Name: 106261-49-8|4-[(4-Methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride|98%
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1
[ 125743-63-7 ]
4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydrogenchloride; water at 100℃; for 10h;
86.2%	With hydrogenchloride; water at 106 - 110℃; for 6h;	1-5 Example 2 A one-pot method for preparing imatin acid includes the following steps:Into a 500L reactor, add 100kgN,N-dimethylformamide, 72kg N-methylpiperazine and 96kg anhydrous potassium carbonate in sequence, turn on the stirring, turn on the jacket circulating water, add 75kg of para-cyanobenzyl chloride 90kg N,N-dimethylformamide, the dropping temperature is controlled at 30-40°C, after the dropwise addition is completed, the temperature is raised to 80°C, the reaction is held for 15h, then suction filtration, the filtrate is distilled under reduced pressure to remove the organic solvent to obtain the intermediate body,The temperature of vacuum distillation is ≤95°C; then the temperature is reduced to 50°C, 50kg water and 300kg 30% hydrochloric acid aqueous solution are added in sequence, the temperature is raised to 106-110°C and refluxed for 6h, the temperature is reduced to 10°C, the crystallization is stirred for 2h, Filter cake by suction filtration, centrifugal spin to dry,After drying, the imanic acid is obtained. The yield of imaic acid is 86.2%, and the purity is 99.0%.
78%	Stage #1: 4-[(4-methyl-1-piperazinyl)methyl]benzonitrile With sodium hydroxide In methanol at 60 - 70℃; for 3h; Stage #2: With hydrogenchloride In water at 0 - 5℃; for 0.5h;

75%	With hydrogenchloride; water In water at 90 - 95℃; for 5h; Large scale;
75%	With hydrogenchloride; water at 90 - 95℃; for 5h;	1.B Step-B: Preparation of 4-(4-Methylpiperazinomethyl) benzoic acid dihydrochloride 4-(4-Methyl piperazinomethyl)benzonitrile (1 17g, 0.542moles) and concentrated hydrochloric acid(35%, 819 ml) were placed in reaction flask and heated to 90-95°C for five hours. After completion of reaction, the reaction mass was brought to 40-45°C and filtered at the same temperature. Filter cake was washed with Isopropanol(200ml) and dried to yield 4-(4-Methylpiperazinomethyl) benzoic acid dihydrochloride. (126g, 75% percentage yield, 99.9% HPLC purity).

Reference： [1]Location in patent: experimental part Liu, Haiyan; Xia, Wenpin; Luo, Yu; Lu, Wei [Monatshefte fur Chemie, 2010, vol. 141, # 8, p. 907 - 911]
[2]Current Patent Assignee: HEFEI LEAF BIO TECH - CN110981833, 2020, A Location in patent: Paragraph 0024-0033
[3]Sairam; Puranik, Ramachandra; Kelkar, Avijit S.; Sasikiran; Veerender; Parvathi [Synthetic Communications, 2003, vol. 33, # 20, p. 3597 - 3605]
[4]Kompella, Amala; Adibhatla, Bhujanga Rao Kalisatya; Muddasani, Pulla Reddy; Rachakonda, Sreenivas; Gampa, Venugopala Krishna; Dubey, Pramod Kumar [Organic Process Research and Development, 2012, vol. 16, # 11, p. 1794 - 1804]
[5]Current Patent Assignee: NATCO PHARMA LIMITED - WO2013/35102, 2013, A1 Location in patent: Page/Page column 20

2
[ 109-01-3 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 81 percent / CHCl₃ / 3 h / 20 °C 2.1: NaOH / methanol / 3 h / 60 - 70 °C 2.2: 78 percent / conc. HCl / H₂O / 0.5 h / 0 - 5 °C / pH 1.0
	Multi-step reaction with 2 steps 1: potassium carbonate / ethanol / 5 h / 78 °C 2: hydrogenchloride; water / 10 h / 100 °C

Reference： [1]Sairam; Puranik, Ramachandra; Kelkar, Avijit S.; Sasikiran; Veerender; Parvathi [Synthetic Communications, 2003, vol. 33, # 20, p. 3597 - 3605]
[2]Liu, Haiyan; Xia, Wenpin; Luo, Yu; Lu, Wei [Monatshefte fur Chemie, 2010, vol. 141, # 8, p. 907 - 911]

3
[ 17201-43-3 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 81 percent / CHCl₃ / 3 h / 20 °C 2.1: NaOH / methanol / 3 h / 60 - 70 °C 2.2: 78 percent / conc. HCl / H₂O / 0.5 h / 0 - 5 °C / pH 1.0
	Multi-step reaction with 2 steps 1: chloroform / 3 h / 20 - 25 °C / Large scale 2: hydrogenchloride; water / water / 5 h / 90 - 95 °C / Large scale

Reference： [1]Sairam; Puranik, Ramachandra; Kelkar, Avijit S.; Sasikiran; Veerender; Parvathi [Synthetic Communications, 2003, vol. 33, # 20, p. 3597 - 3605]
[2]Kompella, Amala; Adibhatla, Bhujanga Rao Kalisatya; Muddasani, Pulla Reddy; Rachakonda, Sreenivas; Gampa, Venugopala Krishna; Dubey, Pramod Kumar [Organic Process Research and Development, 2012, vol. 16, # 11, p. 1794 - 1804]

4
[ 864438-35-7 ]
[ 106261-49-8 ]
[ 864438-36-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 40 - 50℃; for 26h;	21 To a solution of the compound prepared in Example 20 (50 mg) and 4-[(4-methyl-1-piperazinyl)methyl]benzoic acid dihydrochloride (135 mg) in dimethylformamide (1.8 mL) were added triethylamine (184 μL), 1-hydroxy-7-azabenzotriazole (HOAt, 60 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (84 mg), then the mixture was stirred for 19 hours at 40°C, 7 hours at 50°C. The reaction mixture was cooled to room temperature, then added by water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate → ethyl acetate: methanol = 10: 1 → dichloromethane: methanol = 10: 1), then by preparative thin-layer chromatography (dichloromethane: methanol = 9: 1) to give the title compound (7 mg) having the following physical data. TLC: Rf 0.37 (dichloromethane: methanol =10:1); 1H NMR (CDCl3): δ 1.05 (s, 9 H), 2.30 (s, 3 H), 2.34 - 2.73 (m, 8 H), 3.46 (s, 2 H), 3.54 (s, 2 H), 7.3 7 (d, J = 8.42 Hz, 2 H), 7.51 (s, 1 H), 7.67 (d, J = 8.42 Hz, 2 H).

Reference： [1]Current Patent Assignee: ONO PHARMACEUTICAL CO LTD - EP1724264, 2006, A1 Location in patent: Page/Page column 53

