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[ CAS No. 145821-59-6 ] {[proInfo.proName]}

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Chemical Structure| 145821-59-6
Chemical Structure| 145821-59-6
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Product Details of [ 145821-59-6 ]

CAS No. :145821-59-6 MDL No. :MFCD07369025
Formula : C20H26ClNO2S2 Boiling Point : -
Linear Structure Formula :- InChI Key :YUKARLAABCGMCN-PKLMIRHRSA-N
M.W : 412.01 Pubchem ID :91274
Synonyms :
TGB hydrochloride;NO328 hydrochloride;Tiagabine;NO 328;NO 050328;HSDB 7527;Gabatril;(R)-Tiagabine;ABT-569;Tiagabine (hydrochloride);Gabitril hydrochloride;NO050328 hydrochloride;Tiagabine hydrochloride

Calculated chemistry of [ 145821-59-6 ]

Physicochemical Properties

Num. heavy atoms : 26
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.45
Num. rotatable bonds : 6
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 118.6
TPSA : 97.02 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.36 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 3.45
Log Po/w (WLOGP) : 5.47
Log Po/w (MLOGP) : 3.54
Log Po/w (SILICOS-IT) : 6.41
Consensus Log Po/w : 3.77

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.46
Solubility : 0.0144 mg/ml ; 0.0000349 mol/l
Class : Moderately soluble
Log S (Ali) : -5.17
Solubility : 0.00279 mg/ml ; 0.00000678 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -4.94
Solubility : 0.00477 mg/ml ; 0.0000116 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 4.06

Safety of [ 145821-59-6 ]

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

Application In Synthesis of [ 145821-59-6 ]

* 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.

  • Downstream synthetic route of [ 145821-59-6 ]

[ 145821-59-6 ] Synthesis Path-Downstream   1~32

  • 1
  • [ 145821-59-6 ]
  • [ 2125725-84-8 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With metalloporphyrin; dihydrogen peroxide In dichloromethane; water for 8h; Ambient temperature;
  • 2
  • [ 145821-59-6 ]
  • [ 30717-55-6 ]
  • [ 2125725-84-8 ]
YieldReaction ConditionsOperation in experiment
41% With potassium osmate; potassium carbonate; 9-O-(9'-phenanthryl) ether of dihydroquinidine; potassium ferrocyanide In 1,4-dioxane; water for 72h; Ambient temperature;
  • 3
  • [ 145821-59-6 ]
  • [ 2125725-84-8 ]
YieldReaction ConditionsOperation in experiment
for 168h; 6000 lux;
  • 4
  • [ 145821-59-6 ]
  • [ 161014-55-7 ]
YieldReaction ConditionsOperation in experiment
for 4320h; Ambient temperature;
  • 5
  • [ 145821-59-6 ]
  • [ 115103-54-3 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate In water at 20℃; for 3h; 1.A Preparation and Characterization of Tiagabine Free Base Form A Method A(1) Tiagabine hydrochloride monohydrate (4.12 g) was dissolved in a solution of NaHCO3 (0.84 g) in H2O (40 mL) to give a clear yellow solution. The solution was extracted with dichloromethane (40 mL 2) and the organic phases combined and dried over MgSO4. The MgSO4 was removed by filtration and the filtrate was concentrated by rotary evaporation. The resulting residue was dissolved in ethanol. (2) Tiagabine hydrochloride monohydrate (4.12 g) was suspended in H2O (20 mL). A solution of NaHCO3 (0.88 g) in H2O (20 mL) was added, resulting in a clear solution. The solution was extracted with CH2Cl2 (30 mL 2). The organic phases were combined and dried over MgSO4. The MgSO4 was removed by filtration and the filtrate was concentrated to a residue. (3) Tiagabine hydrochloride monohydrate (125.1 g, 0.304 mol) was suspended in H2O (200 mL). A suspension of NaHCO3 (28.0 g, 0.333 mol) in H2O (300 mL) was added over a period of two (2) hours. The mixture was stirred for one (1) hour at ambient temperature, resulting in a clear solution. The solution was extracted with dichloromethane (1000 mL 1; 500 mL 1) and the organic phases combined. After drying over MgSO4, the solution was filtered and the filtrate concentrated to a foam.
