[ CAS No. 99614-01-4 ]

Name: 99614-01-4|9-Methyl-3-((2-methyl-1H-imidazol-1-yl)methyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one hydrochloride|98%
Brand: Ambeed
SKU: A223247
Rating: 91 (22 reviews)

{[proInfo.proName]} (Synonyms:GR 3832 HCl; SN-37 HCl; NSC665799 HCl) ,{[proInfo.pro_purity]}

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2D 3D

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Quality Control of [ 99614-01-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 99614-01-4 ]

SDS Specification

Alternatived Products of [ 99614-01-4 ]

Product Details of [ 99614-01-4 ]

CAS No. :	99614-01-4	MDL No. :	MFCD00764297
Formula :	C₁₈H₂₀ClN₃O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WRZJOBREMUDSSV-UHFFFAOYSA-N
M.W :	329.82 g/mol	Pubchem ID :	2828191
Synonyms :	1. Ondansetron hydrochloride

Calculated chemistry of [ 99614-01-4 ]

Physicochemical Properties

Num. heavy atoms :	23
Num. arom. heavy atoms :	14
Fraction Csp3 :	0.33
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	94.36
TPSA :	39.82 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.12 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.09
Log Po/w (WLOGP) :	3.93
Log Po/w (MLOGP) :	1.99
Log Po/w (SILICOS-IT) :	2.95
Consensus Log Po/w :	2.39

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.15
Solubility :	0.0233 mg/ml ; 0.0000708 mol/l
Class :	Moderately soluble
Log S (Ali) :	-3.59
Solubility :	0.084 mg/ml ; 0.000255 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.93
Solubility :	0.00391 mg/ml ; 0.0000119 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.2

Safety of [ 99614-01-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 99614-01-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 99614-01-4 ]
Downstream synthetic route of [ 99614-01-4 ]

[ 99614-01-4 ] Synthesis Path-Upstream 1~1

1
[ 99614-01-4 ]
[ 99614-02-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydroxide In ethanol; waterHeating / reflux	680 g of ondansetron hydrochloride dihydrate was dissolved in 4000 ml of ethanol at reflux. A solution of 82 g of NAOH in 1000ML of water was added. A solid was formed. 3000 ml of water was added and the mixture was cooled to ambient temperature. The solid was filtered off and washed with 2*500 ml of water. The solid was dried at 50°C under vacuum for 2 days. The product exhibited the DSC curve shown in fig. 1 and the XRPD pattern of fig. 2. Yield : 527 g (96percent)80 g of ondansetron hydrochloride dihydrate was suspended in 500 ml of ethanol and heated to reflux until a clear solution was obtained. To this solution, 250 ml of a 1 M NAOH solution was added. During addition a solid started to form. 250 ml of water was added and the mixture was slowly cooled to room temperature. The mixture was cooled to 10- 15°C and the solid was filtered off. The solid was washed with 2X200 ml of water. After drying in a vacuumoven at 40°C for 3 days. 59.3 g of a white solid was obtained. The product exhibited the DSC curve shown in fig. 3 and the XRPD pattern of fig. 4. Yield : 59.3 g (92percent)

Reference： [1] Patent: WO2004/63189, 2004, A1, . Location in patent: Page 20-21
[2] Patent: WO2005/80381, 2005, A1, . Location in patent: Page/Page column 17-18

