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Chemical Structure| 881681-00-1
Chemical Structure| 881681-00-1
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Product Details of [ 881681-00-1 ]

CAS No. :881681-00-1 MDL No. :
Formula : C17H16FN3O2S Boiling Point : -
Linear Structure Formula :- InChI Key :BFDBKMOZYNOTPK-UHFFFAOYSA-N
M.W : 345.39 Pubchem ID :15981397
Synonyms :
TAK-438 free base

Calculated chemistry of [ 881681-00-1 ]

Physicochemical Properties

Num. heavy atoms : 24
Num. arom. heavy atoms : 17
Fraction Csp3 : 0.12
Num. rotatable bonds : 5
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 89.27
TPSA : 72.37 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -7.02 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.71
Log Po/w (XLOGP3) : 1.95
Log Po/w (WLOGP) : 3.99
Log Po/w (MLOGP) : 2.41
Log Po/w (SILICOS-IT) : 2.31
Consensus Log Po/w : 2.67

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.4
Solubility : 0.136 mg/ml ; 0.000394 mol/l
Class : Soluble
Log S (Ali) : -3.09
Solubility : 0.278 mg/ml ; 0.000804 mol/l
Class : Soluble
Log S (SILICOS-IT) : -6.46
Solubility : 0.000121 mg/ml ; 0.00000035 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.22

Safety of [ 881681-00-1 ]

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

Application In Synthesis of [ 881681-00-1 ]

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

  • Downstream synthetic route of [ 881681-00-1 ]