With sodium hydroxide In water Aqueous phosphate buffer; Sonographic reaction; No light exposure; 1.C; 1.D Preparation and Characterization of Tiagabine Free Base Form A Method CA 0.1M phosphate buffer was generated by dissolving 1.29 g of sodium phosphate monobasic and 1.39 g of sodium phosphate dibasic (anhydrous) in 120 mL of water. The solution pH was 6 using colorPhast strips. Tiagabine hydrochloride monohydrate (2.15 g) and NaOH (0.20 g) were dissolved in 90 mL of the buffer. The resulting solution was extracted with of dichloromethane (3 150 mL). The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and evaporated to dryness to give a light yellow solid (crude yield=1.74 g).Method DA 0.1M phosphate buffer was generated by dissolving 2.58 g of sodium phosphate monobasic and 2.78 g of sodium phosphate dibasic (anhydrous) in 240 ml of water. The pH was found to be 6 using colorPhast strips. Tiagabine hydrochloride monohydrate (4.31 g) and 0.40 g of NaOH were dissolved in 180 mL of the buffer. Sonication was used to assist in the dissolution of the solid. The flask was shielded from exposure to light. The resulting solution was extracted with dichloromethane (3 300 mL). The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and evaporated to dryness to give a light yellow solid (crude yield=3.28 g). This product was dissolved in a minimal amount of hot ethanol using sonication to assist in the dissolution. The solution was filtered through a 0.2 ?m syringe filter into a clean vial. The solution was allowed to stand at 3 C. for 24 hours. The resulting solid was collected by filtration and allowed to dry at room temperature. The solid was stored in a vacuum desiccator (yield=2.55 g).A dichloromethane solution was prepared by dissolving 182 mg of the resulting tiagabine free base in 5 mL of dichloromethane. The solution was filtered through a 20 ?m filter prior to use.
Stage #1: tiagabine hydrochloride With sodium hydroxide In dichloromethane; water at 20℃; for 1 - 2.5h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water at 20℃; for 1 - 2h; 1.B Preparation and Characterization of Tiagabine Free Base Form A Method B (1) Tiagabine hydrochloride monohydrate (4.12 g, 0.01 mol) was suspended in dichloromethane (100 mL). A solution of NaOH (0.38 g, 0.0095 mol) in H2O (5 mL) was added and the mixture was stirred for one (1) hour at ambient temperature to give an almost clear solution. NaHCO3 (0.17 g, 0.002 mol) was added and the mixture was stirred for another one (1) hour at ambient temperature. The organic phase was separated and dried over MgSO4. The MgSO4 was removed by filtration and the filtrate concentrated to an oil. The oil was dissolved in ethanol (20 mL), seeded with tiagabine free base Form A, and refrigerated. The resulting precipitate was collected by filtration and dried under vacuum at ambient temperature for about four (4) hours. XRPD analysis of the sample indicated a mixture of tiagabine free base Forms A and B. (2) Tiagabine hydrochloride monohydrate (113.5 g, 0.275 mol)) was suspended in dichloromethane (1000 mL). A solution of NaOH (10.46 g, 0.262 mol) in H2O (150 mL) was added over a period of 30 minutes. The mixture was stirred for two (2) hours at ambient temperature. NaHCO3 (4.63 g, 0.055 mol) was added and the mixture was stirred for another two (2) hours at ambient temperature. The organic phase was separated and the aqueous layer extracted with an additional 200 mL of dichloromethane. The organic phases were combined and dried over MgSO4. The MgSO4 was removed by filtration and the filtrate concentrated to a foam. (3) Tiagabine hydrochloride monohydrate (103.0 g, 0.25 mol)) was suspended in CH2Cl2 (1000 mL). A solution of NaOH (9.5 g, 0.238 mol) in H2O (150 mL) was added over a period of 30 minutes. The mixture was stirred for one (1) hour at ambient temperature. NaHCO3 (4.2 g, 0.05 mol) was added and the mixture stirred for another two (2) hours at ambient temperature. The organic phase was separated and the aqueous layer extracted with an additional 200 mL of dichloromethane. The organic phases were combined and dried over MgSO4. After filtering off the MgSO4, the filtrate was concentrated to an off-white foam.