5
[ 109-01-3 ]
[ 1642-81-5 ]
4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74.4%		500 g of 4-methylpiperazine was added to 500 g of n-butanol, And then in the 25-35C by adding 169.5 grams of p-chloromethyl benzoic acid,And then at 30-40C for insulation reaction, the control of p-chloromethyl benzoic acid content of less than 1%The reaction is completed, after the end of the reaction should be concentrated by vacuum distillation of excess n-butanol and excess 4-methyl piperazine,To the residue was added 300 g of water,Then concentrated hydrochloric acid to adjust the pH = 1 ~ 2,Then add 1660 grams of methanol,Heating up to 60C ,And then cooled to 0~5 C , precipitation of white crystals, Filtration of solid crystals,The solid crystals were washed with 200 g of methanol and dried at 55 C to give the crude product260 g, yield 84.6%, purity 99%, impurity (Ia) compound content 0.15%; The crude product thus obtained was added to 520 g of water,Heated to 60 C dissolved,3 hours slowly dropping 2080 grams of ethanol,Dripping slowly after cooling to 0 ~ 5 ,A large amount of white solid was precipitated and the white solid was filtered and the white solid was dried at 55 C Dried to obtain high purity 4- (4-methyl-1-piperazinylmethyl) benzoic acid dihydrochloride I 228.8 g, purity 99.6%, total yield 74.4%, impurity (Ia) compound content of 0.042%. The crude product thus obtained was added to 520 g of water,Heated to 60 C dissolved,3 hours slowly dropping 2080 grams of ethanol,Dripping slowly after cooling to 0 ~ 5 ,A large amount of white solid was precipitated and the white solid was filtered and the white solid was dried at 55 C Dried to obtain high purity 4- (4-methyl-1-piperazinylmethyl) benzoic acid dihydrochloride I 228.8 g, purity 99.6%, total yield 74.4%, impurity (Ia) compound content of 0.042%.
35%		Step 1.7. To a well-stirred suspension consisting of 17.1 g. (0.10 mole) of alpha- chloro-p-toluylic acid in 150 ml of absolute ethanol under a nitrogen atmosphere at room temperature (-20 C) a solution consisting of 44.1 g. (0.44 mole) of N-methylpiperazine dissolved in 50 ml of ethanol was added drop wise. The resulting reaction mixture was refluxed for a period of 16 hours and then cooled to room temperature. The cooled reaction mixture was concentrated in vacuo and the thus obtained residue partitioned between 100 ml of diethyl ether and 100 ml of 3N aqueous sodium hydroxide. The separated aqueous layer was then washed three times with 100 ml of diethyl ether, cooled in an ice-water bath and subsequently acidified with concentrated hydrochloric acid. The resulting solids were filtered and air-dried, followed by trituration with 150 ml of boiling isopropyl alcohol and stirring for a period of two minutes. After filtering while hot and drying the product there were obtained 9.4 g. (35%) of pure 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride as the hemihydrate, m.p. 310-312 C. MS: 235.1 (M+H); 1H NMR(D2O) delta 8.04 (d, J= 8.21 Hz, 2H), 7.59 (d, J= 8.21 Hz, 2H), 3.50 (s, 2H), 3.63 (br, 8H), 2.97 (s,3H); 13C NMR delta 170.18, 133.13, 131.91, 130.90, 60.22, 50.61, 48.77, 43.25.
35%	In ethanol; at 20℃; for 16h;Inert atmosphere; Reflux;	To a well-stirred consisting of 17.1g (0.10mol) of alpha-chloro-p-toluic acid 7 in 150mL of absolute ethanol under a nitrogen atmosphere at room temperature (?20C), a solution consisting of 44.1g (0.44mol) of N-methylpiperazine 8a dissolved in 50mL of ethanol was added drop wise. The resulting reaction mixture was refluxed for 16h and then cooled to room temperature. The cooled reaction mixture was concentrated in vacuo, and the residue was partitioned between 100mL of diethyl ether and 100mL of 3N NaOH. The separated aqueous layer was then washed three times with 100mL of diethyl ether, cooled in an ice-water bath and subsequently acidified with concentrated hydrochloric acid. The resulting solids were filtered, air-dried, triturated with 150mL of boiling isopropyl alcohol, and stirred for 2min. After the product was filtered while hot and dried, 9.4g (35%) of pure 4-(6-methylpiperazinomethyl)benzoic acid dihydrochloride 9a was obtained as the hemihydrate (mp 310-312C).

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 1822 - 1839
[2]Patent: CN106905263,2017,A .Location in patent: Paragraph 0013
[3]Patent: WO2008/70350,2008,A2 .Location in patent: Page/Page column 25; 28; 35; 37
[4]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 623 - 632

6
[ 106261-49-8 ]
[ 106261-64-7 ]

Yield	Reaction Conditions	Operation in experiment
90.4%	With thionyl chloride at 78℃; for 31h; Autoclave;	1.1 (1) Synthesis of 4-[(4-methylpiperazin-1-yl)methyl]benzoyl chloride dihydrochloride (Formula II) In a 200 L autoclave, 4 - [(4-methylpiperazin-1-yl) methyl] benzoic acid dihydrochloride and thionyl chloride were added, heated to about 78 ° C, refluxed for about 31 hours, TLC showed the starting material was completed (methanol: methylene chloride: triethylamine: 1/10/1, Rf: 0.5). And the filter cake was washed twice with petroleum ether (60 ° C ~ 90 ° C) and dried at 25 ° C for about 5 hours under reduced pressure to obtain a white solid in a yield of 90.4% %,
81%	With thionyl chloride for 24h; Heating / reflux;	B.1.8; E Step 1.8 To 20 g. (0.065 mole) of 4-(4-methyl-piperazin-l-ylmethyl)-benzoic acid dihydrochloride under a nitrogen atmosphere, there were added 119 ml of thionyl chloride (194 g., 1.625 mole) to form a beige-white suspension. The reaction mixture was refluxed for 24 hours and then cooled to room temperature (-20° C). The resulting suspension was filtered, and the recovered solids were washed with diethyl ether and dried to ultimately afford 17.0 g (81%) of pure 4-(4-methyl-piperazin-l-ylmethyl)-benzoyl chloride dihydrochloride.
81%	With thionyl chloride at 20℃; for 24h; Inert atmosphere; Reflux;	8.2.11 4-(4-Methylpiperazinomethyl)benzoyl chloride dihydrochloride (10a)²⁴ To 20g (0.065mol) of 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride 9a under a nitrogen atmosphere, 119mL of thionyl chloride (194g, 1.625mol) was added to form a beige-white suspension. The reaction mixture was refluxed for 24h and then cooled to room temperature (∼20°C). The resulting suspension was filtered, and the recovered solids were washed with diethyl ether and dried to 17.0g (81%) of pure 4-(4-methylpiperazinomethyl)benzoyl chloride dihydrochloride 10a. The material was used for the next reaction without characterization.