[ 881681-00-1 ] Synthesis Path-Downstream   1~35

  • 1
  • 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine [ No CAS ]
  • [ 110-17-8 ]
  • 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% In methanol at 25 - 50℃; for 0.5h; S5 S5: Preparation of Vonolazan (VI) Fumarate Take 17.3 g of 1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine in 90 ml of anhydrous methanol, Add 5.8g of fumaric acid at 25-30°C with stirring, raise the temperature to 50°C, stir the reaction for 30 minutes, and precipitate largeA white solid was collected, the reaction was cooled to room temperature, suction filtered, and the filter cake was washed three times with 15 ml of anhydrous methanol, and dried at 40-50°C.6-8h, 20.7 g of Verona Raman (VI) fumarate as a white solid, 99.5% HPLC purity, 90% yield, mp 208-210°C, total yield 66%, as shown in Figure 1 HPLC purity 99.7%.
90.45% In methanol; water monomer at 60 - 65℃; for 0.5h; 2-8 The obtained above-mentioned solid was added to 70% methanol aqueous solution, heated to 60-65°C for complete dissolution, then 9.98g of fumaric acid was added, kept stirring for 0.5h, then cooled to 0-10°C, kept stirring for 1.0h, and pumped. Filtration and vacuum drying of the filter cake gave 32.72 g of vonoprazan fumarate as a solid with a yield of 90.45% and HPLC purity of 99.96%. Impurities A, B, C, E and F were not detected, and impurity D was 0.01%.
83.78% In ethanol at 10 - 50℃; for 2h; 3-4 Embodiment 4: the preparation of high-purity fumaric acid vonorazine III Dissolve about 67g (0.19mol) of the free base vonolasan obtained in Example 2 in 1005gIn ethanol, add fumaric acid 24.76g (0.21mol) and be warming up to 50 of insulation 1h,Be cooled to 10 DEG C of insulation 1h and filter, obtain crude product 79g.Above-mentioned crude product was added 790g 70% methanol aqueous solution and warmed up to 60C, added 0.79g activated carbon to decolorize for 10 minutes and filtered, and the obtained filtrate was cooled to 5C and incubated for 2h and filteredThe fine product of Vonola fumarate was obtained, and 75 g of Vonola fumarate was obtained by drying (yield 83.78%).
82.5% In methanol; ethyl acetate at 20℃; for 1h; 1 Preparation of Vonoprazam Fumarate A Crystalline Form At room temperature, in a 1000ml single neck flask was added 34.5g (0.1mol) of fumaric acid vonoprazam free base, was added 345ml ethyl acetate was stirred uniformly, added to the above solution was added (0.1mol) of fumaric acid in methanol 116ml 11.6g stirred crystallization one hour. The filter cake was dried in vacuum at 50 until constant weight. The yield of the Vonoprazam fumarate A was 38.0g and the yield was 82.5%. Characterized in that the Cu-Kα radiation, X-ray powder diffraction spectrum in 2θ angle indicated, 15.290,20.40320.704,21.572,25.182,25.559It has characteristic diffraction peaks, differential thermal analysis spectrum at about 204.8 absorption peak.
82.5% Stage #1: 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine With hydrogen bromide In ethanol at 20℃; for 1h; Large scale; Stage #2: (2E)-but-2-enedioic acid In N,N-dimethyl acetamide; ethyl acetate at 50℃; for 0.5h; Large scale; 1-2 Example 1 Vonorazan was prepared with reference to Comparative Example 7. The HPLC purity was 94.45%, and the impurity content was:The total of impurity A and impurity C was 0.71%, impurity B was not detected, impurity D was 0.31%, and impurity E was 0.14%.15.0 kg of ethanol was added to the residue, and 1.53 kg of 48% hydrobromic acid was added dropwise at room temperature. After the dropwise addition was completed, the mixture was stirred at room temperature for 1 h.After filtration, the filter cake was rinsed with 9.0 kg of ethanol, and the filter cake was dried to obtain 2.95 kg of Vonolazan hydrobromide with a yield of 76.22%.HPLC purity was 98.38%, impurity content: impurity A was 0.03%, impurity B was 0.01%, impurity C was 0.01%, impurity D was 0.01%, and impurity E was 0.13%. Into a 50L reactor, add 12.5 kg of ethyl acetate, 1.65 kg of ammonia, 12.5 kg of purified water,2.5 kg of Vonolazan hydrobromide, stir until the system is free of solids and continue to stir for 15 min,The phases were allowed to stand, the aqueous phase was added with 6.25 kg of ethyl acetate, and the organic phases were combined.The organic phase was washed with a saturated sodium chloride solution 6.25 kg × 2, and concentrated under reduced pressure until almost no droplets dripped.8.0 kg of ethyl acetate and 17.8 kg of N, N-dimethylacetamide were added to the residue, and the temperature was raised to 50 ° C.Add 0.683 kg of fumaric acid and stir at 50 ° C for 0.5 h.The temperature was lowered to 25 ° C, and the crystallization was maintained for 1.0 h.After filtration, the filter cake was rinsed with a mixed solution of 1.13 kg of ethyl acetate and 2.35 kg of N, N-dimethylacetamide and 4.5 kg of ethyl acetate,Vonorazan fumarate product was dried at 2.35 kg with a yield of 86.71%.HPLC purity was 99.81%, impurity content: impurity A was 0.02%, impurity B was 0.01%, impurity C was 0.01%, impurity D was not detected, and impurity E was 0.01%. Add 14.26 kg of methanol and 7.8 kg of purified water to a clean 50L reaction kettle, and raise the temperature to 62 ° C.Add 2.0kg of Wonolazan fumarate product, stir and dissolve, add 0.10kg of activated carbon to decolorize, stir for 15min,Filtrate while hot, add the filtrate to a clean 50L reaction kettle, lower the temperature to 5 ° C, and keep crystallization for 1.0h.Filtration, the filter cake was rinsed with a mixed solvent of 1.6 kg of methanol and 2.0 kg of purified water, and dried to obtain 1.65 kg of voronazan fumarate refined product, with a yield of 82.50%.Purity 99.93%, impurity content: impurity A is not detected, impurity B is not detected, impurity C is not detected, impurity D is not detected, impurity E is 0.01%.
80.1% In N,N-dimethyl acetamide; ethyl acetate at 50℃; for 0.5h; 7 To the residue were added 9.6 kg of ethyl acetate and 21.36 kg of N, N-dimethylacetamide,The temperature was raised to 50 ° C, 1.05 kg of fumaric acid was added, and the mixture was stirred at 50 ° C to form a salt for 0.5h. After cooling, the temperature was reduced to 25 ° C and the temperature was maintained for 1.0h.After filtration, the filter cake was rinsed with a mixed solution of 1.35 kg of ethyl acetate and 2.82 kg of N, N-dimethylacetamide and 5.40 kg of ethyl acetate, and dried to obtain 2.97 kg of Vonorazant fumarate. Yield It was 71.00%.HPLC purity was 98.91%, impurity content: impurity A was 0.38%, impurity B was 0.12%, impurity C was 0.15%, impurity D was 0.05%, and impurity E was 0.15%. Add 18.20 kg of methanol and 9.75 kg of purified water to a clean 50L reaction kettle, and raise the temperature to 60 ° C.Add 2.50kg of Wonolazan fumarate product, stir and dissolve, add 0.125kg of activated carbon to decolorize, stir for 15min,Filtrate while hot, add the filtrate to a clean 50L reaction kettle, lower the temperature to 5 ° C, and keep crystallization for 1.0h.After filtration, the filter cake was rinsed with a mixed solvent of 2.0 kg of methanol and 2.5 kg of purified water, and dried to obtain 2.06 kg of wonolazan fumarate with a yield of 82.4%.HPLC purity was 99.65%, impurity content: impurity A was not detected, impurity B was 0.08%, impurity C was 0.11%, impurity D was not detected, and impurity E was 0.09%. The second purification was carried out according to the above process. The yield was 80.1%, the purity of HPLC was 99.75%, and the content of impurities: Impurity A was not detected, Impurity B was 0.03%, Impurity C was 0.06%, Impurity D was not detected, and Impurity E was 0.05%.
74% In methanol; ethyl acetate at 10 - 35℃; 166 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate Example 166 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate 5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.52 g) was dissolved in methanol (30 mL), 40% methylamine methanol solution (3.57 g) was added at room temperature and the mixture was stirred for 30 min. Sodium borohydride (523 mg) was added at room temperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (50 mL) was added and the mixture was stirred for 5 min. The reaction mixture was basified with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3) to give a free base of the title compound as a pale-yellow oil (yield 1.30 g). The obtained free base (750 mg) was dissolved in ethyl acetate (30 mL), and a solution of fumaric acid (278 mg) in methanol (3 mL) was added dropwise at room temperature. After stirring for 30 min, the obtained crystals were collected by filtration, and washed with ethyl acetate to give the title compound as colorless crystals (yield 912 mg, 74%). 1H-NMR (DMSO-d6)δ: 2.43 (3H, s), 3.87 (2H, s), 6.47 (2H, s), 6.49 (1H, d, J=1.8 Hz), 7.07-7.13 (1H, m), 7.19-7.26 (2H, m), 7.49-7.56 (1H, m), 7.59-7.64 (1H, m), 7.74 (1H, d, J=1.8 Hz), 7.86-7.90 (1H, m), 8.56-8.57 (1H, m), 8.87-8.89 (1H, m), 3H not detected.