[ 99614-01-4 ] Synthesis Path-Downstream 1~7

1
[ 99614-02-5 ]
[ 99614-01-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; In ethanol; water; at -10 - 20℃; for 2h;Product distribution / selectivity;	Example 12: Synthesis of 12*3n9-tetrahydro-9-methyl-3-[(2-methyl-lH- imidazole-1-yl) methyll-4H-carbazol-4-one hydrochloride dihydrate 29.4 g of 1, 2,3, 9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-l- yl) methyl]-4H- carbazol-4-one obtained in Example 9 was suspended in 300ml of ethanol and 14ml of water, which was then cooled at-10C. 12. 5g of conc. HC1 was slowly added to the reaction mixture, which was then stirred at room temperature for 2 hours. The resulting solid was filtered and washed with cold ethanol, and then dried in vacuous at 35 C to give 32.6 g of title compound (yield 90%).
87%	With hydrogenchloride; pyrographite; In water; at 0 - 100℃; for 5.16667h;pH 1 - 6;	Under nitrogen, 10 g of crude ondansetron base (prepared according to the method described in example 3b of the HU-Pat. 212 785, and in example 3 of the Hungarian patent application Number of P-00-01287; impurity content measured by HPLC: 3.8 %, colour brownish red) is suspended in 150 ml of desalinated water, the pH is adjusted to 6 with concentrated hydrochloric acid at [95-100 C,] 2 g of charcoal is added to the solution, and the mixture is stirred at this temperature for 1 h. The charcoal is filtered off at [95-100 C,] the pH of the filtrate is adjusted to 1-2 with concentrated hydrochloric acid and the solution is cooled slowly, at a rate of not more, than 0. 3 C/min to 20- [25 C,] then after cooling to [0-5 C] the product is filtered off, washed with cooled [(0-5 C)] desalinated water [(2X5] ml), and dried below [35 C.] The obtained dried ondansetron hydrochloride dihydrate is 10.8 g (87 %) (water content: 9.5 %, which is equivalent to 2 mol of water). Additional measured data: the purity of the product is 99.90 w/w % according to HPLC after system peak correction, the total amount of the impurities is 0.10 w/w %, they are 0.03 w/w % (RT 6.76), 0.02 w/w % (RT 7.10) and 0.05 w/w % (RT [8.] 65), respectively. Colour: white, AE = 0.5 on the range of colours Granule size results: <63 [PM 36 %] [&LT;150UM 72%] <250 [URN 95 %] The above results were obtained by the following analytical methods: A. HPLC measurements: Type of the apparatus: Spectra [SYSTEM/TSP] (manufacturer: Thermo Separation Products, USA) Column: LICHROCART 250-4, LICHROSPHER 100 CN (5 [URN)] Eluent : 70 % of 0.02 M [KH2PO4] 30 % of acetonitrile Flow rate: 1.00 ml/min Wavelength: 216 nm Temperature: [25 C] Dissolution of samples: in the eluent B. Colour measurement: Type of the apparatus: Minolta chromometer with CR-200 measuring head. Before measuring the sample the apparatus is calibrated to standard white CR- A43. Measured parameters: L lightness factor [A) CHROMAPARAMETER] b [AE,] the colour deviation from the standard, is calculated from the measured data according to the following equation: AEab = [[(DL) 2] + [(DA)] [2] + (db) [2 % 2] If AEab value is between 0-0.5, the deviation from the white colour is not visible; if tE value is between 0.5-1. 5, in some cases the deviation can be visible to good eyes, this value fulfils a very good colour requirement. C. Granule size: the granule size was determined by sieve analysis, using Alpine [AIRJCT] sieve
85%	With hydrogenchloride; In ethanol; water; at 20 - 70℃;	Example 22 5 g of 1, 2,3, 9-tetrahydro-9-methyl-3-[(2-methyl-lH-imidazol-1-yl) methyl]- 4H-carbazol-4-one obtained in Example 8 was suspended in 50 ml of ethanol and 5 ml of water. 1.9 g of conc. HCl was slowly added to the suspension, which was then stirred for 30 min at room temperature. The reaction mixture was dissolved at 70 C, and then filtered to remove insoluble impurities. The reaction mixture was cooled to room temperature, and solidified for 3 hours. The resulting solid was filtered, washed with cold ethanol, and then dried in vacuous at 25 C to give 5.3 g of a pure title compound as white solid (yield 85%). Example 23 6 g of 1, 2,3, 9-tetrahydro-9-methyl-3- [ (2-methyl-1H-imidazol-1-yl) methyl] - 4H-carbazol-4-one obtained in Example 21 was suspended in 60 ml of ethanol and 6 ml of water. 2.1 g of conc. HCl was slowly added to the suspension, which was then stirred at room temperature for 30min. The reaction mixture was dissolved at 70 C, and then filtered to remove insoluble impurity. The mixture was cooled to ambient temperature, and solidified for 3 hours. The resulting solid was filtered, washed with cold ethanol, and then dried in vacuous at 25 C to give 6.51 g of a pure title compound as a white solid (yield 87%).