	With thionyl chloride In toluene at 60 - 62℃; for 21h;	7 Example 7 Synthesis of 4-[(4-methyl-1-piperazinyl)methyl]benzoyl chloride dihydrochloride To a suspension of compound II (n=2, A=Cl) (20 g) in toluene (35 mL) and DMF (1 mL) under N2 at 60° C., (20 g) was added over a period of 1 h SOCl2. The mixture was kept under stirring at 62° C. for 20 h. After cooling at 20° C., toluene (20 mL) was added and the mixture was stirred for 0.5 h. The solid was filtered off, washed with toluene (50 mL) and dried at 65° C. under vacuum for 15 h. The product was obtained as a white powder (21 g).
	With thionyl chloride for 2h; Reflux;	5.D Method D; A mixture of 4-(4-methylpiperzin- l -ylmethyl)benzoic acid dihydrochloride hemihydrate (45.6g, 0.316 mol), thionyl chloride (182.4 ml) and N,N-dimethylformamide (10.5 ml) was refluxed for 2 hours. After the completion of reaction, reaction mixture was distilled out completely under vacuum. The resulting residue was diluted with acetone (137 ml). The solid thus precipitated was filtered and washed to give 4-(4-methylpiperzin- l -ylmethyl)benzoyl chloride dihydrochloride. Above intermediate was added to a solution of 4-methyl-N-(4-pyridin-3-yl-pyridiin-2-yl)benzene- l ,3-diamine (25g, 0.09mol) and potassium carbonate (99.5g, 0.72mol) in acetone (500 ml) at 0-5 °C. After completion of reaction, ethyl acetate (250 ml) was added to the reaction mixture, acidified with aqueous hydrochloric acid and layers were separated. Aqueous layer was washed with ethyl acetate and then basified with aqueous sodium hydroxide solution (20%). The solid thus precipitated was filtered and washed with demineralized water to give 42g (94%) of title compound having purity: 99.2% by HPLC
	With thionyl chloride; N,N-dimethyl-formamide for 20h; Reflux;	1.1 Step I: Preparation of 4-(4-methyIpiperazin-l-ylmethyl)benzoyl chloride dihydrochloride A mixture of 4-(4-methylpiperazin-l-ylmethyl) benzoic acid dihydrochloride (150 g), thionyl chloride (600 ml) and N,N-dimethylformamide (37.2 ml) was refluxed for 20 hours. After completion of reaction, the reaction mass was distilled out completely under vacuum to give residue which was diluted with dichloromethane (300ml). The solid thus precipitated was filtered and washed to give 135 g of the title compound.
198.7 kg	With thionyl chloride at 80℃; for 24h; Large scale;
42 g	With thionyl chloride at 80℃; for 24h;	1.C Step-C: Preparation of 4-(4-Methylpiperazinomethyl) benzoyl chloride dihydrochloride A mixture of 4-(4-Methylpiperazinomethyl) benzoic acid dihydrochloride (42g, 0.136moles) and thionyl chloride (384g, 3.22moles) were placed in a reaction flask and heated to 80°C for 24 hours. After completion of reaction, the reaction mass was filtered and washed with chloroform to yield 4-(4-Methylpiperazinomethyl) benzoyl chloride dihydrochloride. (42g yield)
	With thionyl chloride for 24h; Reflux;	Commercially available 4-((4-methylpiperazin-1-yl)methyl)benzoic acid dihydrochloride (5 g, 0.016 mol) was added into SOCl2 (40 mL) and the mixture was heated to reflux for 24 h. The volatiles were removed under reduced pressure to give 4-((4-methylpiperazin-1-yl)methyl)benzoyl chloride dihydrochloride (45) as a white solid.
52 g	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 65℃; for 13h; Inert atmosphere;	1 Synthesis of 4-[(4-methyl-1-piperazinyl)methyl]-benzoyl chloride hydrochloride (1:2) of formula (III) with X=Cl. 50 g of 4-[(4-methyl-1-piperazinyl)methyl]-benzoic acid, hydrochloride (1:2), were loaded into a reactor under nitrogen at 20 °C. 200 g of thionyl chloride (SOCl2) and 12.5 ml of dimethylformamide (DMF) were added, while maintaining a temperature below 25 °C. The reaction mixture was stirred and heated to 65 °C for about 13 hours then cooled to 20 °C and the excess thionyl chloride was removed by distillation. The residue was dissolved in 100 ml of methylene chloride and the reaction mixture was stirred for 1 hour. The crystallized product was filtered, washed with 15 ml of methylene chloride and vacuum dried at 40 °C for 1 hour; 52 g of 4-[(4-methyl-1-piperazinyl)methyl] benzoyl chloride, hydrochloride (1:2) were obtained as a white powder.
153 g	With thionyl chloride In N,N-dimethyl-formamide; toluene at 60℃; for 8h;	1 Preparation of 4- (4-methyl-1-piperazinomethyl) benzoyl chloride dihydrochloride salt 150 g of 4 - [(4-methyl-1-piperazinyl) methyl] benzoic acid dihydrochloride and 75.5 g of thionyl chloride were added to 495 mL of dimethylformamide / toluene (1:10) and the mixture was heated to 60 ° C. , And the mixture was stirred for 8 hours.The mixture was cooled at 25 ° C. and the resulting solid was filtered, washed with 900 mL of acetone, and dried under reduced pressure at 40 ° C., 153 g of 4- (4-methyl-1-piperazinomethyl) benzoyl chloride dihydrochloride was obtained.
20 kg	With thionyl chloride In N,N-dimethyl-formamide at 45 - 75℃; for 4h; Industrial scale;	1-2 Among them,The preparation process of imatinib mesylate intermediate I [4-(4-methylpiperazinemethyl)benzoyl chloride dihydrochloride] is as follows: (1) Put 25.0kg imatinic acid and about 300kg thionyl chloride,4-7kg DMF is added to the 300L replacement reaction tank,The temperature is increased to 45-70°C for 1 hour, and then the temperature is gradually increased to above 75°C.Reflux and stir for 3 hours;(2) Post-processing: After the reaction is completed, the temperature is reduced to 20-30°C and filtered with an acid-resistant filter.The filter cake is fully washed three times with 20.0kg*3 petroleum ether,Drain, the filter cake is quickly transferred to a double cone dryer for vacuum drying at 45-55°C for 5 hours,About 20kg of intermediate I was obtained, and the yield range was 80%-95%.
	With pyridine; thionyl chloride; N,N-dimethyl-formamide at 0 - 50℃;

Reference： [1]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - CN103570676, 2016, B Location in patent: Paragraph 0071-0076
[2]Current Patent Assignee: THE UNIVERSITY OF TEXAS SYSTEM - WO2008/70350, 2008, A2 Location in patent: Page/Page column 25; 28-29; 35; 37
[3]Peng, Zhenghong; Maxwell, David S.; Sun, Duoli; Bhanu Prasad, Basvoju A.; Pal, Ashutosh; Wang, Shimei; Balatoni, Julius; Ghosh, Pradip; Lim, Seok T.; Volgin, Andrei; Shavrin, Aleksander; Alauddin, Mian M.; Gelovani, Juri G.; Bornmann, William G. [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 623 - 632]
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - US2008/103305, 2008, A1 Location in patent: Page/Page column 7
[5]Current Patent Assignee: IND-SWIFT LABORATORIES LIMITED - WO2011/39782, 2011, A1 Location in patent: Page/Page column 16
[6]Current Patent Assignee: IND-SWIFT LABORATORIES LIMITED - WO2012/131711, 2012, A1 Location in patent: Page/Page column 14
[7]Kompella, Amala; Adibhatla, Bhujanga Rao Kalisatya; Muddasani, Pulla Reddy; Rachakonda, Sreenivas; Gampa, Venugopala Krishna; Dubey, Pramod Kumar [Organic Process Research and Development, 2012, vol. 16, # 11, p. 1794 - 1804]
[8]Current Patent Assignee: NATCO PHARMA LIMITED - WO2013/35102, 2013, A1 Location in patent: Page/Page column 20
[9]Mao, Yongjun; Zhu, Wenxiu; Kong, Xiaoguang; Wang, Zhen; Xie, Hua; Ding, Jian; Terrett, Nicholas Kenneth; Shen, Jingkang [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 11, p. 3090 - 3104]
[10]Current Patent Assignee: HOLDING F.I.S. S.P.A. - EP2927223, 2015, A1 Location in patent: Paragraph 0077
[11]Current Patent Assignee: JEIL PHARMA HOLDINGS INC - JP2015/521656, 2015, A Location in patent: Paragraph 0049; 0050
[12]Current Patent Assignee: ZHEJIANG JIANFENG GROUP CO., LTD. - CN111961031, 2020, A Location in patent: Paragraph 0009
[13]Current Patent Assignee: SAKAR HEALTHCARE - WO2021/140425, 2021, A1 Location in patent: Page/Page column 10; 13-15

7
[ 106261-49-8 ]
[ 148077-69-4 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; triethylamine In dichloromethane at 18 - 32℃; for 1h;	4.B Method B Preparation of the acid chlorideTo a mixture of 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid dihydrochloride (1.0 eq), dichloromethane (7 vol) and triethylamine (2.15 eq), thionyl chloride (1.2 eq) was added at 18-28°C . The reaction mixture was stirred at 28-32°C for 1 hour. Coupling of acid chloride with amino thiazole To a chilled (0-50C) suspension of 4-Methyl-N3-(4-pyridin-3-yl-thiazol-2-yl)-benzene- 1,3-diamine (0.8 eq) and thiethylamine (2.2 eq) in dichloromethane (3 vol), the acid chloride solution (prepared above) was maintaining the temperature below 5°C. The reaction mixture was warmed to 25-300C and stirred at the same temperature for 1O h. Methanol (2 vol) and water (5 vol) were added to the reaction mixture and stirred. After separating the layers, methanol (2 vol), dihloromethane (5 vol) and sodium hydroxide solution (aqueous, 10%, till pH was 9.5-10.0) were added to the aqueous layer and stirred for 10 minutes. The layers were separated. The organic layer was a washed with water and saturated sodium chloride solution. The organic layer was concentrated and ethanol (2 vol) was added and stirred. The mixture was concentrated. Ethanol was added to the residue and stirred. The product was filtered and dried at 50-550C in a vaccum tray drier. Yield = 65-75%.