64.3% In isopropanol at 50℃; for 1h; 2 30 g of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrolo-3-carbonitrile and 450 mlMethanol was added to the reaction vessel, Raney nickel was added, the mixture was purged with nitrogen three times, and the hydrogen gas was substituted three times to maintain 2 atmospheres. After stirring for 15 hours at 15-25 ° C,Raney Nickel was filtered off, and 4g of paraformaldehyde was added to the filtrate. The mixture was refluxed for 8 hours at 65 ° C, cooled to 0 ° C, 10.4g of sodium borohydride was added in portions, and the mixture was stirred at room temperature for 4 hours.Add 450g of purified water to stop the reaction, concentrated, extracted with 240ml of dichloromethane.The organic phase is dried over anhydrous sodium sulphate. Filtration, concentration, adding 300ml isopropanol, heated to 50 ° C, stirring to dissolve. Fumaric acid was added and stirred for 1 hour.Cooled to room temperature, filtered, washed with isopropanol, the solid was collected, dried at 50 ° C to give a white solid 27 · 2g, yield 64 • 3%
In methanol; ethyl acetate 8 Example 8 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate; 5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.52 g) was dissolved in methanol (30 mL), a 40% methylamine methanol solution (3.57 g) was added at room temperature and the mixture was stirred for 30 min. Sodium borohydride (523 mg) was added at room temperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (50 mL) was added and the mixture was stirred for 5 min. The reaction mixture was basified with a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3) to give a free salt of the title compound as a pale-yellow oil (yield 1.30 g). The obtained free salt (750 mg) was dissolved in ethyl acetate (30 mL), a solution of fumaric acid (278 mg) in methanol (3 mL) was added dropwise at room temperature. After stirring for 30 min, the obtained crystals were collected by filtration, and washed with ethyl acetate to give the title compound as colorless crystals (yield 912 mg, 74%). 1H-NMR (DMSO-d6) δ: 2.43 (3H, s), 3.87 (2H, s), 6.47 (2H, s), 6.49 (1H, d, J=1.8 Hz), 7.07-7.13 (1H, m), 7.19-7.26 (2H, m), 7.49-7.56 (1H, m), 7.59-7.64 (1H, m), 7.74 (1H, d, J=1.8 Hz), 7.86-7.90 (1H, m), 8.56-8.57 (1H, m), 8.87-8.89 (1H, m), 3H not detected. melting point 201-203° C.
In methanol; ethyl acetate at 20℃; for 0.5h;
912 mg In methanol; ethyl acetate at 20℃; for 0.5h;
55.74 g at 0 - 50℃; for 1.5h; 3 Example 3Synthesis of 5- (2-fluorophenyl) -N-methyl-1- (3-pyridylsulfonyl) -1H-pyrrole-3-methylamine fumarate (TAK438) A mixture of 5- (2-fluorophenyl) -1-(Pyridine-3-sulfonyl) -1H-pyrrole-3-methylamine (50 g, 0.151 mol) was dissolved in 200 ml of methanol,Slowly add 200 ml of absolute ethanol to dissolve 20 g of 36%Formaldehyde aqueous solution.The mixture was stirred at room temperature for 1-2 h.Sodium borohydride (2.856 g, 0.075 mol)In 50 mlDimethylacetamide, & lt; / RTI & gt;The mixture was stirred at 0-10 & lt; 0 & gt; C for 1-2 h.At the end of the reaction,20 ml of 1 N hydrochloric acid was added dropwise,Stir at room temperature for 2 h.Thereafter, 200 ml of water was added,Saturated sodium bicarbonate adjusts PH7-9.Ethyl acetate (200 ml * 3) was added to the extract, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was warmed to 50 ° C and fumaric acid (21.03 g, 0.1812 mol) was added. The mixture was stirred at the same temperature for 30 min and stirred at room temperature for 1 h at 0-10 ° C. Filtered and the filter cake washed with ethyl acetate to give 55.74 g of product in 80% yield.
210 g In N,N-dimethyl-formamide at 50℃; for 0.5h; 12 Example 12 Preparation of compound I fumarate fumarate III: In a 3000 ml reaction flask,The compound IX, which had been concentrated in Example 9,1600 ml DMF,The temperature was raised to 50 ° C,70 g of fumaric acid was added,The mixture was stirred at 50 ° C for 30 min,Cooling to room temperature,Stir for 1h,filter,Rinse the filter cake with DMF,And then washed with ethyl acetate filter cake,Get fulvic acid Vorola Zan crude,The crude product was added to methanol,Heating up to reflux,Dissolve,Add activated charcoal decolorization 1h,filter,Cooling to room temperature,Stir for 1h,Filter,Vacuum drying at 50 for 6h,That is, to get fulvic acid Voronazan 210g,Two-step yield of 75%Purity: 99.6%Single complex <0.1%.
4.6 g In ethyl acetate at 25℃; for 0.5h; Vonoprazan fumarate (1) To a solution of compound 12 (5.0 g, 13.9 mmol) in tetrahydrofuran (40 mL), was slowly added a solution of LiAlH4 under the nitrogen atmosphere at 0 °C, and the mixture was stirred for 5 h. After the completion of the reaction, tetrahydrofuran in water was added and extracted with ethyl acetate. The extract was washed with sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate. Fumaric acid (1.6 g, 13.9 mmol) was added in the mixture during stirring at 25 °C for 30 min. After filtration, the filter cake was recrystallized with 50 ml of 70% methanol solution. The final product vonoprazan fumarate (1) is obtained after filtration (4.6 g, yield 72.4%, purity 99.9%). mp 206.2- 207.6 °C; 1H NMR (600 MHz, DMSO-d6) δ 8.82-8.83 (d, J = 4 Hz, 1H), 8.57 (s, 1H), 7.89-7.90 (d, J = 4 Hz, 1H), 7.82 (s, 1H), 7.52-7.57 (m, 2H), 7.21-7.22 (t, J = 4, 1H), 7.10-7.16 (m, 2H), 6.70 (s, 2H), 6.46 (s, 1H), 4.12 (s, 2H), 2.72 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 168.18, 158.90, and 161.35 (d, JCF = 245 Hz), 155.01, 146.79, 135.11, 134.67, 134.21, 132.61, 131.74, 131.66, 128.31, 124.53, 124.31, 123.87 (d, JCF = 3 Hz), 120.63, 118.26, and 118.41 (d, JCF = 15 Hz), 115.14 and 115.36 (d, JCF = 22 Hz), 43.58, 31.84; HRMS (ESI) calcd for C17H16FN3O2S [M+H]+ 346.1020, found 346.1019.
4.38 kg for 2h; Reflux; 2 Example 2: 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1-H-pyrrole-3-carbaldehyde (3.3 Kg 10 mol) was added to 15.5 liters of methanol and 33 % Methylamine methanol solution (4.70Kg 50mol), maintaining the reaction at about 10 6h.Sodium triacetoxyborohydride was added at 0 ° C(2.54Kg 12mol), the reaction 6h, the reaction of TLC to the basic reaction is complete, add 4mol / L sodium hydroxide to adjust the PH = 7 ~ 8, 45 dry concentrated methanol, was added 3 liters of * 2 dichloromethane extraction, combined organic phase , Dry, filter,The filtrate was added fumaric acid (1160 g 10mol), heated to reflux for 2h, cooled to room temperature to precipitate a solid, filtered, and the solid dried weight 4.38Kg, yield: 95%, HPLC: 99.2%.
In methanol; ethyl acetate at 45 - 50℃; 1 Preparation Example 1: Preparation of Volno Zambia Fumarate Salt (Formula II) vonoprazan 3.80 g (8.69 mmol) was dissolved in 120 ml of ethyl acetate, and 1.1 mg (9.56 mmol, 1.1 eq) of fumaric acid was dissolved in 12 ml of methanol.This fumaric acid methanol solution was added to the Volnozan AG solution at 45-50°C.Cool to about 10 °C.It was filtered, washed with ethyl acetate, and dried under reduced pressure at 45-50°C to obtain vonoprazan fumarate.
118 g In N,N-dimethyl acetamide at 10 - 50℃; for 11.8333h; 10 Example 10: Preparation of the fine (fumarate) fumarazin of formula (1) Will be free Vono Lazan crude 118Ke is dissolved in 585ml DMA,Keep the temperature at 48 ° C,Then fumaric acid (41.5 g, 257 mmole)Add to the reaction solution, add,Stir at 50 ° C for 50 minutes.Then cool down to 10 ° C and stir for 11 hours.Filtering,The solid was dried to obtain 129.8 g (81.4%) of crude fumarate.Add 129 grams of crude fumarazin fumarateAmong 600 ml of methanol and 600 ml of water,Dissolved at 70 ° C,Add 4.9 grams of activated carbon,Stir for 15 minutes,Filtered and the filtrate was lowered to room temperature.Then stir at 0-10 ° C for 9 hours.Filtration and drying gave 118 g (yield 91.5%) of fumarate fumarate.High performance liquid chromatography for purity,The chromatogram is shown in Figure 3, with a single impurity of less than 0.1%.
132.5 g Stage #1: 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine With sodium hydroxide In water monomer; ethyl acetate Stage #2: (2E)-but-2-enedioic acid 11-13 Add 107.3g of 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-carboxamide to 200mL of tetrahydrofuran, cool to 010, and divide Add 14.5g of sodium borohydride solid in batches. After the addition is complete, add 24.0g of boron trifluoride tetrahydrofuran solution dropwise. After the dropwise addition is completed, heat up to 50°C and keep stirring for 2h. After the reaction, add 1mol/L hydrochloric acid aqueous solution dropwise. Adjust pH 45, remove tetrahydrofuran by distillation under reduced pressure, then add 300mL ethyl acetate to the remaining liquid, add dropwise 20% NaOH aqueous solution, adjust pH 89, extract the phases, wash the organic phase with saturated brine three times, then add petroleum ether dropwise 600mL, after the dripping is completed, keep stirring at 10°C for 2h, filter with suction, and vacuum-dry the filter cake at 20-30°C to obtain an off-white solid. The solid was refined with fumaric acid to form a salt to obtain 132.5 g of vornorazan fumaric acid,
41.5 g In methanol at 25 - 30℃; 1.4; 2.4; 3.4; 4.4; 5.4 (4) Preparation of vonoprazan fumarate Compound VII (44.6 g, 0.1 mol) was added to the reaction flask at room temperature,Add an appropriate amount of hydrochloric acid,Stir at 0-5°C under temperature control,Add 20% sodium carbonate solution to adjust pH to 9-10,Collect the organic phase,The aqueous phase was extracted with dichloromethane once.The organic phases were combined, washed twice with water,The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure.Devonolax free base,vonoprazan free base was added to methanol and stirred to dissolve.Fumaric acid (11.6g, 0.1mol) was added at 25-30°C,Heat to reflux, stir,Cooling and crystallization filtration, methanol leaching filter cake,40-50 blast drying,41.5 g of vonoprazan fumarate was obtained, and the yield was about 90%.