49%

With hydrogenchloride; In water; isopropyl alcohol; for 1h;pH 1 - 2;Heating / reflux;

Example 5 Synthesis of Ondansetron Hydrochloride Dihydrate The crude ondansetron from Example 4 (190 grams; 0.65 mol) was suspended in a mixture of isopropanol (1.2 L) and water (0.24 L). Concentrated hydrochloric acid (32% (w/w)) was added until the pH of the mixture was about 1-2 (about 70 mL). The solution was heated to reflux temperature for one hour and then cooled to room temperature. The precipitated crystals were collected by filtration, and dried to provide 117 grams (0.32 mol; 49% yield) of crude ondansetron hydrochloride dihydrate. The purity was determined to be about 98-99% by HPLC. The crude ondansetron hydrochloride dihydrate was recrystallized from a mixture of isopropanol and water (6:1 v/v) to provide a crystalline product having a purity of at least 99.8% by HPLC.

Reference： [1]Patent: WO2005/37822,2005,A1 .Location in patent: Page/Page column 12
[2]Patent: WO2004/35567,2004,A1 .Location in patent: Page 4-6
[3]Patent: WO2005/37823,2005,A1 .Location in patent: Page/Page column 15-16
[4]Patent: US2006/41004,2006,A1 .Location in patent: Page/Page column 8

Yield	Reaction Conditions	Operation in experiment
	With pyrographite; In water; at 5 - 80℃; for 5.16667h;Purification / work up;	Under nitrogen, 10 g of <strong>[99614-01-4]ondansetron hydrochloride</strong> dihydrate of beige colour (AE = 4.2 on the range of colours) is dissolved in 150 ml of ion- exchanged water at [75-80 C.] 2 g of charcoal is added to the homogeneous solution. After 1 h stirring the mixture is filtered and the pH of the filtrate is adjusted to 1-2. The solution is cooled slowly (at a rate of not more, than 0.3 [C/MIN)] to [5-10 C,] stirred at this temperature for 1 h, the product is filtered off, washed 2x5 ml of desalinated water at [5-10 C,] and dried below 35 [C.] Dried weight: 9.6 g (96 %) The colour of the product is white, AE = 0.55 on the range of colours The amount of the impurities in the product: The purity of the product is 99.92 [W/W] % according to HPLC after system peak correction, the total amount of the impurities is 0.08 w/w %, they are 0.01 w/w % (RT [2.] 08), 0.01 w/w % (RT 2.43), 0.02 w/w % (RT 6.51), 0.01 [W/W] % (RT 6.83) and 0.03 w/w % (RT 7. [74),] respectively. Granule size results: <63 um 31 % <150 [LLM 71 %] [&LT;250 UM 97 %] These results were obtained according to the methods described in example 1.

3
[ 99614-01-4 ]
[ 99614-02-5 ]

Yield	Reaction Conditions	Operation in experiment
92 - 96%	With sodium hydroxide; In ethanol; water;Heating / reflux;	680 g of <strong>[99614-01-4]ondansetron hydrochloride</strong> dihydrate was dissolved in 4000 ml of ethanol at reflux. A solution of 82 g of NAOH in 1000ML of water was added. A solid was formed. 3000 ml of water was added and the mixture was cooled to ambient temperature. The solid was filtered off and washed with 2*500 ml of water. The solid was dried at 50C under vacuum for 2 days. The product exhibited the DSC curve shown in fig. 1 and the XRPD pattern of fig. 2. Yield : 527 g (96%)80 g of <strong>[99614-01-4]ondansetron hydrochloride</strong> dihydrate was suspended in 500 ml of ethanol and heated to reflux until a clear solution was obtained. To this solution, 250 ml of a 1 M NAOH solution was added. During addition a solid started to form. 250 ml of water was added and the mixture was slowly cooled to room temperature. The mixture was cooled to 10- 15C and the solid was filtered off. The solid was washed with 2X200 ml of water. After drying in a vacuumoven at 40C for 3 days. 59.3 g of a white solid was obtained. The product exhibited the DSC curve shown in fig. 3 and the XRPD pattern of fig. 4. Yield : 59.3 g (92%)
	With ammonia; In methanol; water; at 30℃; for 2h;pH 9;	Example 5; Preparation of Base ondansetron Form E (industrial plant method); A stirred suspension of 16 kg of <strong>[99614-01-4]ondansetron hydrochloride</strong> in 80 L of methanol and 80 L of water is heated at 30 C to total dissolution. 6 L of 25% aqueous ammonia is added over the course of 2 hours, until pH 9 is reached. Base ondansetron precipitates out and the resulting suspension is heated to 35 C and stirred at that temperature for 1 hour. It is then cooled to 22-25 C and the suspension is centrifuged. The resulting cake is washed with water (2 x 40 L) and suspended again in 60 L of water. The suspension is stirred at 35 C for 30 minutes, cooled to 22-25C and centrifuged again, washing finally with water (2 x 40 L). The water-moistened solid is suspended in 180 L of methanol and the mixture brought to reflux with stirring for 1 hour. The suspension fluidises but does not reach dissolution. It is cooled to 20-22 C and the suspension is stirred for 30 minutes. It is cooled to 0-5 C and the suspension is stirred for 1 hour at that temperature. The suspension is centrifuged and the cake washed with 20 L of cold methanol. The product is dried at 60C in vacuo for 15 hours. 10.8 kg of base ondansetron Form E (84%) is obtained.