Reference： [1]Current Patent Assignee: AB SCIENCE SA - WO2008/98949, 2008, A2 Location in patent: Page/Page column 21-22

8
[ 152460-10-1 ]
4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride [ No CAS ]
[ 152459-95-5 ]

Yield	Reaction Conditions	Operation in experiment
92.5%	Stage #1: 4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride With pyridine; thionyl chloride at 50 - 60℃; for 3h; Stage #2: 6-methyl-1-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine at -10 - 0℃; for 1h;	1 Example 1 Preparation of crude imatinib 80.0 g of 4 - ((4-methylpiperazin-1-yl) methyl) benzoic acid dihydrochloride and 400 ml of pyridine were placed in a reaction flask,36.0 g of thionyl chloride was added and the temperature was raised to 50 to 60 ° C for 3 hours. The reaction mixture was cooled to -10 ° C and added with 58.0 g of N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine. The temperature was controlled at -5 to 0 ° C 1 hour. The reaction was quenched by addition of 320 ml of water, warmed to 60 ° C, added dropwise with 7% aqueous ammonia and added dropwise over 1.5 hours. Finished, stirring insulation for 1 hour. Cooling to room temperature, crystallization 4 hours. The filter cake was washed with water until neutral. After drying under vacuum at 60-65 ° C for 16 hours, 95.5 g of a white powdery solid (crude imatinib) was obtained in a yield of 92.5% and a purity of 98.6%. The content of the compound of formula B was 220 ppm.
91%	Stage #1: 4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide at 50℃; for 2h; Stage #2: 6-methyl-1-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine In N,N-dimethyl-formamide at 70℃; for 12h;
90%	Stage #1: 4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride With pyridine; thionyl chloride at 20 - 50℃; for 1 - 2h; Stage #2: 6-methyl-1-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine With pyridine at 0 - 25℃; for 1h;	3 Example 3 Preparation of Imatinib To a suspension of 4-[(4-methyl-1-piperazinyl)methyl]benzoic acid dihydrochloride (30 g) in pyridine (100 g) at 20° C., SOCl2 (11.5 g, 1.05 eq) is added and the mixture is kept under stirring at 45-50° C. for 1-2 h. After cooling at 0° C., N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyridineamine (20 g) is added. The reaction is kept under stirring at 15-25° C. for 1 h, then water (100 mL) is added. The mixture is heated up to 40° C., then 26% NH4OH (50 g) and water (225 mL) are added. The reaction mixture is kept under stirring at room temperature overnight. The solid is filtered off, washed with water and dried at 75° C. under vacuum overnight. Imatinib is obtained as a yellowish powder (32 g, 90% yield, <98% purity).

86%	Stage #1: 4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.166667h; Stage #2: 6-methyl-1-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine In N,N-dimethyl-formamide at 20℃; for 12h;	a Synthesis of N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)-4-((4-methyl-piperazin-1- yl)methyl)benzamide (Imatinib, Formula IV) Using DMF as solvent (0225) To a solution of 4-((4-methylpiperazin-1-yl)methyl)benzoic acid dihydrochloride (18, 1.45 g, 4.70 mmol) in DMF (20 ml), DIPEA (4.0 ml, 23.5 mmol), EDC (1 .08 g, 5.63 mmol) and HOBt (0.83 g, 6.1 mmol) were added and stirred for 10 minutes. 6-Methyl-N1-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1 ,3-diamine (Formula III, 1 .0 g, 3.6 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was poured into water (50 ml) and extracted with the EtOAc (2 x 30 ml). The EtOAc layer was dried (Na2SO4) and concentrated to afford the crude product which was triturated n-heptane and filtered. The filtered solid was washed with n-heptane containing a few drops of acetonitrile to afford N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)-4-((4-methyl-piperazin-1-yl)methyl)benzamide (Formula IV) as an off-white solid (1.53 g, 86%).
85%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; N,N-dimethyl-formamide at 60℃; for 2.5h;	1 Preparation of imatinib free base In a 5 L reactor were added 100 g (1 equivalent) of the "acid compound" dihydrochloride, 5.7 g (0.15 equivalents) of DMAP, 44.8 g (1.05 equivalents) of HOBt and 65.8 g (0.75 equivalents) of the "amino compound". After 700 mL of dimethylformamide and 136 mL (3.1 equivalents) of TEA were added. The suspension was heated to 60 °C and a solution of 66.6 g (1.1 equivalents) of EDC.HC1 in 600 mL of dichloromethane was slowly added during 30 minutes. After 2 hours at 60 °C, the reaction mixture was cooled to room temperature during 1 hour and then 600 mL of dichloromethane were added. Then, 720 mL of a 0.5 M NaOH solution were added dropwise until complete solubilization of imatinib in the organic phase. The organic phase was separated and washed once with 600 mL of water. 600 mL of dichloromethane were removed by distillation and 1,200 mL of isopropanol as a precipitation solvent were added to the organic mixture. The distillation proceeded and 600 mL of solvent were distilled up to 74-80 °C for the removal of residual dichloromethane. The suspension was cooled to room temperature and filtered after 1 hour. The obtained solid was washed with isopropanol (2 x 150 mL) . The humid solid was dried during 12 hours at 60 °C providing 99.2 g of imatinib free base (yield: 85%; HPLC purity of 99.69%; N- ( 2-methyl-5-aminophenyl ) -4- (3- pyridyl-2-pyrimidine ) amine = 50-70 ppm; 4-chloromethyl-N- [ 4- methyl-3- (pyridin-3-yl-pirimidin-2-yl-amino ) -phenyl] - benzamide ≤ 10 ppm) .
	Stage #1: 4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride With 1,1'-carbonyldiimidazole In dimethyl sulfoxide at 40℃; for 2h; Inert atmosphere; Stage #2: 6-methyl-1-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine In dimethyl sulfoxide at 45 - 50℃; Stage #3: With ammonia In water; ethyl acetate for 2h;	2 A mixture of 4-(4-methyl-piperazinomethyl)benzoic acid dihydrochloride (8.65 g) and dimethylsulfoxide (25 g) was stirred and followed by the addition of N,N'- carbonyldiimidazole (4.53 g) under nitrogen atmosphere. The temperature of the resulting mixture was raised to 400C and then stirred for 2 hours at 400C. To the resulting mass was added portion wise N-(5-Amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (6.25 g) under stirring, the temperature of the reaction was raised to 45-500C and then stirred for 5 hours. Upon completion of the reaction, the reaction mass was cooled to 30-350C, followed by quenching the mass with water (276 ml) and sodium dihydrogen phosphate (50 g) under stirring at a temperature of 30-350C, and the stirring was continued for 20 minutes. The resulting mass was washed two times with dichloro methane (2 x 100 ml) and the aqueous layer was separated. Ethyl acetate (22 ml) and aqueous ammonia (15 ml) were added to the aqueous layer and then stirred for 2 hours. The separated solid was filtered, washed with water (100 ml) and then the solid was dried in a vacuum oven for 12 hours at 70-750C to yield 8.5 g of pure imatinib base (Purity by FiPLC: 98.90%).Content of Impurities measured by HPLC:1. Formamide impurity at 0.72 RRT: 0.87%.2. Carbonylimidazole impurity at 0.96 RRT: 0.01%.3. Amine intermediate at 0.69 RRT: Not Detected.
	Stage #1: 4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride With 1,1'-carbonyldiimidazole In dimethyl sulfoxide at 40℃; for 2h; Inert atmosphere; Stage #2: 6-methyl-1-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine In dimethyl sulfoxide at 45 - 50℃; for 5h;	2 A mixture of 4-(4-methyl-piperazinomethyl)benzoic acid dihydrochloride (8.65 g) and dimethylsulfoxide (25 g) was stirred and followed by the addition of N,N'-carbonyldiimidazole (4.53 g) under nitrogen atmosphere. The temperature of the resulting mixture was raised to 40° C. and then stirred for 2 hours at 40° C. To the resulting mass was added portion wise N-(5-Amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (6.25 g) under stirring, the temperature of the reaction was raised to 45-50° C. and then stirred for 5 hours. Upon completion of the reaction, the reaction mass was cooled to 30-35° C., followed by quenching the mass with water (276 ml) and sodium dihydrogen phosphate (50 g) under stirring at a temperature of 30-35° C., and the stirring was continued for 20 minutes. The resulting mass was washed two times with dichloromethane (2*100 ml) and the aqueous layer was separated. Ethyl acetate (22 ml) and aqueous ammonia (15 ml) were added to the aqueous layer and then stirred for 2 hours. The separated solid was filtered, washed with water (100 ml) and then the solid was dried in a vacuum oven for 12 hours at 70-75° C. to yield 8.5 g of pure imatinib base (Purity by HPLC: 98.90%). Content of Impurities Measured by HPLC:1. Formamide impurity at 0.72 RRT: 0.87%.2. Carbonylimidazole impurity at 0.96 RRT: 0.01%.3. Amine intermediate at 0.69 RRT: Not Detected.
	Stage #1: 4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride With triethylamine In dichloromethane for 0.666667h; Reflux; Stage #2: With thionyl chloride In dichloromethane at 25℃; for 4h; Stage #3: 6-methyl-1-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine With potassium carbonate In dichloromethane at 25℃;	4 Example 1 A mechanical stirrer, a thermometer and a reflux condenser were charged in a 1000 ml three-necked flask, followed by the addition of 31.6 g (100 mmol) of imatinibic acid and 22.2 g (220 mmol) of triethylamine followed by 900 ml of methylene chloride. reaction,Reaction after 40min, And 13.0 g of110 mmol)(90 mmol) of imatinibamine and 22.2 g (220 mmol) of triethylamine were added to the reaction at the completion of the TLC reaction. The reaction was continued at -5 ° C for 5 hours.After 2h ~ 12h,After filtration, the filter cake was dissolved in 20% dilute hydrochloric acid, then adjusted to pH 9 ~ 10 with 20% sodium hydroxide aqueous solution, then 50ml of absolute ethanol was added, and the mixture was stirred, filtrated and washed with water. Cake and dried to obtain 40.7 g of crude imatinib in a yield of 91.6% and a purity of 99.3% as shown by the HPLC area normalization method in Fig.