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  • [ 881677-11-8 ]
  • [ 74-89-5 ]
  • 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
80.2% Add 50 mL of methanol solution containing 10 g of Intermediate 1 (0.033 mol) to a methanol solution containing 33% methylamine (4.66 g, 0.050 mol) under nitrogen protection, and react at 20-30 C for 30 min.The temperature of the ice bath was controlled below 5 C, and 20 mL containing 1.34 g of sodium borohydride (0.036 mol) was added dropwiseDimethylacetamide solution, react at 0 for 1h; after TLC monitors the completion of the reaction,Reduce the temperature to below 20 , adjust pH = 7 with 1N hydrochloric acid solution, keep at 20 30 for 30min, extract twice with 100mL ethyl acetate, wash twice with 70mL saturated brine, dry with anhydrous sodium sulfate, filter, Concentrate, add 100mL water to the residue and stir to dissolve,Adjust pH = 10 with ammonia water, precipitate a lot of solids, cool to 0 , crystallize for 1h, filter,9.14 g of white solid was obtained with a yield of 80.2%.
57% With sodium cyanoborohydride; In methanol; at 20℃; 230 mg of the intermediate VII-1 and 43 mg of methylamine were dissolved in 15 ml of methanol, and 66 mg of sodium cyanoborohydride was added thereto, and the reaction was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with small amount of water was added, the system was concentrated to remove methanol, the residue was added an appropriate amount of water and extracted 3 times with ethyl acetate, the organic layer was collected, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography The compound of the formula 1-1 was isolated by chromatography, 137 mg of white solid, yield 57%
1.3 g Example 166 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate 5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.52 g) was dissolved in methanol (30 mL), 40% methylamine methanol solution (3.57 g) was added at room temperature and the mixture was stirred for 30 min. Sodium borohydride (523 mg) was added at room temperature and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (50 mL) was added and the mixture was stirred for 5 min. The reaction mixture was basified with saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0?7:3) to give a free base of the title compound as a pale-yellow oil (yield 1.30 g). The obtained free base (750 mg) was dissolved in ethyl acetate (30 mL), and a solution of fumaric acid (278 mg) in methanol (3 mL) was added dropwise at room temperature. After stirring for 30 min, the obtained crystals were collected by filtration, and washed with ethyl acetate to give the title compound as colorless crystals (yield 912 mg, 74%). 1H-NMR (DMSO-d6)delta: 2.43 (3H, s), 3.87 (2H, s), 6.47 (2H, s), 6.49 (1H, d, J=1.8 Hz), 7.07-7.13 (1H, m), 7.19-7.26 (2H, m), 7.49-7.56 (1H, m), 7.59-7.64 (1H, m), 7.74 (1H, d, J=1.8 Hz), 7.86-7.90 (1H, m), 8.56-8.57 (1H, m), 8.87-8.89 (1H, m), 3H not detected.
1.8 kg With 5%-palladium/activated carbon; hydrogen; ammonium bicarbonate; In methanol; at 17 - 30℃; under 3000.3 Torr; for 4h;Autoclave; Large scale; (1) equipped with a stirrer, a thermometer 50L autoclave 24kg of methanol was added, 2kg 5- (2- fluorophenyl) -1- (pyridin-3-ylsulfonyl) lH-pyrrole-3-carbaldehyde and 1.2kg ammonium bicarbonate, stirring, about 17 temperature control was added slowly 5kg30% methylamine methanol solution. Was added 0.1kg 5% palladium / carbon, ventilation, temperature was raised to 30 , introducing hydrogen to a pressure of 0.4MPa, to control the reaction temperature 30 4 hours. Filter press The catalyst was removed by filtration through a hydraulic 50L autoclave, stirring down to room temperature, washed with 5% hydrochloric acid adjusted to pH 5, controlling the degree of vacuum ?-0.07MPa, temperature below 50 , vacuum distillation recovery of methanol, fractionated after cooling to room temperature, aqueous sodium carbonate and then adjusted to pH = 8 ~ 9 compound () free, 40kg with ethyl acetate. The organic phase was distilled under reduced pressure to recover the solvent, controlling the degree of vacuum ?-0.08MPa, temperature below 50 , until no distillate up to give an oil 2.2kg 1- [5- (2-fluorophenyl) -1- ( pyridin-3-ylsulfonyl) lH-pyrrol-3-yl] -N- methylmethanamine compound () crude. (2) in a 5L reaction vessel, methanol was added 3.6kg, 2.2kg compound () crude and 0.2kg activated carbon, feeding port closed, purged with nitrogen gas to maintain air pressure ?0.01MPa, warmed to 60 decolorizing 20 minutes, 7.3kg filter press to preheat the crystalline isopropyl ether 20L kettle, cooled slowly with stirring to 2 crystallization time of 0.5 hours incubation, by centrifugation, washed with diisopropyl ether, after drying, the material, the wet product into to double cone dryer under reduced pressure and then passed through a small flow of nitrogen was replaced three times, control the drying temperature is 40 , vacuum degree ?-0.08MPa, dried for 4 hours to give 1.8kg compound () fine. Compound () HPLC purity 99.87%, the maximum individual impurity 0.05%.
(5) 5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (120 g, 363 mmole)Soluble in methanol (600ml),Join at 20-30 C30-33% methylamine ethanol solution 45.8g,Stir for 45 minutes,The reaction solution is cooled to -10-0 C,29.4 g (372.9 mmol) of pyridine was added.Sodium borohydride (6.2 g, 163.4 mmole)Dissolved into 238 ml of DMA,Then, it is added dropwise to the above reaction solution at -10 C.After the addition, the reaction was continued to stir at -10 C for 1 hour.The reaction solution was quenched with 820 ml of 1N hydrochloric acid.Adjust PH=4,Control the temperature of the reaction solution not to exceed 20 CThen add ammonia to adjust to PH=9,Add to the reaction solution550 ml of ethyl acetate and 550 ml of saturated sodium chloride solution,Stir and let standSplit the upper organic layer,The aqueous layer was re-extracted with 210 ml of ethyl acetate.Combine the organic layers,Concentrated under reduced pressure,Concentrated under reduced pressure to give crude free Like Wonuo La 118 g.
Into a clean 100L reactor, add 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carboxaldehyde 3.00 kg, and methanol 12.0 kg.1.35 kg of 27% methylamine alcohol solution was added dropwise with stirring. After the dropwise addition was completed, the temperature was kept at 25 C. and stirred for 0.5 h.The temperature was lowered to -10 C, and a solution of sodium borohydride in N, N-dimethylacetamide (0.15 kg of sodium borohydride dissolved in 5.1 kg of N, N-dimethylacetamide) was added dropwise.During the dropwise addition, control the temperature of the system not to exceed 0 C. After the dropwise addition is completed, the temperature is maintained at -5 C for 1.0h.Then, 18.0 kg of 1mol / L hydrochloric acid was added dropwise. During the dropwise addition, the temperature of the system was controlled to not exceed 20 C. After the dropwise addition was completed, the temperature was kept at 15 C for 0.5h.Then add 25% ammonia water 6.0kg, ethyl acetate 27.0kg and purified water 15.0kg,Extraction, taking the organic phase, adding 12.0 kg of purified water and 16.35 kg of ethyl acetate to the aqueous phase,The organic phases were extracted and combined. The organic phases were washed with a 5% sodium chloride solution 18.0 kg × 2, and then concentrated under reduced pressure until there were no liquid droplets.
18.2 g In methanol; at 20℃; General procedure: Add 20g to a reaction flask equipped with a stirrer and a thermometer <strong>[881677-11-8]5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carboxaldehyde</strong> and a certain amount of solvent methanol, with stirring, Slowly add controlled amount of methylamine methanol solution at a controlled temperature of about 20 C. Add a certain amount of reducing agent to the reaction until the reaction is complete, adjust PH6 after the reaction, A reaction mixture of 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-yl] -N-methylmethylamine was prepared. Step (2): Prepared by step (1) The reaction mixture of 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-yl] -N-methylmethylamine was added to the distillation reaction flask , Control the vacuum degree ?-0.08Mpa, the temperature is below 40 50 , and recover the solvent by distillation under reduced pressure. After the distillation, cool down to room temperature, adjust the pH to 8 with an aqueous solution of sodium carbonate, and extract three times with 300ml of dichloromethane. The organic phase was distilled under reduced pressure to recover the solvent, and the vacuum degree was controlled to be -0.08 MPa, and the temperature was below 40 C until no distillate was obtained, and 22 g of an oily substance was obtained.Crude 1-[5-(2-fluorophenyl) -1-(pyridin-3-ylsulfonyl) -1H-pyrrole-3-yl] -N-methylmethylamine. Step (3): 22g obtained from step (2) To 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-yl]-N-methylmethylamine was added 29.3 g of methanol and 58.7 g of isopropyl Propyl ether, 1.1g of activated carbon was added under stirring, the air was replaced with nitrogen, and the temperature was dissolved to 65 C, and the solution was decolorized for 30 minutes and filtered. The filtrate was slowly cooled to 5 C with stirring, and the temperature was maintained for 0.5 hours. Filtration, washing with isopropyl ether, drying after filtration, discharge, wet product drying under reduced pressure, the drying process is replaced with a small flow of nitrogen 3 times, the drying temperature is controlled at 40 C, the degree of vacuum is ? -0.08MPa, and the drying is performed for 4 hours. 17.3 g of 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-yl] -N-methylmethylamine were obtained, with an HPLC content of 99.87%.