Reference： [1]Patent: WO2004/63189,2004,A1 .Location in patent: Page 20-21
[2]Patent: WO2005/80381,2005,A1 .Location in patent: Page/Page column 17-18

4
[ 693-98-1 ]
[ 27387-31-1 ]
[ 51-80-9 ]
[ 99614-01-4 ]

Yield	Reaction Conditions	Operation in experiment
78%		Example 13: Synthesis of 1, 2, 3, 9-tetrahydro-9-methyl-3-F (2-methyl-IH- imidazole-1-yl methyl]-4H-carbazol-4-one hydrochloride dihydrate To the solution of 11 ml of acetyl chloride in 350 ml of actonitrile, was slowly added 21 ml of N, N, N', N'-tetramethyldiaminomethane at 0C, which was then stirred for 10min. 20 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4- one and 50 g of 2-methyl imidazole was subsequently added to the reaction mixture under reflux. After completion of reaction, the resulting solid was filtered and washed with acetonitrile and water, and then dried. The resulting solid was suspended in 250 ml of ethanol, and 11 ml of cone. HCl was slowly added thereto, which was then stirred for 2 hours. The resulting solid was filtered and washed with cold ethanol, and then re-crystallized with water to give 28.3 g of pure white title compound (yield 78%).
53%		Example 3: Synthesis of 123z9-tetrahydro-9-methyl-3-[(2-methyl-lH- imidazole-l-yl . methyll-4H-carbazol-4-one hydrochloride dihydrate 2.0 g of 1, 2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one, 1.65 g of 2- methyl imidazole and 2 ml of N, N, N', N'-tetramethyldiaminomethane were suspended in 5 ml of acetonitrile and 30 ml of toluene, and then 4 ml of chlorotrimethylsilane was slowly added thereto. The reaction mixture was stirred under reflux for 10 hours. The reaction mixture was concentrated to remove the solvent, and then 50 ml of water was added to the resulting residue. The resulting solid was filtered and dried, which was then suspended in acetone and stirred for 3 hours. The resulting solid was filtered and dried under a reduced pressure, which was then suspended in acetone, and then HCl was slowly added to thereto. The resulting suspension was stirred for 3 hours and cooled at 10C and below, which was then additionally stirred for 1 hour. The resulting solid was filtered and washed with acetone. The resulting solid was suspended in dichloromethane, which was then stirred under reflux for 1 hour and cooled at room temperature. The resulting solid was filtered and recrystallized with 10% aq. isopropyl alcohol to give 1.94 g of title compound (yield 53%).

Reference： [1]Patent: WO2005/37822,2005,A1 .Location in patent: Page/Page column 12
[2]Patent: WO2005/37822,2005,A1 .Location in patent: Page/Page column 8