  • 6
  • [ 88-14-2 ]
  • [ 145821-59-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
In methanol for 0.1h; Agate ball mill used; 15.1 Method 1Tiagabine hydrochloride monohydrate (0.0863 grams), 2-furancarboxylic acid (0.0226 grams) and methanol (1 drop) were charged to an agate lined canister. The mixture was processed using an agate ball mill for approximately 2 minutes using a Retsch mm200 milling apparatus set at 30 Hz. The solids were scraped from the sides of the canister and milled for an additional 4 minutes at 30 Hz.
for 0.0833333h; Agate ball mill used; 15.2 Method 2Tiagabine hydrochloride monohydrate (ca. 58 mg) and 2-furancarboxylic acid (ca. 15 mg) were processed using an agate ball mill for approximately 5 minutes using a Retsch mm200 milling apparatus. Approximately 56 mg of solid was isolated from the grinding jar.
  • 7
  • [ 115103-54-3 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride In dichloromethane; water at 20℃; for 1h;
With hydrogenchloride In methanol; dichloromethane; chloroform at 3℃; for 24h; 16 Example 16Preparation and Characterization of Tiagabine Hydrochloride Form G182 mg of tiagabine free base was dissolved in 5 mL dichloromethane. Approximately 50 ?L of the resulting solution was delivered to the well of a well plate. The solvent was evaporated under high vacuum for 4 hours, producing a clear glass. Chloroform (approximately 50 ?L) was added to the well and the solution reacted with 50 ?L of 0.1M HCl solution in methanol. The plate was sealed and stored at 3 C. for 24 hours after which time solids were precipitated with cyclohexane (30 ?L). The plate was store at 3 C. for 24 hours and then the solvent allowed to slowly evaporate at room temperature.
  • 8
  • [ 145821-57-4 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
In isopropyl alcohol at 20℃; 1.1; 1.2 Preparation Method 1Approximately 127 mg of tiagabine HCl monohydrate was dissolved in approximately 0.75 mL of 2-propanol. A clear solution was obtained at first and solid quickly precipitated out. The sample was capped and placed in hood at ambient temperature overnight. The liquid was decanted and the remaining solids were air dried. Preparation Method 2A saturated solution of tiagabine HCl monohydrate in 2-propanol was filtered through a 0.2 μm nylon filter into a vial. The resulting solution in an open vial was allowed to evaporate quickly until dryness. A white, needle-like, solid was obtained.
In ethanol at 20℃; for 96h; 5.1; 5.2 Preparation Method 1Approximately 98 mg of tiagabine HCl monohydrate was dissolved in approximately 1 mL of EtOH to give a clear solution. The solution was placed in a refrigerator overnight. The liquid was decanted and the remaining solids were air dried.Preparation Method 2A mixture of 180 mg of tiagabine HCl monohydrate and 3 mL of EtOH was slurried for 4 days at room temperature. The white solids were collected by filtration and air dried.
In acetone at 20℃; for 96h; 13 A mixture of 114 mg of tiagabine HCl monohydrate and 4 mL of acetone was slurried for 4 days at room temperature. The white solids were collected by filtration and air dried.
In acetone at 20℃; Heating / reflux; 4 A mixture of 103 mg of tiagabine HCl monohydrate and 10 mL of acetone was heated at reflux on a hotplate to give a clear solution. The resulting solution was left on the hotplate and allowed to slow cool to ambient temperature after the heating was discontinued. The liquid was decanted and the remaining white solids were air dried.
at 150℃; for 0.166667h; Heating / reflux; 16 Approximately 501 mg of tiagabine HCl monohydrate was heated at 1500C under nitrogen atmosphere for about 10 minutes. It was observed that some solids on the bottom were partially melted. The sample was then stored under subambient conditions in a desiccator containing phosphorus pentoxide.