  • 3
  • [ 881674-56-2 ]
  • 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine [ No CAS ]
  • 4
  • [ 655-15-2 ]
  • [ 881681-00-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: potassium carbonate / 0.75 h / 40 - 45 °C 1.2: 18 h / 20 °C 2.1: hydrogenchloride / tetrahydrofuran / 20 °C / Cooling with ice 3.1: 10% Pd/C; hydrogen / ethanol / 24 h / 20 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran; toluene / 1 h / -78 °C 5.1: tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide / acetonitrile / 1.5 h / 20 °C / Molecular sieve 6.1: sodium hydride / tetrahydrofuran / 0.5 h / 0 °C 6.2: 0 - 20 °C 7.1: methanol / 0.5 h / 20 °C 7.2: 0.17 h / 20 °C
Multi-step reaction with 6 steps 1.1: potassium carbonate / 1 h / 45 °C 1.2: 1.33 h / 45 °C 2.1: hydrogenchloride / ethyl acetate / 18 h / 10 - 35 °C 3.1: 10% Pd/C; hydrogen / ethanol / 36 h / 10 - 35 °C 4.1: diisobutylaluminium hydride / tetrahydrofuran; toluene / 1.17 h / -78 °C 4.2: 1.5 h / 10 - 35 °C / Molecular sieve 5.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 10 - 35 °C 5.2: 0.5 h 5.3: 3 h 6.1: methanol / 0.5 h / 10 - 35 °C 6.2: 0.17 h / 10 - 35 °C
Multi-step reaction with 6 steps 1: potassium hydroxide / ethanol; water / 2 h / 20 °C 2: hydrogenchloride / ethyl acetate / 20 °C 3: 10% Pd/C; hydrogen / methanol / 20 °C 4: hydrogen; acetic acid / water; tetrahydrofuran / 2 h / 20 °C 5: lithium hexamethyldisilazane / tetrahydrofuran / 1.08 h / 0 - 20 °C 6: sodium cyanoborohydride / methanol / 20 °C
Multi-step reaction with 4 steps 1.1: sodium ethanolate / tetrahydrofuran / 0.5 h / 20 °C 1.2: 4 h / 20 °C 2.1: acetic acid / 12 h / 100 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 6 h / 0 - 20 °C 4.1: triethylamine / tetrahydrofuran / 0.17 h / 20 °C 4.2: 0.5 h / 20 °C 4.3: 6 h / 20 - 40 °C
Multi-step reaction with 5 steps 1: tetrabutylammomium bromide; sodium carbonate / ethyl acetate / 20 °C 2: 10% Pd/C / 1,4-dioxane / 16 h / 80 °C 3: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / acetonitrile / 16 h / 80 °C 4: triethylamine; dmap / dichloromethane / 8 h / 20 °C 5: potassium carbonate; potassium iodide / dichloromethane / 20 °C

