Page/Page column
[2]Patent: WO2014/31601,2014,A1 .Location in patent: Page/Page column 51; 52
[3]Patent: US9751953,2017,B2 .Location in patent: Page/Page column 48; 49

31
[ 63234-80-0 ]
2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(2-((3-(1-(2-(2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-yl)ethyl)piperidin-4-yl)benzo[d]isoxazol-6-yl)oxy)ethyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2014/31601,2014,A1

32
[ 96-50-4 ]
[ 63234-80-0 ]
2-methyl-3-(2-(thiazol-2-ylamino)ethyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one [ No CAS ]