In dichloromethane at 20℃; for 24 - 96h; 6.1; 6.3 Preparation Method 1A mixture of 120 mg of tiagabine HCl monohydrate and 5 mL of dichlorom ethane was slurried for 1 day at room temperature. The white solids were collected by filtration and air dried. Preparation Method 3A mixture of tiagabine HCl monohydrate (88 mg) and dichloromethane (4 mL) was slurried for four (4) days at room temperature. The white solids were collected by filtration and air dried.
In cyclohexane; acetone 10.3 Tiagabine HCl monohydrate (116 mg) was mixed with acetone (10 mL). Cyclohexane (10 mL) was added. White solids were collected by decantation.
In 1,4-dioxane at 20℃; for 144h; 7.1 A mixture of 99 mg of tiagabine HCl monohydrate and 5 mL of 1,4-dioxane was slurried for 6 days at room temperature. The white solids were collected by filtration and air dried.
In water; acetonitrile at 20℃; 2.4 Tiagabine HCl monohydrate (88 mg) was dissolved in acetonitrile/water (1/1, v/v) and filtered through a 0.2 μm filter. The solvent was allowed to evaporate under ambient conditions. The resulting gummy residue was treated with acetonitrile (1 mL) and the sample placed on a shaker block. Solids formed after approximately two (2) hours and were collected by decantation of the liquid phase after one (1) day.
In acetonitrile at 20℃; for 0.5h; Heating / reflux; 2.1 A mixture of 99 mg of tiagabine HCl monohydrate and 10 mL of acetonitrile was heated at reflux on a hotplate for about 30 min to give a clear solution. The resulting solution was left on the hotplate and allowed to slow cool to ambient after the heating was discontinued. The liquid was decanted and the remaining white solids were air dried.
In acetonitrile at 20℃; for 96h; 2.2; 2.3 Preparation Method 2 A saturated solution of tiagabine HCl monohydrate in acetonitrile was filtered through a 0.2 μm nylon filter into a vial. The resulting solution in an open vial was allowed to evaporate quickly until dryness. A white, blade-like, solid was obtained.Preparation Method 3 A mixture of 122 mg of tiagabine HCl monohydrate and 4 mL of acetonitrile was slurried for 4 days at room temperature. A white solid was collected by filtration and air dried.
In acetone at 0℃; for 1.08333h; Heating / reflux; 10.1 A mixture of 115 mg of tiagabine HCl monohydrate and 10 mL of acetone was heated at reflux for about 5 minutes to give a saturated solution. The remaining solids were removed by filtration. The filtrate was collected and cooled in an ice/water bath for about 1 hour. A white precipitate was formed. The liquid was decanted and the remaining white solids were allowed to air dry.
In methanol at 20℃; for 288h; 8.3 Tiagabine HCl monohydrate (130 mg) was dissolved in methanol (250 μL) and refrigerated for 5 days. The solution was removed from the refrigerator and the solvent was evaporated under ambient conditions. The resulting glassy residue was'treated with methanol (100 μL), capped, covered with Parafilm, and slurried for 7 days during which time solids formed.

Reference: [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 21-22
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 28
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 42
[4]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 27
[5]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 46
[6]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 30
[7]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 38
[8]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 31
[9]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 23
[10]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 23
[11]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 23
[12]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 37
[13]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/21518, 2008, A2 Location in patent: Page/Page column 35
  • 9
  • [ 145821-59-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
In 1,4-dioxane 11 Approximately 27 mg of tiagabine HCl amorphous was dissolved in approximately 0.05 mL of 1,4-dioxane. A clear solution was obtained at first and solids quickly precipitated out. The solvent was removed under a gentle stream of nitrogen and a solid was obtained. 1H NMR analysis indicated that the tiagabine hydrochloride Form Y contained 0.92 moles of dioxane per mole of tiagabine HCl.
  • 10
  • [ 145821-59-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran 12 Approximately 28 mg of tiagabine HCl amorphous was dissolved in approximately0.05 mL of THF. A clear solution was obtained at first and solids quickly precipitated out. The solvent was removed under a gentle stream of nitrogen and a solid was obtained. 1H NMR analysis indicated that the tiagabine hydrochloride Form Z contained 0.59 moles of tetrahydrofuran per mole of tiagabine HCl.