  • 5
  • [ 445-27-2 ]
  • [ 881681-00-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: copper(ll) bromide / ethyl acetate / 4 h / Reflux 2.1: potassium carbonate / 1 h / 45 °C 2.2: 1.33 h / 45 °C 3.1: hydrogenchloride / ethyl acetate / 18 h / 10 - 35 °C 4.1: 10% Pd/C; hydrogen / ethanol / 36 h / 10 - 35 °C 5.1: diisobutylaluminium hydride / tetrahydrofuran; toluene / 1.17 h / -78 °C 5.2: 1.5 h / 10 - 35 °C / Molecular sieve 6.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 10 - 35 °C 6.2: 0.5 h 6.3: 3 h 7.1: methanol / 0.5 h / 10 - 35 °C 7.2: 0.17 h / 10 - 35 °C
Multi-step reaction with 5 steps 1: acetic acid / ethanol / 6 h / 50 °C 2: copper(l) iodide; triphenylphosphine / 1,4-dioxane / 16 h / 40 °C / Inert atmosphere 3: dmap; N-ethyl-N,N-diisopropylamine / acetonitrile / 4 h / 40 °C / Inert atmosphere 4: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / tetrachloromethane / 3 h / Inert atmosphere; Reflux 5: potassium carbonate; potassium iodide / acetonitrile / 5 h / 40 °C / Inert atmosphere
Multi-step reaction with 7 steps 1: copper(I) bromide / ethyl acetate / 80 °C 2: potassium hydroxide / ethanol; water / 2 h / 20 °C 3: hydrogenchloride / ethyl acetate / 20 °C 4: 10% Pd/C; hydrogen / methanol / 20 °C 5: hydrogen; acetic acid / water; tetrahydrofuran / 2 h / 20 °C 6: lithium hexamethyldisilazane / tetrahydrofuran / 1.08 h / 0 - 20 °C 7: sodium cyanoborohydride / methanol / 20 °C
Multi-step reaction with 3 steps 1.1: triethylamine / acetonitrile / 20 °C / Inert atmosphere 2.1: rhodium(II) acetate dimer / 1,2-dichloro-ethane / 80 °C 2.2: 20 °C 3.1: hydrogenchloride / water / 0 - 5 °C
Multi-step reaction with 3 steps 1.1: triethylamine / acetonitrile / 20 °C / Inert atmosphere 2.1: rhodium(II) acetate dimer / 1,2-dichloro-ethane / 80 °C 2.2: 20 °C 3.1: hydrogenchloride / water / 0 - 5 °C
Multi-step reaction with 3 steps 1.1: sodium iodide; triethylamine / acetonitrile / 20 °C / Inert atmosphere 2.1: rhodium(II) acetate dimer / 1,2-dichloro-ethane / 80 °C 2.2: 20 °C 3.1: hydrogenchloride / water / 0 - 5 °C