Reference： [1]Current Patent Assignee: SHANGHAI ACEBRIGHT PHARMACEUTICALS GROUP CO LTD - CN107245070, 2017, A Location in patent: Paragraph 0081; 0082; 0083
[2]Location in patent: experimental part Liu, Haiyan; Xia, Wenpin; Luo, Yu; Lu, Wei [Monatshefte fur Chemie, 2010, vol. 141, # 8, p. 907 - 911]
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - US2008/103305, 2008, A1 Location in patent: Page/Page column 6
[4]Current Patent Assignee: ESCO ASTER; CLEGG RICHARD - WO2021/74138, 2021, A1 Location in patent: Page/Page column 39-40
[5]Current Patent Assignee: CRISTALIA PRODUTOS QUIMICOS FARMACEUTICOS, LTDA; CRISTALIA PRODUTOS QUIMIICOS FARM LTDA - WO2015/188243, 2015, A1 Location in patent: Page/Page column 8; 22; 23
[6]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2010/133976, 2010, A2 Location in patent: Page/Page column 25
[7]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - US2010/330130, 2010, A1 Location in patent: Page/Page column 10
[8]Current Patent Assignee: CHINA STATE SHIPBUILDING CORPORATION LIMITED - CN105585556, 2016, A Location in patent: Paragraph 0023

9
[ 3945-69-5 ]
4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride [ No CAS ]
[ 1166872-12-3 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; for 0.166667h;Product distribution / selectivity;	5 g of 4-(4-methylpiperazinyl-methyl) benzoic acid dihydrochloride hemihydrate were added to the reaction mixture. All solid material was completely dissolved after10 minutes forming slightly yellow clear solution.;
	In water; acetonitrile; at 20 - 25℃; for 0.75h;Product distribution / selectivity;	1O g of 4-(4-methylpiperazinyl-methyl) benzoic acid dihydrochloride hemihydrate dissolved in50 ml of water were subsequently added to the reaction mixture at 20-25 0C. Suspension turned to a clear homogeneous solution after 15 minutes of vigorous stirring. Reaction mixture was stirred for 0.5 h

Reference： [1]Patent: WO2009/80366,2009,A1 .Location in patent: Page/Page column 8
[2]Patent: WO2009/80366,2009,A1 .Location in patent: Page/Page column 9

10
[ 530-62-1 ]
[ 106261-49-8 ]
[ 2118894-75-8 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide at 40℃;

Reference： [1]Location in patent: experimental part Ivanov, Andrey S.; Shishkov, Sergey V. [Monatshefte fur Chemie, 2009, vol. 140, # 6, p. 619 - 623]

11
[ 314268-40-1 ]
4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogenchloride In water at 100℃; for 3h;	General procedure for acid hydrolysis of methyl 4-[(4-methylpiperazin-1-yl)methyl]-benzoate (4a): a mixture of methyl 4-[(4-methylpiperazin-1-yl)methyl]benzoate (4a) (61.6 g, 0.25 mol), H2O (60 mL) and concentrated HCl (120 mL) was heated to boiling, then the mixture was diluted with 120 mL of hot H2O and refluxed for 3 h. The hot reaction mixture was treated with activated charcoal, filtered and the H2O was evaporated. The solid residue was boiled in benzene to remov residual H2O using a Dean-Stark trap, then filtered and dried to afford 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride (4b × 2HCl): white powder; yield: 75.2 g, 98%; purity (by HPLC): 99.3%.
96%	With hydrogenchloride In water Reflux;
286 mg	With hydrogenchloride; water for 10h; Reflux;

Reference： [1]Location in patent: experimental part Koroleva, Elena V.; Kadutskii, Aleksey P.; Farina, Alexander V.; Ignatovich, Janna V.; Ermolinskaya, Anastasiya L.; Gusak, Klaudiya N.; Kalinichenko, Elena N. [Tetrahedron Letters, 2012, vol. 53, # 38, p. 5056 - 5058]
[2]Koroleva; Gusak; Ermolinskaya; Ignatovich [Russian Journal of Organic Chemistry, 2013, vol. 49, # 4, p. 563 - 567][Zh. Org. Khim., 2013, vol. 49, # 4, p. 580 - 584]
[3]Location in patent: experimental part Ivanov, Andrey S.; Shishkov, Sergey V. [Monatshefte fur Chemie, 2009, vol. 140, # 6, p. 619 - 623]

12
[ 152460-10-1 ]
[ 106261-49-8 ]
[ 1256080-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride With 1,1'-carbonyldiimidazole In dimethyl sulfoxide at 25 - 30℃; for 0.5h; Stage #2: 6-methyl-1-N-(4-(pyridin-3-yl)pyrimidin-2-yl)benzene-1,3-diamine In dimethyl sulfoxide at 45 - 55℃; Stage #3: With ammonia In water; ethyl acetate at 20 - 30℃; for 4h;	8 A mixture of 4-(4-methyl-piperazinomethyl)benzoic acid dihydrochloride (277.1 g), dimethylsulfoxide (880 g) and carbonyldiimidazole (147 g) was stirred for 30 minutes at 25-300C. The resulting mixture was heated at 40-450C and followed by the addition of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (200 g). The reaction mixture was further heated at 50-550C and maintained for 2 hours. The resulting mass was cooled to 20-250C and followed by quenching with a mixture of water (8000 ml), ethyl acetate (720 ml), and aqueous ammonia (250 ml). The resulting slurry was stirred for 2 hours at 25-300C for 2 hours. The separated solid was filtered, washed with water (500 ml) and then dried the solid in air oven at 65-700C for 10 to 12 hours. The dried material was subjected to column chromatography to isolate the desired impurity (Yield: 6.6 g, Purity by HPLC: 99.35%).