  • 11
  • [ CAS Unavailable ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
at 115 - 120℃; for 0.166667h; Heating / reflux; 9 A sample of tiagabine HCl Form T was heated to about 115-1200C for approximately 10 minutes. XRPD analysis indicated tiagabine. HCl Form B.A sample of tiagabine HCl Form T was dried under vacuum for about 4 days at room temperature. XRPD analysis indicated tiagabine HCl Form C.
at 20℃; for 96h; 9 A sample of tiagabine HCl Form T was heated to about 115-1200C for approximately 10 minutes. XRPD analysis indicated tiagabine. HCl Form B.A sample of tiagabine HCl Form T was dried under vacuum for about 4 days at room temperature. XRPD analysis indicated tiagabine HCl Form C.
  • 12
  • [ 875690-55-4 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Stage #1: tiagabine ethyl ester-L-(+)-tartrate With sodium hydroxide In ethanol at 20℃; for 3 - 5h; Stage #2: With hydrogenchloride In ethanol; water 4 A solution sodium hydroxide (10.8 ml, 8M) was added to a stirred solution of L (+)tartaric acid salt of tiagabine ethyl ester (12 g, purity: >99.5 %) in ethanol at ambienttemperature. The solution was stirred for about 3 to 5 hours until completion of thereaction. The mixture was diluted with water (50 mL) and acidified with dilutehydrochloric acid until a pH of about 1.0 was obtained. The acidic solution was extractedtwice with ethyl acetate (100 mL). The ethyl acetate layer was then washed with water(25 mL) and concentrated by evaporation under vacuum to yield crude product. Crudetiagabine hydrochloride was recrystallized from ethanol to yield pure tiagabinehydrochloride.HPLC Chiral Purity: 99.9 %HPLC purity: 99.9 %Yield: 6.3 gImpurity at RRT 1.13: 0.07 %(By HPLC)
  • 13
  • [ 145821-59-6 ]
  • [ CAS Unavailable ]
  • [ 872003-40-2 ]
YieldReaction ConditionsOperation in experiment
In methanol; ethyl acetate at 5 - 55℃; for 4h; 4 5 gm of tiagabine hydrochloride is dissolved in 5 ml of methanol at 50-55° C., 50 ml acetonitrile is added to the methanol solution at 40-55° C. and cooled to room temperature in 1 hr period and further cooled to 5-10° C. and stirred for 2 hrs. Allowed the product to settle down and decanted the clear liquid. 50 ml ethyl acetate is added to the solid mass and stirred at 5-10° C. for 30 min, allowed the product to settle down the and decanted the clear liquid. Once again 50 ml ethyl acetate is added to the solid mass and stirred at 5-10° C. for 30 min, allowed the product to settle down the and decanted the clear liquid and dried the product mass in rotavapour under mild vaccum at 50° C. for 2 hrs. The obtained acetonitrile solvate form was dried at 85-90° C. under vacuum to obtain form III of tiagabine hydrochloride. X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at 7.8620, 11.7636, 12.7349, 13.4762, 14.3981, 14.8732, 15.7568, 16.8937, 17.1116, 17.4938, 18.0955, 18.8451, 19.8842, 21.5213, 22.0078, 23.2299, 23.6888, 24.2776, 24.6823, 24.9106, 25.6034, 26.2117, 26.6924, 27.5132, 27.7983, 28.4213, 28.9876, 29.7388, 30.1996, 30.5997, 31.5065, 31.5065, 32.7371, 36.1356, 38.1619.