Yield	Reaction Conditions	Operation in experiment
		Preparation of Ondansetron Form A Monohydrate from Ondansetron Hydrochloride Form A Dihydrate Example 12 Ondansetron hydrochloride Form A dihydrate (5 g) in 70 ml of a 96% aqueous solution of EtOH was heated to reflux temperature for 22 hrs. The reaction mixture was then allowed to cool to room temperature and then was cooled to 0 C. The solid that precipitated was filtered and dried at 65 C. for 20 hrs, yielding 1.2 g of ondansetron hydrochloride Form A monohydrate, KF =5.4%. Example 13 Ondansetron hydrochloride Form A dihydrate (5.0 g) in 70 ml of a 90% aqueous solution of EtOH was heated to reflux temperature for 22 hrs. The reaction mixture was allowed to cool to room temperature and then cooled to 0 C. The solid was then filtered, dried at 65 C. for 20 hrs. to give 4.0 g of ondansetron hydrochloride Form A monohydrate; KF =5.0%. Example 14 Ondansetron hydrochloride Form A dihydrate (5.0 g) was slurried in 70 ml of a 90% aqueous solution of EtOH at room temperature for 22 hrs. The solid was then filtered, dried at 65 C. for 20 hrs. to give 3.5 g of ondansetron hydrochloride Form A monohydrate; KF =5.2%. Example 15 Ondansetron hydrochloride Form A dihydrate (5 g) was slurried in 70 ml of a 50% aqueous solution of EtOH at room temperature for 22 hrs. Methyl ethyl ketone (100 ml) was then added to preciptate the ondansetron hydrochloride. The mixture was cooled to 0 C. and the precipitate was filtered and dried at 65 C. for 20 hrs. to give 0.4 g of ondansetron hydrochloride Form A monohydrate; KF =5.2%. Example 16 Ondansetron hydrochloride Form A dihydrate (5 g) was slurried in 70 ml of a 50% aqueous solution of EtOH at room temperature for 22 hrs. The solid was then filtered, dried at 65 C. for 20 hrs. to give 0.4 g of ondansetron hydrochloride Form A monohydrate; KF =5.7%. Some of the compound was recovered from the mother liquor by adding 125 ml of MEK for precipitation and filtering under vacuum. The solid was dried at 65 C. for 20 hrs. to give 1.7 g of ondansetron hydrochloride Form A monohydrate; KF 5.4%. Example 17 Ondansetron hydrochloride Form A dihydrate (5 g) was slurried in 70 ml of a 96% aqueous solution of EtOH at room temperature for 22 hrs. The solid was then filtered and dried at 65 C. for 20 hrs. to give 3.8 g of ondansetron hydrochloride Form A; KF =6.1 %.

Yield	Reaction Conditions	Operation in experiment
46%		Step 2 9-Methyl-3-(2-methyl-imidazol-1ylmethyl)-1,2,3,9-tetrahydro-carbazol-4-one hydrochloride: At about 0 C., hydrochloric gas was introduced over a period of about 30 minutes to a stirred solution of 9-methyl-3-((2-methyl-1H-imidazol-1-yl)methyl)-2,3-dihydro-1H-carbazol-4(9H)-one (190 mg, 0.65 mmol, 1.00 equiv) and methanol (20 mL). The resulting mixture was concentrated in vacuo, and the resulting residue was purified by re-crystallization from methanol to give the title compound as a light yellow solid (100 mg, yield=46%). 1H NMR (300 MHz, CDCl3) delta: 8.07 (d, J=8.1 Hz, 1H), 7.61(s, 1H), 7.45-7.61 (m, 2H), 7.22-7.33 (m, 2H), 4.72 (dd, J=6.9, 14.4 Hz, 1H), 4.40 (dd, J=6.9, 14.4 Hz, 1H), 3.77 (s, 3H), 3.00-3.30 (m, 3H), 2.73 (s, 3H), 2.30-2.48 (m, 1H), 2.00-2.20 (m, 1H); LC-MS: m/z=310 (MH)+.
		After stirring at 0 C. for 1 hour, the solid was filtered under vacuum and dried under vacuum at 50 C. to give 90 mg of ondansetron hydrochloride Form A. KF=10%.
		Ondansetron base (400 mg, 1.36*10-3 mole) was suspended in 12 ml of absolute ethanol at room temperature. The suspension was heated to reflux to dissolve the ondansetron. After 20 min. of stirring at reflux, an ethanolic solution containing 1.1 equivalents of HCl was added. The reaction mixture was stirred at this temperature for an additional 10 min and then cooled slowly to 0 C. After stirring at 0 C. for 1 hour, the solid was filtered under vacuum and dried under vacuum at 50 C. to give 536 mg of ondansetron hydrochloride Form A. KF=8.1%.