  • 6
  • [ 50-00-0 ]
  • [ 1807642-41-6 ]
  • [ 881681-00-1 ]
YieldReaction ConditionsOperation in experiment
With sodium tetrahydroborate; N,N-dimethyl acetamide In methanol; ethanol at 0 - 20℃; 3 A mixture of 5- (2-fluorophenyl) -1-(Pyridine-3-sulfonyl) -1H-pyrrole-3-methylamine (50 g, 0.151 mol) was dissolved in 200 ml of methanol,Slowly add 200 ml of absolute ethanol to dissolve 20 g of 36%Formaldehyde aqueous solution.The mixture was stirred at room temperature for 1-2 h.Sodium borohydride (2.856 g, 0.075 mol)In 50 mlDimethylacetamide, & lt; / RTI & gt;The mixture was stirred at 0-10 & lt; 0 & gt; C for 1-2 h.At the end of the reaction,20 ml of 1 N hydrochloric acid was added dropwise,Stir at room temperature for 2 h.Thereafter, 200 ml of water was added,Saturated sodium bicarbonate adjusts PH7-9.Ethyl acetate (200 ml * 3) was added to the extract, and the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The mixture was warmed to 50 ° C and fumaric acid (21.03 g, 0.1812 mol) was added. The mixture was stirred at the same temperature for 30 min and stirred at room temperature for 1 h at 0-10 ° C. Filtered and the filter cake washed with ethyl acetate to give 55.74 g of product in 80% yield.
Stage #1: formaldehyd; [5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methylamine at 65℃; for 8h; Stage #2: With sodium tetrahydroborate at 0 - 20℃; for 4h; 2 30 g of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrolo-3-carbonitrile and 450 mlMethanol was added to the reaction vessel, Raney nickel was added, the mixture was purged with nitrogen three times, and the hydrogen gas was substituted three times to maintain 2 atmospheres. After stirring for 15 hours at 15-25 ° C,Raney Nickel was filtered off, and 4g of paraformaldehyde was added to the filtrate. The mixture was refluxed for 8 hours at 65 ° C, cooled to 0 ° C, 10.4g of sodium borohydride was added in portions, and the mixture was stirred at room temperature for 4 hours.Add 450g of purified water to stop the reaction, concentrated, extracted with 240ml of dichloromethane.The organic phase is dried over anhydrous sodium sulphate. Filtration, concentration, adding 300ml isopropanol, heated to 50 ° C, stirring to dissolve. Fumaric acid was added and stirred for 1 hour.Cooled to room temperature, filtered, washed with isopropanol, the solid was collected, dried at 50 ° C to give a white solid 27 · 2g, yield 64 • 3%
  • 7
  • [ 64-18-6 ]
  • [ 1807642-41-6 ]
  • [ 881681-00-1 ]
YieldReaction ConditionsOperation in experiment
With N,N-dimethyl acetamide; sodium cyanoborohydride In methanol at 0 - 20℃; 5 5- (2-fluorophenyl) -1- (pyridin-3-sulfonyl) lH-pyrrole-3-methylamine (25g, 0.075mol), formic acid (5.18g, 0.1125mol), 100ml methanol was added to three-necked flask.The mixture was stirred at room temperature for 1-2h.Solution of sodium cyanoborohydride (3.142g, 0.050mol) in 20ml of dimethylacetamide was added.The mixture was stirred at 0-10 1-2h.15ml1N hydrochloric acid was added dropwise, stirred at room temperature 2h.After addition of 100ml of water, 12.5% aqueous ammonia solution PH7-9.Was added ethyl acetate (100ml * 3), washed with water and saturated brine, dried over anhydrous sodium sulfate.The mixture was warmed 50 , fumaric acid was added at the same temperature for 30min, approaching room temperature, the ice bath was 0-10 stirred for 1h.Filter cake washed with ethyl acetate to give the product 23.14g, 66.78% yield.
  • 8
  • [ 1870905-88-6 ]
  • [ 593-51-1 ]
  • [ 881681-00-1 ]
YieldReaction ConditionsOperation in experiment
82.31% With potassium carbonate; potassium iodide In dichloromethane at 20℃; 5 Preparation of compound 06 50.00g of compound 05, 17.56g of methylamine hydrochloride, 35.93g of potassium carbonate, 33.20g of potassium iodide, and 600ml of dichloromethane were added to the reaction flask at room temperature. The result shows that the reaction of the raw materials is complete, and the reaction is stopped; the temperature is lowered to 30°C and 500ml of water is added to extract and separate the water phase, add 500ml of dichloromethane to extract the liquids, combine the organic phases, reduce the pressure to 35°C and concentrate to dryness, add 250ml of n-hexane The temperature was raised to 60°C for beating for 2h, the temperature was lowered to 20°C for suction filtration, and the filter cake was vacuum-dried at 80°C for 12h to obtain 35.96 g of compound 06 as a yellow solid product with a yield of 82.31% and a purity of 98.34%.
With potassium carbonate; potassium iodide In acetonitrile at 40℃; for 5h; Inert atmosphere; 7 Example 7 Preparation of Compound Voronazanzine Method 1: In a 3000 ml reaction flask,Adding compound 240g,125.8 g of potassium carbonate,Potassium iodide 100g,Acetonitrile 1440 ml,Under nitrogen protection,Heating up to 40 ,82 g of monomethylamine hydrochloride was added in 8 portions,After joining the insulation 5h,TLC detection,After completion of the reaction, the mixture was cooled to room temperature,Filtration, filtrate concentration,To give a yellow oil,Add 480ml methylene chloride dissolved,Wash the organic phase with water three times,Organic phase by adding anhydrous sodium sulfate,Activated carbon, stirring 1h,Filter, filter cake with dichloromethane rinse,Dry, the filtrate is concentrated to dry,A yellow oil was obtained.
  • 9
  • [ 2054536-04-6 ]
  • [ 881681-00-1 ]
YieldReaction ConditionsOperation in experiment
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 5h; Inert atmosphere; Vonoprazan fumarate (1) To a solution of compound 12 (5.0 g, 13.9 mmol) in tetrahydrofuran (40 mL), was slowly added a solution of LiAlH4 under the nitrogen atmosphere at 0 °C, and the mixture was stirred for 5 h. After the completion of the reaction, tetrahydrofuran in water was added and extracted with ethyl acetate. The extract was washed with sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate. Fumaric acid (1.6 g, 13.9 mmol) was added in the mixture during stirring at 25 °C for 30 min. After filtration, the filter cake was recrystallized with 50 ml of 70% methanol solution. The final product vonoprazan fumarate (1) is obtained after filtration (4.6 g, yield 72.4%, purity 99.9%). mp 206.2- 207.6 °C; 1H NMR (600 MHz, DMSO-d6) δ 8.82-8.83 (d, J = 4 Hz, 1H), 8.57 (s, 1H), 7.89-7.90 (d, J = 4 Hz, 1H), 7.82 (s, 1H), 7.52-7.57 (m, 2H), 7.21-7.22 (t, J = 4, 1H), 7.10-7.16 (m, 2H), 6.70 (s, 2H), 6.46 (s, 1H), 4.12 (s, 2H), 2.72 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 168.18, 158.90, and 161.35 (d, JCF = 245 Hz), 155.01, 146.79, 135.11, 134.67, 134.21, 132.61, 131.74, 131.66, 128.31, 124.53, 124.31, 123.87 (d, JCF = 3 Hz), 120.63, 118.26, and 118.41 (d, JCF = 15 Hz), 115.14 and 115.36 (d, JCF = 22 Hz), 43.58, 31.84; HRMS (ESI) calcd for C17H16FN3O2S [M+H]+ 346.1020, found 346.1019.