  • 14
  • [ 872003-40-2 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
at 85 - 90℃; 4 5 gm of tiagabine hydrochloride is dissolved in 5 ml of methanol at 50-55° C., 50 ml acetonitrile is added to the methanol solution at 40-55° C. and cooled to room temperature in 1 hr period and further cooled to 5-10° C. and stirred for 2 hrs. Allowed the product to settle down and decanted the clear liquid. 50 ml ethyl acetate is added to the solid mass and stirred at 5-10° C. for 30 min, allowed the product to settle down the and decanted the clear liquid. Once again 50 ml ethyl acetate is added to the solid mass and stirred at 5-10° C. for 30 min, allowed the product to settle down the and decanted the clear liquid and dried the product mass in rotavapour under mild vaccum at 50° C. for 2 hrs. The obtained acetonitrile solvate form was dried at 85-90° C. under vacuum to obtain form III of tiagabine hydrochloride. X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 theta at 7.8620, 11.7636, 12.7349, 13.4762, 14.3981, 14.8732, 15.7568, 16.8937, 17.1116, 17.4938, 18.0955, 18.8451, 19.8842, 21.5213, 22.0078, 23.2299, 23.6888, 24.2776, 24.6823, 24.9106, 25.6034, 26.2117, 26.6924, 27.5132, 27.7983, 28.4213, 28.9876, 29.7388, 30.1996, 30.5997, 31.5065, 31.5065, 32.7371, 36.1356, 38.1619.
  • 15
  • [ 145821-58-5 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
81% Stage #1: ethyl (R)-1-<4,4-bis(3-methyl-2-thienyl)-3-butenyl>-3-piperidinecarboxylate With water; sodium hydroxide In ethanol at 20℃; for 4h; Stage #2: With hydrogenchloride In water at 5℃;
76% Stage #1: ethyl (R)-1-<4,4-bis(3-methyl-2-thienyl)-3-butenyl>-3-piperidinecarboxylate With sodium hydroxide In ethanol; water at 23℃; for 4h; Stage #2: With hydrogenchloride In ethanol; water
2.56 kg Stage #1: ethyl (R)-1-<4,4-bis(3-methyl-2-thienyl)-3-butenyl>-3-piperidinecarboxylate With lithium hydroxide In ethanol at 20℃; for 3h; Large scale; Stage #2: With hydrogenchloride In water Large scale; 1; 5; 6; 7; 8; 9; 10; 11 Example 5: Preparation and purification of tiagabine hydrochloride The compound was prepared by the direct addition of 1,1-bis(3-methyl-2-thiophene-2-yl)-4-bromo-1-butene A 50 L autoclave was charged with the crude crude tiagabine ethyl ester of the previous step 3. 25 Kg and 95% ethanol 7. 8 L, stirredDissolved. With stirring, 4.0 M NaOH solution 3. 21 L was added. The mixture was stirred at room temperature for 3 hours in the dark. After controlling the temperature of the material below 20 ° C, 6.0 M hydrochloric acid was added to neutralize to pH 1-2. The material was evaporated under reduced pressure and then transferred back to the reaction kettle. Dichloromethane was added to the oil-water mixture , Precipitation of a large number of solid, suction filtration, dichloromethane to get thiabarbital hydrochloride crude I. A 50 L autoclave was charged with crude I of tiagabine hydrochloride, 7. 5 L of distilled water and 7. 5 L of dichloromethane, Mixing, add 4. 0 M NaOH solution 1. 7L, stirring a few minutes later, still, two-phase about the clear, solid near-total solution. Under cooling with ice water, the internal temperature was not more than 25 ° C, and 6.0 M hydrochloric acid was slowly added dropwise to pH 1-2. Precipitation crystallization, suction filtration, washing with dichloromethane, in crude solid thiabarim hydrochlorideII. Repeat the purification process to obtain an off-white solid, and then vacuum extraction of methylene chloride to get the pure water containing tiagabine hydrochloride (due to large changes in water content, this step does not calculate the weight). The results showed that the total content was 99.67%, the impurity (RRT = 1.13) was 0.29%, and the other single impurity content was 0.10%. In a 50 L glass autoclave, 10 g of the above purified product of tiagabine hydrochloride and 10 L of distilled water were added. Stirring, folderThrough the hot water heated to 67 ~ 72 ° C all dissolved. Adding activated carbon, stirring lOmin, the filter to remove activated carbon. After purging the autoclave, the filtrate was transferred to a 50 L autoclave and the filtrate was cooled to 30-40 ° C. 700mL of hydrochloric acid was slowly added dropwise, and the crystals were cooled and crystallized. The filter cake was poured twice with ice-purified water, drained and dried in vacuo to obtain a tiagabine hydrochloride product in good quality and accurately weighed. (Total theoretical yield 62.7%), water is less than 0.3%; Μρ: 192.3 ~ 195.1 ° C; other test results in line with the USP35 version of the standard.