		Ondansetron base (2.5 g, 8.5*10-3 mole) was dissolved in 87.5 ml of chloroform at room temperature. Then 1.1 eq of HCl gas was bubbled into the solution over 20 min. The reaction mixture was stirred at room temperature for an additional 30 min. The solid was filtered under vacuum and dried under vacuum at 50 C. to give 2.5 g of ondansetron hydrochloride Form A.
		Ondansetron base (400 mg, 1.36*10-3 mole) was suspended in 40 ml of absolute ethanol at room temperature. The suspension was heated to reflux to dissolve the ondansetron. After 20 min. of stirring at reflux, an ethanolic solution containing 1.5 equivalents of HCl was added. The reaction mixture was stirred at this temperature for an additional 10 min and then cooled slowly to 0 C. After stirring at 0 C. for 1 hour, the solid was filtered under vacuum and dried under vacuum at 50 C. to give 320 mg of ondansetron hydrochloride Form A. KF=8.1%.
		Ondansetron base (400 mg, 1.36*10-3 mole) was suspended in 20 ml of absolute ethanol at room temperature. The suspension was heated to reflux to dissolve the ondansetron. After 20 min. of stirring at reflux, a solution containing 1.1 equivalents of HCl in isopropanol was added. The reaction mixture was stirred at this temperature for an additional 10 min and then cooled slowly to 0 C. After stirring at 0 C. for 1 hour, the solid was filtered under vacuum and dried under vacuum at 50 C. to give 290 mg of ondansetron hydrochloride Form A. KF=9.5%.
		Ondansetron base g (5 g, 17.06*10-3 mole) was dissolved in 175 ml of chloroform at room temperature. Then HCl gas was bubbled at room temperature for 15 min. 0.6 equivalent of H2O was added slowly to the reaction mixture. The reaction mixture was stirred at room temperature for an additional 3 hrs. Then, the solid was filtered under vacuum and dried under vacuum at 50 C. to give 6.3 g of ondansetron hydrochloride Form A. KF=8.4%.
		Ondansetron base (5 g, 17.06*10-3 mole) was suspended in a mixture of H2O/CHCl3 (140/20 v/v) at room temperature. The reaction mixture was heated to reflux temperature and then 1.1 eq. of 1 N aqueous HCl was added by syringe pump at 1 ml/min. The reaction mixture was stirred at room temperature for 30 min. and then slowly cooled to 5 C. The partial precipitation that was obtained during cooling was filtered (1.7 g) under vacuum and dried under vacuum at 50 C. to give a white solid. The mother liquor was left overnight at room temperature to give an extra precipitate (1.7 g) that was filtered and dried under vacuum. Both fractions gave ondansetron hydrochloride Form A.
		Ondansetron base (2.5 g, 8.5*10-3 mole) was dissolved in 80 ml of chloroform at room temperature. Then 1.1 eq of HCl gas was bubbled into the solution over 20 min. The reaction mixture was stirred at room temperature for an additional 30 min. The solid was filtered under vacuum and dried under vacuum at 50 C. to give 2.8 g of ondansetron hydrochloride Form A. KF=5.4%.
		Ondansetron base (5 g) (17.0*10-3 mole) was suspended in 250 ml of absolute ethanol, EtOH. Then, an ethanolic solution of HCl (1.5 eq) was added. The reaction mixture was warmed (45 C.) to get a clear solution. The reaction mixture was allowed to cool to room temperature and then dry ether was added (430 ml) to precipitate a solid. The precipitate was filtered under vacuum and dried in oven 65 C. for 24 hours to give 3.16 g of ondansetron hydrochloride Form B anhydrous. KF=1.7%.
		Ondansetron base (2.0 g, 6.8*10-3 mole) was suspended in MEK (220 ml) for 30 minute until a complete dissolution occurred. Then HCl gas was bubbled until the solution reached pH=1. The reaction mixture was refluxed for an additional 1 hour, cooled to at room temperature, filtered under vacuum and dried at 65 C. for 20 hrs. The white solid obtained was slurried in absolute ethanol (70 ml) at room temperature for 22 hours, using CaCl2 tube. The reaction mixture was then filtered under vacuum and dried at 65 C. for 20 hrs to give 1.9 g of ondansetron hydrochloride Form B anhydrous.
		Ondansetron base (5 g) (17.0*10-3 mole) was suspended in 250 ml of absolute ethanol. Then, an ethanolic solution of HCl (1.5 eq) was added. The ethanolic solution was prepared by bubbling HCl gas into absolute ethanol under dry conditions. The reaction mixture was warmed (45 C.) to get a clear solution, and a hot filtration of the clear solution was done. To this filtrate was added, at room temperature, dry ether (430 ml) to precipitate a solid. The precipitate was filtered under vacuum and dried in oven 65 C. for 18 hours to give 3.16 g of ondansetron hydrochloride Form B anhydrous. KF=1.0%
		Ondansetron base (3 g) (10.*2 10-3 mole) was suspended in MEK (330 ml) for 15 minutes until a complete dissolution occurred. Then an ethanolic solution of HCl (1.5 eq) was added. The reaction mixture was refluxed for an additional 30 minutes, cooled to at room temperature, filtered under vacuum and dried at 65 C. for 20 hrs. The white solid obtained was then slurried in 105 ml of a mixture EtOH abs/IPA (65/40 ml) at room temperature for 22 hours, using CaCl2 tube. Then the reaction mixture was filtered under vacuum and dried at 65 C. for 20 hrs to give 3.16 g of ondansetron hydrochloride Form B anhydrous.