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2010/133976, 2010, A2 Location in patent: Page/Page column 27; 28

13
[ 106261-49-8 ]
[ 152459-95-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / Reflux 2: potassium carbonate / acetone / 0 - 5 °C
	Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / 20 h / Reflux 2.1: potassium carbonate / dichloromethane / 0.5 h / 20 °C 2.2: 10 h / 0 - 5 °C / Reflux
	Multi-step reaction with 2 steps 1.1: thionyl chloride / 24 h / 80 °C / Large scale 2.1: potassium carbonate / isopropyl alcohol / 0.25 h / 20 °C / Large scale 2.2: 1.5 h / 20 °C / Large scale 2.3: 0.5 h / 20 °C / Large scale

	Multi-step reaction with 2 steps 1: thionyl chloride / 24 h / 20 °C / Inert atmosphere; Reflux 2: pyridine / 18 h / 20 °C
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 2 h / 40 - 50 °C 2: N,N-dimethyl-formamide / 6 h / 40 - 50 °C
	Multi-step reaction with 2 steps 1.1: thionyl chloride / 31 h / 78 °C / Autoclave 2.1: pyridine / 0.33 h / Autoclave 2.2: 8 h / 0 - 25 °C
	Multi-step reaction with 2 steps 1: thionyl chloride / N,N-dimethyl-formamide; toluene / 8 h / 60 °C 2: N,N-dimethyl-formamide; ethyl acetate / 5 h / 50 °C
	Multi-step reaction with 2 steps 1: thionyl chloride / N,N-dimethyl-formamide / 4 h / 45 - 75 °C / Industrial scale 2: pyridine / 1 h / 20 - 30 °C / Industrial scale
	Multi-step reaction with 2 steps 1: pyridine; N,N-dimethyl-formamide; thionyl chloride / 0 - 50 °C 2: pyridine / 8 h / 15 °C

Reference： [1]Current Patent Assignee: IND-SWIFT LABORATORIES LIMITED - WO2011/39782, 2011, A1
[2]Current Patent Assignee: IND-SWIFT LABORATORIES LIMITED - WO2012/131711, 2012, A1
[3]Kompella, Amala; Adibhatla, Bhujanga Rao Kalisatya; Muddasani, Pulla Reddy; Rachakonda, Sreenivas; Gampa, Venugopala Krishna; Dubey, Pramod Kumar [Organic Process Research and Development, 2012, vol. 16, # 11, p. 1794 - 1804]
[4]Peng, Zhenghong; Maxwell, David S.; Sun, Duoli; Bhanu Prasad, Basvoju A.; Pal, Ashutosh; Wang, Shimei; Balatoni, Julius; Ghosh, Pradip; Lim, Seok T.; Volgin, Andrei; Shavrin, Aleksander; Alauddin, Mian M.; Gelovani, Juri G.; Bornmann, William G. [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 623 - 632]
[5]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN105399724, 2016, A
[6]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - CN103570676, 2016, B
[7]Current Patent Assignee: JEIL PHARMA HOLDINGS INC - JP2015/521656, 2015, A
[8]Current Patent Assignee: ZHEJIANG JIANFENG GROUP CO., LTD. - CN111961031, 2020, A
[9]Current Patent Assignee: SAKAR HEALTHCARE - WO2021/140425, 2021, A1

14
[ 106261-49-8 ]
[ 220127-57-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: thionyl chloride / 2 h / Reflux 2: potassium carbonate / acetone / 0 - 5 °C 3: acetonitrile / 0.5 h / 25 - 30 °C
	Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / 20 h / Reflux 2.1: potassium carbonate / dichloromethane / 0.5 h / 20 °C 2.2: 10 h / 0 - 5 °C / Reflux 3.1: dimethyl sulfoxide / 40 - 45 °C
	Multi-step reaction with 3 steps 1: thionyl chloride / 24 h / 20 °C / Inert atmosphere; Reflux 2: pyridine / 18 h / 20 °C 3: ethanol / 2 h / 45 °C

	Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 2 h / 40 - 50 °C 2: N,N-dimethyl-formamide / 6 h / 40 - 50 °C 3: isopropyl alcohol; acetone / 3 h / Reflux
	Multi-step reaction with 3 steps 1.1: thionyl chloride / 31 h / 78 °C / Autoclave 2.1: pyridine / 0.33 h / Autoclave 2.2: 8 h / 0 - 25 °C 3.1: ethanol / 1.33 h / 60 - 78 °C / Autoclave
	Multi-step reaction with 3 steps 1: thionyl chloride / N,N-dimethyl-formamide; toluene / 8 h / 60 °C 2: N,N-dimethyl-formamide; ethyl acetate / 5 h / 50 °C 3: ethyl acetate; isopropyl alcohol; water / 1 h / 65 - 75 °C
	Multi-step reaction with 3 steps 1: thionyl chloride / N,N-dimethyl-formamide / 4 h / 45 - 75 °C / Industrial scale 2: pyridine / 1 h / 20 - 30 °C / Industrial scale 3: methanol / 40 °C / Industrial scale
	Multi-step reaction with 3 steps 1: pyridine; N,N-dimethyl-formamide; thionyl chloride / 0 - 50 °C 2: pyridine / 8 h / 15 °C 3: isopropyl alcohol / 1 h / 50 °C

Reference： [1]Current Patent Assignee: IND-SWIFT LABORATORIES LIMITED - WO2011/39782, 2011, A1
[2]Current Patent Assignee: IND-SWIFT LABORATORIES LIMITED - WO2012/131711, 2012, A1
[3]Peng, Zhenghong; Maxwell, David S.; Sun, Duoli; Bhanu Prasad, Basvoju A.; Pal, Ashutosh; Wang, Shimei; Balatoni, Julius; Ghosh, Pradip; Lim, Seok T.; Volgin, Andrei; Shavrin, Aleksander; Alauddin, Mian M.; Gelovani, Juri G.; Bornmann, William G. [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 623 - 632]
[4]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN105399724, 2016, A
[5]Current Patent Assignee: SINO BIOPHARMACEUTICAL LIMITED - CN103570676, 2016, B
[6]Current Patent Assignee: JEIL PHARMA HOLDINGS INC - JP2015/521656, 2015, A
[7]Current Patent Assignee: ZHEJIANG JIANFENG GROUP CO., LTD. - CN111961031, 2020, A
[8]Current Patent Assignee: SAKAR HEALTHCARE - WO2021/140425, 2021, A1

15
[ 874-86-2 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / ethanol / 5 h / 78 °C 2: hydrogenchloride; water / 10 h / 100 °C

Reference： [1]Liu, Haiyan; Xia, Wenpin; Luo, Yu; Lu, Wei [Monatshefte fur Chemie, 2010, vol. 141, # 8, p. 907 - 911]

16
[ 67-68-5 ]
[ 530-62-1 ]
[ 152460-10-1 ]
[ 106261-49-8 ]
[ 1256080-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	at 25 - 55℃; for 2.5h;	5 A mixture of 4-(4-methyl-piperazinomethyl)benzoic acid dihydro chloride (277.1 g), dimethylsulfoxide (880 g) and carbonyl diimidazole (147 g) was stirred for 30 minutes at 25- 30°C. The resulting mixture was heated at 40-45 °C and followed by the addition of N-(5- amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (200 g). The reaction mixture was further heated at 50-55°C and maintained for 2 hours. The resulting mass was cooled to 20-25°C, followed by quenching with a mixture of water (8000 ml), ethyl acetate (720 ml), and aqueous ammonia (250 ml). The resulting slurry was stirred for 2 hours at 25-30°C for 2 hours. The separated solid was filtered, washed with water (500 ml) and then dried in an air oven at 65-70°C for 10 to 12 hours. The dried material was subjected to column chromatography to isolate the desired impurity (Yield: 6.6 g; Purity by HPLC: 99.35%).