  • 16
  • [ 847233-27-6 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: triethylamine / diethyl ether / 1 h 2: potassium iodide; potassium carbonate / acetone / 120 h / 20 °C 3: sodium hydroxide / water; methanol / 2 h / 20 - 50 °C 4: hydrogen; C63H78IrNOP(2+)*C32H12BF24(1-) / methanol / 12 h / 60 °C / 4560.31 Torr / Autoclave 5: hydrogenchloride / water; dichloromethane / 1 h / 20 °C
  • 17
  • [ 148319-38-4 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogen; C63H78IrNOP(2+)*C32H12BF24(1-) / methanol / 12 h / 60 °C / 4560.31 Torr / Autoclave 2: hydrogenchloride / water; dichloromethane / 1 h / 20 °C
  • 19
  • [ 92600-27-6 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: methanol / 2 h / Reflux 1.2: 0.5 h 2.1: potassium iodide; potassium carbonate / acetone / 120 h / 20 °C 3.1: sodium hydroxide / water; methanol / 2 h / 20 - 50 °C 4.1: hydrogen; C63H78IrNOP(2+)*C32H12BF24(1-) / methanol / 12 h / 60 °C / 4560.31 Torr / Autoclave 5.1: hydrogenchloride / water; dichloromethane / 1 h / 20 °C
  • 20
  • [ 495-19-2 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium iodide; potassium carbonate / acetone / 120 h / 20 °C 2: sodium hydroxide / water; methanol / 2 h / 20 - 50 °C 3: hydrogen; C63H78IrNOP(2+)*C32H12BF24(1-) / methanol / 12 h / 60 °C / 4560.31 Torr / Autoclave 4: hydrogenchloride / water; dichloromethane / 1 h / 20 °C
  • 21
  • [ 14282-76-9 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: magnesium / tetrahydrofuran / 1 h / 35 °C 1.2: 2 h / 0 °C / Reflux 2.1: hydrogenchloride / water; methanol / 1 °C / Reflux 3.1: triethylamine / diethyl ether / 1 h 4.1: potassium iodide; potassium carbonate / acetone / 120 h / 20 °C 5.1: sodium hydroxide / water; methanol / 2 h / 20 - 50 °C 6.1: hydrogen; C63H78IrNOP(2+)*C32H12BF24(1-) / methanol / 12 h / 60 °C / 4560.31 Torr / Autoclave 7.1: hydrogenchloride / water; dichloromethane / 1 h / 20 °C
Multi-step reaction with 7 steps 1.1: magnesium / tetrahydrofuran 2.1: hydrogenchloride / methanol 3.1: sodium azide / N,N-dimethyl-formamide / 3 h / 80 °C 4.1: triphenylphosphine; water / tetrahydrofuran / 2 h / 50 °C 5.1: potassium carbonate / acetonitrile / 2 h / 70 °C 6.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 15 min / -78 °C 6.2: 32 min / -78 - 20 °C 7.1: 2-methyl-but-2-ene; sodium chlorite; sodium dihydrogenphosphate / water; tetrahydrofuran; <i>tert</i>-butyl alcohol / 0.5 h 7.2: pH 1
  • 22
  • [ 847233-26-5 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: hydrogenchloride / water; methanol / 1 °C / Reflux 2: triethylamine / diethyl ether / 1 h 3: potassium iodide; potassium carbonate / acetone / 120 h / 20 °C 4: sodium hydroxide / water; methanol / 2 h / 20 - 50 °C 5: hydrogen; C63H78IrNOP(2+)*C32H12BF24(1-) / methanol / 12 h / 60 °C / 4560.31 Torr / Autoclave 6: hydrogenchloride / water; dichloromethane / 1 h / 20 °C
Multi-step reaction with 6 steps 1.1: hydrogenchloride / methanol 2.1: sodium azide / N,N-dimethyl-formamide / 3 h / 80 °C 3.1: triphenylphosphine; water / tetrahydrofuran / 2 h / 50 °C 4.1: potassium carbonate / acetonitrile / 2 h / 70 °C 5.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 15 min / -78 °C 5.2: 32 min / -78 - 20 °C 6.1: 2-methyl-but-2-ene; sodium chlorite; sodium dihydrogenphosphate / water; tetrahydrofuran; <i>tert</i>-butyl alcohol / 0.5 h 6.2: pH 1