8.7 g (77%)		Ondansetron base (10 g, 34.1 mmol, 1 eq.), 250 ml absolute ethanol and 8.4 ml of 23.3% HCl in ethanol (51.2 mmol, 1.5 eq.) were added to a 500 ml round bottle flask equipped with a calcium chloride tube and a mechanical stirrer. The mixture was stirred at room temperature for 66 hours. The solid was then filtered, washed with absolute ethanol (2*20 ml) and dried at 65 C. for 20 hours to obtain 8.7 g (77%) of ondansetron hydrochloride Form B, KF=0.66%.
8.5 g (76%)		Ondansetron base (10 g. 34.1 mmol, 1 eq.), 250 ml absolute ethanol and 8.4 ml of 23.3% HCl in ethanol (51.2 mmol, 1.5 eq.) were added to a 500 ml round bottle flask equipped with a calcium chloride tube, a mechanical stirrer and a condenser. The mixture was heated to reflux to obtain a clear solution for about 30 min. The reaction mixture was then cooled to room temperature during which time a precipitation was formed. The reaction mixture was stirred for an additional 45 hours. The solid was then filtered, washed with absolute ethanol (2*20 ml) and dried at 65 C. for 20 hours to obtain 8.5 g (76%) of ondansetron hydrochloride Form B, KF=0.34%.
		Ondansetron hydrochloride Form A dihydrate (5 g) in absolute EtOH/toluene (45 ml/20 ml) was heated to reflux temperature for a few hours. After stirring at room temperature overnight, the solid was filtered under vacuum and dried in a vacuum oven at 50 C. for 16 hours to give 4.0 g of ondansetron hydrochloride Form A; KF =7.8%. Example 24 Ondansetron hydrochloride dihydrate Form A (2.1 g) in a mixture of EtOH/toluene (45 ml/20 ml) were heated to reflux temperature. Then 25 ml of the solvent was distilled off at atmospheric pressure. The reaction mixture was then allowed to cool to 10 C. over 3 hrs. The white precipitate was filtered under vacuum and dried in a vacuum oven at 50 C. for 5 hrs. to give 1.4 g of ondansetron hydrochloride Form A; KF =8.8%
		Preparation of Ondansetron Hydrochloride Form C Example 33 Ondansetron base (1.5 g, 5.11*10-3 mole) was dissolved in absolute ethanol(150 ml) freshly distilled at reflux temperature. Then an ethanolic solution of HCl (1.1 eq) was added at reflux. The reaction mixture was stirred for 20 minutes and allowed to cool slowly to room temperature. A very thick precipitate appeared at room temperature. The mixture was then filtered under vacuum to give 536 mg of a white solid. The ethanolic phase was evaporated under reduced pressure to give 824 mg of ondansetron hydrochloride Form C. KF=9.9%
		Ondansetron base (5 g) (17.010-3 mole) was suspended in absolute ethanol (150 ml) freshly distilled with 10 g of 4A molecular sieves. The reaction mixture was heated to 80 C. until the complete dissolution of the starting material. Then an ethanolic solution of HCl (1.5 eq) was added dropwise at this temperature and the reaction mixture was stirred for 15 minutes. The mixture was allowed to cool slowly to room temperature and then to 0 C. to complete the precipitation. The solid mixture was then filtered under vacuum, washed 3 times with IPA (310 ml) to give 3.07 g of a white solid. The ethanolic phase was left at 4 C. overnight and then the precipitate was filtered under reduced pressure to give 600 mg of a solid. The mother liquor of this fraction was then evaporated under reduced pressure to give 1 g of ondansetron hydrochloride Form C. KF=9.9%
		The resulting solid was stirred in absolute EtOH for 30 minutes at -10 C. and then gravity filtered. The solid was dried in oven at 65 C. for 18 hours to afford 1.31 g of ondansetron hydrochloride Form D. KF=3.84%
		Preparation of Ondansetron Hydrochloride Form E Example 36 Ondansetron hydrochloride Form A (5 g, 13.6*10-3 mole) was slurried in IPA (70 ml), at room temperature overnight. The white solid was then filtered under vacuum and dried in an oven 65 C. for 24 hours to afford 4.9 g of ondansetron hydrochloride Form E as a white solid. KF=1.8%.
		Ondansetron hydrochloride Form A (5 g, 13.6*10-3 mole) was slurried in IPA (40 ml) at reflux temperature overnight. The white solid was filtered under vacuum and dried in oven at 65 C. for 24 hours to afford 5 g of ondansetron hydrochloride Form E as a white solid. KF=2.1%.
		Preparation of Ondansetron Hydrochloride Form H Example 38 Ondansetron base (5 g) (17.0*10-3 mole) was suspended in 250 ml of absolute EtOH. Then, an ethanolic solution of HCl (1.5 eq) was added. The reaction mixture was warmed (45 C.) until a clear solution was obtained, and a hot filtration of the clear solution was done. To this filtrate was added tert-butyl methyl ether (200 ml) to deposit a solid. Then the precipitate was filtered under vacuum and dried in oven at 65 C. for 24 hours to give 0.4 g of ondansetron hydrochloride Form H. KF=1.7%.
		The solid that crystallized was filtered off, washed with ice-cold, dry dimethylformamide (32 ml) and dry ether (210 ml) and then dried. The resulting solid (0.60 g) was suspended in a mixture of absolute ethanol (30 ml) and ethanolic hydrogen chloride (1 ml), and warmed gently to obtain a solution, which was filtered whilst warm. The filtrate was then diluted with dry ether to deposit a solid (0.6 g) which was recrystallized from absolute ethanol to give the title compound as a solid (0.27 g) m.p. 186-187. Analysis--Found: C,61.9;H,6.4;N,11.8. C18 H19 N3 O.HCl.H2 O requires C,62.3;H,6.1;N,12.1%.