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2011/95835, 2011, A1 Location in patent: Page/Page column 35

17
[ 109-01-3 ]
[ 1571-08-0 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium tetrahydroborate; acetic acid / chloroform / 13 h / 0 - 20 °C 2: hydrogenchloride / water / 3 h / 100 °C
	Multi-step reaction with 2 steps 1: sodium tetrahydroborate; acetic acid / chloroform / 0 - 20 °C 2: hydrogenchloride / water / Reflux

Reference： [1]Koroleva, Elena V.; Kadutskii, Aleksey P.; Farina, Alexander V.; Ignatovich, Janna V.; Ermolinskaya, Anastasiya L.; Gusak, Klaudiya N.; Kalinichenko, Elena N. [Tetrahedron Letters, 2012, vol. 53, # 38, p. 5056 - 5058]
[2]Koroleva; Gusak; Ermolinskaya; Ignatovich [Russian Journal of Organic Chemistry, 2013, vol. 49, # 4, p. 563 - 567][Zh. Org. Khim., 2013, vol. 49, # 4, p. 580 - 584]

18
[ 106261-48-7 ]
4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrogenchloride; In water; at 100℃; for 3h;pH 1 - 2;	Evaporation of the aqueous phase to the one third of the original volume, and refluxing of the residue with 60 mL of concentrated HCl (pH of the mixture must be 1-2) for 3 h and evaporation of H2O gave <strong>[106261-48-7]4-[(4-methylpiperazin-1-yl)methyl]benzoic acid</strong> dihydrochloride (4b × 2HCl): white powder; yield: 81.9 g, 95%; mp. 308-309 C (lit.2b 309-311 ); 1 NMR (500 MHz, D2O) delta: 3.07 (s, 3, 3-N), 3.72 (m, 8, CHpip), 4.58 (s, 2, 2), 7.65 (d, J = 8.0 Hz, 2, HAr) 8.06 (d, J = 8.0 Hz, 2, HAr); 13 NMR (125 MHz, D2O) delta:43.08, 48.56, 50.40, 59.99, 130.66, 131.69, 131.90, 132.87, 169.81; IR (KBr) nu: 3430, 2890, 2650-2400, 1720, 1460, 1248 m-1; MS (70 eV) m/z: 234 [M-2l]+ (60%). Anal. Calcd for 1320Cl2N2O2: , 50.81; , 6.51; Cl, 23.13; N, 9.12. Found: , 50.70; , 6.35; Cl, 22.89; N, 8.94.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 5056 - 5058

19
[ 104-85-8 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: dibenzoyl peroxide; N-Bromosuccinimide / chloroform / 3.5 h / 60 - 65 °C / Large scale 2: chloroform / 3 h / 20 - 25 °C / Large scale 3: hydrogenchloride; water / water / 5 h / 90 - 95 °C / Large scale

Reference： [1]Kompella, Amala; Adibhatla, Bhujanga Rao Kalisatya; Muddasani, Pulla Reddy; Rachakonda, Sreenivas; Gampa, Venugopala Krishna; Dubey, Pramod Kumar [Organic Process Research and Development, 2012, vol. 16, # 11, p. 1794 - 1804]

20
[ 109-01-3 ]
[ 6232-88-8 ]
[ 1417780-78-9 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
22 g	Stage #1: 1-methyl-piperazine; 4-bromomethylbenzoic Acid With potassium carbonate In butan-1-ol at 20℃; for 13h; Stage #2: With hydrogenchloride In isopropyl alcohol; butan-1-ol for 1h;	1 Step-2: Preparation of highly pure (>99%) 4-(4-Methylpiperazino)methyl benzoic acid dihydrochloride (I) 4-bromomethyl benzoic acid (25g, 0.116moles) from step-l and potassium carbonate (32. 1g, 0.232moles) were added successively to n-butanol(125ml). N-methyl piperazine(29.1 g, 0.290 moles) in n-butanol (62.5ml) was added slowly during one hour at room temperature. The reaction mass was maintained at room temperature for 12 hours and water (120ml) was charged. The reaction mass was maintained under stirring for 30minutes. The *aqueous layer was separated and extracted with n-butanol(50ml xl). The n-butanol extract were combined and the aqueous layer was kept aside. The organic layer was pH adjusted with isopropanolic hydrochloride solution (120ml) and maintained under stirring for one hour. The product was filtered and washed with n-butanol( 100ml) to get 4-(4-methylpiperazinomethyl)benzoic acid dihydrochloride. [Weight: 22g, purity by HPLC: 98.5%, (impurity-III content: 0.25%) Sulphated ash: 0.3%]. The above wet product was dissolved in 2N sodium hydroxide solution (50ml) and acidified with concentrated hydrochloric acid (40ml). The reaction mass was filtered and washed with water (10ml). The wet product was dried in oven at 50-60°C to get 4-(4- methylpiperazinomethyl) benzoic acid dihydrochloride. [Weight: 13g; purity by HPLC: 99.5%, (impurity-III content: 0.2%) Sulphated ash: 0.1 %] The aqueous layer was acidified with concentrated hydrochloric acid, filtered to yield impurity (III) ( 1 Og, 92% purity by HPLC).

Reference： [1]Current Patent Assignee: NATCO PHARMA LIMITED - WO2013/8242, 2013, A1 Location in patent: Page/Page column 6; 7

21
[ 99-94-5 ]
[ 1417780-78-9 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-Bromosuccinimide; dibenzoyl peroxide / chloroform / 20 h / Reflux 2.1: potassium carbonate / butan-1-ol / 13 h / 20 °C 2.2: 1 h

Reference： [1]Current Patent Assignee: NATCO PHARMA LIMITED - WO2013/8242, 2013, A1

22
[ 109-01-3 ]
[ 6232-88-8 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: 1-methyl-piperazine; 4-bromomethylbenzoic Acid With triethylamine In methanol at 25 - 30℃; for 5h; Stage #2: With hydrogenchloride In methanol at 10 - 15℃; for 1h;	4-(4-Methyl-piperazin-1-ylmethyl)benzoic acid dihydrochloride (3) To a mixture of 4-bromomethylbenzoic acid 2 (3.00 g, 14 mmol) in 30mL of methanol,triethylamine (4.24 g, 42 mmol) and N-methylpiperazine (2.11 g, 21 mmol) were added,and the mixture was stirred for 5 hrs at 25-30 C. The progress of the reaction wasmonitored by TLC (mobile phase dichloromethane:methanol 9:1). The reaction masswas cooled to 10-15 C and the pH of the reaction mixture was adjusted to 1-2 withmethanolic hydrochloric acid and stirred for 1 hr at 10-15 C. The precipitate was filtered,dried and crystallized from diethyl ether to afford 4-(4-methyl-piperazin-1-ylmethyl)benzoic acid dihydrochloride 3, 93%, mp 309-311 C, lit mp 310-312 C.16,17 IR:(cm1) 2503, 1712. 1H NMR (D2O): d 2.90 (s, 3H), 3.46-3.67 (m, 8H), 4.41 (s, 2H),7.44-7.46 (d, J8.0 Hz, 2H), 7.81-7.83 (d, J8.0 Hz, 2H). MS (m/z): 235.45[M1].
	Stage #1: 1-methyl-piperazine; 4-bromomethylbenzoic Acid With potassium carbonate In butan-1-ol at 20℃; for 13h; Stage #2: With hydrogenchloride In butan-1-ol for 1h;	3 Preparation of highly pure (>99%)4-(4-methyIpiperazino)methyl benzoic acid dihydrochloride of formula-I : 4-bromomethyl benzoic acid (25g, 0.1 16moles) from Example- 1 (step- 1 ) and potassium carbonate (24g, 0.173moles) were added successively to n-butanol( 125ml). N-methyl piperazine(17.5g, 0.174moles) in n-butanol(62.5ml)was added slowly during one hour at room temperature. The reaction mass was maintained at room temperature for 12hours and water (1 10ml) was charged. The reaction mass was maintained under stirring for 30rhinutes. The aqueous layer was separated and extracted with n-butanol(50ml) .The n- butanol layers were combined and the *aqueous layer was kept aside. The organic layer was pH adjusted with concentrated hydrochloric acid (30ml) and maintained under stirring for one hour. The product was filtered and washed with n-butanol( 100ml) to yield 4-(4-methylpiperazino)methyl benzoic acid dihydrochloride. [Weight: 12.5, purity by HPLC: 99.0%, (impurity-Ill content: 0.09%)Sulphated ash : 0.3%] ·