  • 23
  • [ 847233-13-0 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium iodide; potassium carbonate / acetone / 120 h / 20 °C 2: sodium hydroxide / water; methanol / 2 h / 20 - 50 °C 3: hydrogen; C63H78IrNOP(2+)*C32H12BF24(1-) / methanol / 12 h / 60 °C / 4560.31 Torr / Autoclave 4: hydrogenchloride / water; dichloromethane / 1 h / 20 °C
Multi-step reaction with 5 steps 1.1: sodium azide / N,N-dimethyl-formamide / 3 h / 80 °C 2.1: triphenylphosphine; water / tetrahydrofuran / 2 h / 50 °C 3.1: potassium carbonate / acetonitrile / 2 h / 70 °C 4.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 15 min / -78 °C 4.2: 32 min / -78 - 20 °C 5.1: 2-methyl-but-2-ene; sodium chlorite; sodium dihydrogenphosphate / water; tetrahydrofuran; <i>tert</i>-butyl alcohol / 0.5 h 5.2: pH 1
  • 24
  • [ 1499189-55-7 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: sodium hydroxide / water; methanol / 2 h / 20 - 50 °C 2: hydrogen; C63H78IrNOP(2+)*C32H12BF24(1-) / methanol / 12 h / 60 °C / 4560.31 Torr / Autoclave 3: hydrogenchloride / water; dichloromethane / 1 h / 20 °C
  • 25
  • [ 862600-47-3 ]
  • [ 83602-37-3 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium iodide / acetone / 72 h / 20 °C 2.1: lithium hydroxide / ethanol / 3 h / 20 °C / Large scale 2.2: Large scale
  • 26
  • [ 862600-47-3 ]
  • [ 25137-01-3 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium iodide / acetone / 72 h / 20 °C 2.1: lithium hydroxide / ethanol / 3 h / 20 °C / Large scale 2.2: Large scale
  • 27
  • [ 109857-81-0 ]
  • [ 83602-37-3 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium iodide / acetone / 72 h / 15 - 25 °C / Darkness; Large scale 2.1: lithium hydroxide / ethanol / 3 h / 20 °C / Large scale 2.2: Large scale
  • 28
  • [ 109857-81-0 ]
  • [ 25137-01-3 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium iodide / acetone / 72 h / 20 °C / Darkness; Large scale 2.1: lithium hydroxide / ethanol / 3 h / 20 °C / Large scale 2.2: Large scale
  • 29
  • [ 862600-49-5 ]
  • [ 83602-37-3 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium iodide / acetone / 72 h / 20 °C 2.1: lithium hydroxide / ethanol / 3 h / 20 °C / Large scale 2.2: Large scale
  • 30
  • [ 862600-49-5 ]
  • [ 25137-01-3 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium iodide / acetone / 72 h / 20 °C 2.1: lithium hydroxide / ethanol / 3 h / 20 °C / Large scale 2.2: Large scale
  • 31
  • [ 862600-51-9 ]
  • [ 25137-01-3 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium iodide / acetone / 72 h / 20 °C 2.1: lithium hydroxide / ethanol / 3 h / 20 °C / Large scale 2.2: Large scale
  • 32
  • [ 25137-01-3 ]
  • [ 145821-59-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: caesium carbonate / acetonitrile / 5 h / Reflux 2.1: (<SUP>Cy</SUP>APDI)CoCH<SUB>3</SUB> / toluene / 16 h / 23 °C / Inert atmosphere; Glovebox; Sealed tube 3.1: di-μ-bromobis(tri-tert-butylphosphino)dipalladium(I); potassium hydroxide / toluene; tetrahydrofuran; water / 1 h / 23 °C / Inert atmosphere 4.1: sodium hydroxide / ethanol; water / 4 h / 23 °C 4.2: pH 1
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