7
2,3,4,9-Tetrahydro-N,N,N,9-tetramethyl-4-oxo-1H-carbazole-3-methanaminium iodide [ No CAS ]
[ 693-98-1 ]
[ 99614-01-4 ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide; ethanol;	1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]4H-carbazol-4-one hydrochloride A solution of 2,3,4,9-tetrahydro-N,N,N,9-tetramethyl-4-oxo-1H-carbazole-3-methanaminium iodide (2.0 g) and 2-methylimidazole (5.0 g) in dry dimethylformamide (30 ml) was stirred, under nitrogen, at 95 for 16.75 h and then allowed to cool. The solid that crystallized was filtered off, washed with ice-cold, dry dimethylformamide (32 ml) and dry ether (210 ml) and then dried. The resulting solid (0.60 g) was suspended in a mixture of absolute ethanol (30 ml) and ethanolic hydrogen chloride (1 ml), and warmed gently to obtain a solution, which was filtered whilst warm. The filtrate was then diluted with dry ether to deposit a solid (0.6 g) which was recrystallized from absolute ethanol to give the title compound as a solid (0.27 g) m.p. 186-187. Analysis Found: C, 61.9; H, 6.4; N, 11.8. C18 H19 N3 O.HCl.H2 O requires C, 62.3; H, 6.1; N, 12.1%.

Reference： [1]Patent: US4753789,1988,A

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[ CAS No. 99614-01-4 ]

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