Reference： [1]Shroff; Mishra; Mohanta; Baitharu; Behera [Organic Preparations and Procedures International, 2022, vol. 54, # 5, p. 483 - 491]
[2]Current Patent Assignee: NATCO PHARMA LIMITED - WO2013/8242, 2013, A1 Location in patent: Page/Page column 8

23
[ 109-01-3 ]
[ 619-66-9 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: 1-methyl-piperazine; 4-Carboxybenzaldehyde With sodium tetrahydroborate; acetic acid In chloroform at 0 - 20℃; Stage #2: With hydrogenchloride In water for 3h; Reflux;

Reference： [1]Koroleva; Gusak; Ermolinskaya; Ignatovich [Russian Journal of Organic Chemistry, 2013, vol. 49, # 4, p. 563 - 567][Zh. Org. Khim., 2013, vol. 49, # 4, p. 580 - 584]

24
[ 120418-31-7 ]
[ 106261-49-8 ]
[ 1886973-35-8 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide at 40 - 50℃; for 2h;	1.2 340 g of DMF was added to a 1000 ml three-necked flask, stirred, and then 51 g of imatinic acid and 77 g of CBMIT were added successively, followed by reaction at 40 to 50 ° C for 2 h. 45 g of imamamine was then added and the reaction was carried out at 40 to 50 ° C for 6 h. After the completion of the reaction, 400g of purified water is added, the pH is adjusted to 10~11 with 30% sodium hydroxide solution, filtered and washed with purified water. The obtained solid is dried at 80-85 ° C for 5-7 hours, Nitidine base 62g. HPLC content of 99.6%, this step crystal yield 97. 8%

Reference： [1]Current Patent Assignee: QILU PHARMACEUTICAL GROUP CO LTD - CN105399724, 2016, A Location in patent: Paragraph 0042; 0045; 0046

25
C₂₂H₃₁N₅Si₂ [ No CAS ]
4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride [ No CAS ]
[ 152459-95-5 ]

Yield	Reaction Conditions	Operation in experiment
91.3%	Stage #1: 4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 10 - 20℃; for 0.5h; Stage #2: With tetrabutyl ammonium fluoride; 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 3h; Stage #3: C₂₂H₃₁N₅Si₂ In dichloromethane at 0 - 20℃; for 3h;	1; 2 Synthesis of Compound (I) In the second step, 4-[(4-methyl-1-piperazine)methyl]benzoic acid dihydrochloride 33.1 g (107.8 mmol, 1.1 eq) and 100 g of tetrahydrofuran were placed in a reaction flask at a temperature of 10-20 ° C. After adding 21.8 g (215.6 mmol, 2.2 eq) of triethylamine under stirring for 30 minutes, 0.26 g (0.98 mmol, 1% eq) of tetrabutylammonium fluoride was added, and N,N'-carbonyldiimidazole 17.5 g was added in portions. (107.8 mmol, 1.1 eq) was stirred at room temperature for 3 hours, and 41.3 g of the compound (IV) (98.1 mmol, 1.0 eq) obtained in the above step was added dropwise to a solution of 60 g of tetrahydrofuran at 0-10 ° C, and the mixture was stirred at room temperature for 2 hours. The TLC controlled raw material was completely reacted, the solvent was distilled off under reduced pressure, 150 g of a 10% aqueous hydrochloric acid solution was added, stirred for 2 hours, extracted with dichloromethane (90 g×2), and the aqueous layer was adjusted to adjust the pH with 10% sodium hydroxide. 8-9, filtration, solid recrystallized from isopropanol to give a white solid imatinib 43.8 g, yield 90.6%,
91.3%	Stage #1: 4-(4-N-methylpiperazine-1-yl)methyl benzoic acid dihydrochloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 10 - 20℃; for 0.5h; Stage #2: With tetrabutyl ammonium fluoride; 1,1'-carbonyldiimidazole In dichloromethane at 20℃; for 3h; Stage #3: C₂₂H₃₁N₅Si₂ In dichloromethane at 20℃; for 3h;	1-3 Synthesis of imatinib In the second step, 4-[(4-methyl-1-piperazine)methyl]benzoic acid dihydrochloride salt 168.3g (0.548mol, 1.1eq) and 500g dichloromethane were placed in the reaction flask, temperature control 10- 28.2 g (218.2 mmol, 2.2 eq) of diisopropylethylamine was added at 20 °C.After stirring for 30 minutes, 6.5 g (49.8 mmol, 1% eq) of tetrabutylammonium fluoride was added, and 84.8 g (0.523 mol, 1.05 eq) of N,N'-carbonyldiimidazole was added in portions and stirred at room temperature for 3 hours, 0- 209.7 g of the compound (IV) (0.498 mol, 1.0 eq) obtained in the above step was added dropwise to a solution of 300 g of dichloromethane, and the mixture was stirred at room temperature for 3 hours. The reaction of the TLC controlled material was completed, and the concentration of 750 g was 10 % aqueous hydrochloric acid, stirred for 2 hours, layered, the aqueous layer was extracted once with 450 g of dichloromethane, and the aqueous layer was adjusted to pH 8-9 with 10% sodium hydroxide, filtered, and the solid was recrystallized from isopropyl alcohol to give white. Solid imatinib 224.2 g, yield 91.3%, mp: 208.5-209.2 ° C, HPLC purity 99.6%, no more than 0.05% of a single impurity

Reference： [1]Current Patent Assignee: ANHUI HAIKANG PHARMACEUTICAL - CN108752314, 2018, A Location in patent: Paragraph 0015; 0016; 0028; 0033; 0036; 0037
[2]Current Patent Assignee: ANHUI HAIKANG PHARMACEUTICAL - CN108774210, 2018, A Location in patent: Paragraph 0028; 0031; 0032; 0033

26
[ 125743-59-1 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
95.5%	Stage #1: 1-<4-(4-methylpiperazin-1-ylmethyl)phenyl>ethanone With sodium hypochlorite In water at 0 - 55℃; for 2h; Stage #2: With hydrogenchloride In water at 0 - 5℃; for 1h;	1-6 Example 4 In a clean reaction flask, add 21.3g of 4-bromomethylacetophenone (equivalent to 0.1mol), add 200ml of methanol,After stirring and mixing uniformly, add 12g of N-methylpiperazine (equivalent to 0.12mol) and 50ml of potassium hydroxide aqueous solution with a mass percentage of 10%. After stirring and reacting at 25-30°C for 4.5h,Central Control, HPLC detected purity of 99.4%, 4-bromomethylacetophenone residue was 0.06%, after the completion of the reaction,Cool the reaction liquid to 0-5°C, and slowly drop 400ml of 10% sodium hypochlorite aqueous solution directly into the reaction liquid, and control the temperature at 0-5°C for dropwise addition.After the dripping is completed, the temperature is raised to 50-55°C for an insulation reaction for 2.0 hours, and the purity detected by the central control HPLC is 99.5%The intermediate residue is 0.04%. Add concentrated hydrochloric acid dropwise to the reaction solution to adjust PH=1-2, and then cool to 0-5°C to crystallize for 1 hour.After the crystallization is finished, it is filtered and dried to obtain 29.3 g of imate hydrochloride with a content of 99.6% and a molar yield of 95.5%.

Reference： [1]Current Patent Assignee: JIANGSU BAJU PHARMACEUTICAL - CN112321535, 2021, A Location in patent: Paragraph 0035; 0042-0056

27
[ 109-01-3 ]
[ 54589-56-9 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydroxide / water; ethanol / 5 h / 20 - 30 °C 2.1: sodium hypochlorite / water / 2 h / 0 - 55 °C 2.2: 1 h / 0 - 5 °C / pH 1 - 2

Reference： [1]Current Patent Assignee: JIANGSU BAJU PHARMACEUTICAL - CN112321535, 2021, A

28
[ 99-94-5 ]
[ 106261-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 1-bromopyrrolidine-2,5-dione; (E)-2,2'-(diazene-1,2-diyl)bis( 2-methylpropanenitrile) / dichloromethane / 6 h / 25 - 30 °C 2.1: triethylamine / methanol / 5 h / 25 - 30 °C 2.2: 1 h / 10 - 15 °C / pH 1 - 2