With sodium tetrahydroborate; boron trifluoride-tetrahydrofuran complex In tetrahydrofuran at 0 - 50℃; for 2h; 11-13 Add 107.3g of 5-(2-fluorophenyl)-N-methyl-1-(3-pyridylsulfonyl)-1H-pyrrole-3-carboxamide to 200mL of tetrahydrofuran, cool to 010, and divide Add 14.5g of sodium borohydride solid in batches. After the addition is complete, add 24.0g of boron trifluoride tetrahydrofuran solution dropwise. After the dropwise addition is completed, heat up to 50°C and keep stirring for 2h. After the reaction, add 1mol/L hydrochloric acid aqueous solution dropwise. Adjust pH 45, remove tetrahydrofuran by distillation under reduced pressure, then add 300mL ethyl acetate to the remaining liquid, add dropwise 20% NaOH aqueous solution, adjust pH 89, extract the phases, wash the organic phase with saturated brine three times, then add petroleum ether dropwise 600mL, after the dripping is completed, keep stirring at 10°C for 2h, filter with suction, and vacuum-dry the filter cake at 20-30°C to obtain an off-white solid. The solid was refined with fumaric acid to form a salt to obtain 132.5 g of vornorazan fumaric acid,
  • 10
  • [ 881681-00-1 ]
  • [ 64-19-7 ]
  • [ 1957202-37-7 ]
YieldReaction ConditionsOperation in experiment
88% In ethyl acetate at 2 - 15℃; for 1h; 1 In a 100 ml single-port in the bottle, add 5-(2-fluorophenyl)-N-methyl-1-(3-pyridyl sulfonyl)-1H-pyrrole-3-ammonia (3.0 g, 8.7 mmol) and ethyl acetate (15 ml), and at room temperature (15 °C) stirring and dissolving, to the reaction system in the adds the acetic acid drop (0.6 ml, 9.1 mmol), stirring at the temperature for 30 minutes, then temperature dropped to 2 °C, and stirring 30 minutes, solids are separated out, the solid filtered, washing and ethyl acetate (8 ml * 2 times), the obtained solid drying in vacuum oven (35 °C) 4 hours, getting white solid 3.1g, yield is 88%.
74% In ethyl acetate at 25℃; for 1h; 1 Example 1 Form A In a 100 mL single-mouth flask, 5-(2-fluorophenyl)-Ν-methyl-1-(3-pyridylsulfonyl)-1Η-pyrrole-3-methylamine (5.0 g, 14.49 mmol) was added and ethyl acetate (25 mL) was dissolved with stirring at room temperature (25 °C), glacial acetic acid (0.5 mL, 17.39 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at this temperature for 60 min. Solid precipitated and cooled. The mixture was filtered and washed with ethyl acetate (10 mLx2 times) at 0-5 °C with stirring for 1 h. The resulting solid was dried in a vacuum oven (35 °C) for 4 h to give an off-white solid (4.3 g). The yield was 74%.
In ethyl acetate at 45 - 50℃; 20 Example 20: Preparation of Vonoprazan Acetate (Formula XVI) Form A Vonoprazan 3.80 g (8.69 mmol) was dissolved in 20 ml of ethyl acetate, and 0.52 g (8.69 mmol, 1.0 eq) of acetic acid was dissolved in 10 ml of ethyl acetate.The ethyl acetate ethyl acetate solution was added dropwise to the voraolac ethyl acetate solution at 45-50°C.Cool to about 25°C.The mixture was filtered, washed with ethyl acetate, and dried under reduced pressure at 55 to 60° C. to obtain Vonoprazan acetate crystal form
  • 11
  • [ 2127152-98-9 ]
  • [ 881681-00-1 ]
YieldReaction ConditionsOperation in experiment
With sodium triacetoxyborohydride at 0℃; for 6h; 2 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1-H-pyrrole-3-carbaldehyde (3.3 Kg 10 mol) was added to 15.5 liters of methanol and 33 % Methylamine methanol solution (4.70Kg 50mol), maintaining the reaction at about 10 6h.Sodium triacetoxyborohydride was added at 0 ° C(2.54Kg 12mol), the reaction 6h, the reaction of TLC to the basic reaction is complete, add 4mol / L sodium hydroxide to adjust the PH = 7 ~ 8, 45 dry concentrated methanol, was added 3 liters of * 2 dichloromethane extraction, combined organic phase , Dry, filter,The filtrate was added fumaric acid (1160 g 10mol), heated to reflux for 2h, cooled to room temperature to precipitate a solid, filtered, and the solid dried weight 4.38Kg, yield: 95%, HPLC: 99.2%.
With methanol; sodium tetrahydroborate at -15 - -10℃; 2 Example 2: Preparation of Compound 5 Between 10 and 20 °C, add 450.00 g of methylamine methanol solution, 423.00 g of methanol and 200.00 g of compound 3 into the reaction kettle in turn, keep stirring for 1 to 2 h; at -15 to -10 °C, divide Add 10.31 g of sodium borohydride in batches (1/4 every hour),After the addition is completed, keep stirring for 1 h; control the temperature between -15 and 10 °C, add the reaction dropwise to 1211.85 g of 2N hydrochloric acid, and the pH of the system after the dropwise addition is 3 to 4; control the temperature at 45 °C,After concentrating to no fraction under reduced pressure, add 2000.00 g of toluene, cool down to below 30°C, add 444.00 g of 10% sodium hydroxide solution dropwise to adjust the pH of the system to 10-11; proceed to the next feeding,The quantitative yield of a small sample was 100%.
99.02 % With Pd/C; hydrogen In ethanol at 5℃; 1; 2; 3; 4; 5 A method for preparing Vonorazan free base, which involves reusing the recovered solvent and crystallization mother liquor recovered in Example 2.Specifically include the following steps: Add 170.24g (0.50mol, purity 98.21%) 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde to the four reaction flask, add 1700mL solvent ethanol , Stir, cool down to -10±2°C, slowly feed 46.59g (1.50mol) of methylamine gas within 1 hour, keep warm (-10±2°C) for 4 hours after ventilation, and the condensation reaction is complete.Transfer the reaction material to a hydrogenation kettle, add about 17g of catalyst Pd/C, start stirring, replace nitrogen twice, and then pass in hydrogen to 0.1Mpa, hydrogenation reaction at 5°C±5°C until the system does not absorb hydrogen, the reaction The purity of 1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylformimine in the liquid is lower than 0.1%, and the reaction At the end, the catalyst was recovered by filtration to obtain the catalyst , the filtrate was distilled and recovered to obtain the recovered solvent , the crystallization mother liquor in Example 2 was added to the distillation residue, and 100 mL of n-heptane was added.Cool down to -20°C±2°C, stir for two hours to crystallize, filter, and dry to obtain 172.30 g of Vonorazan free base. The purity was 99.25% and the yield was 99.02%, and about 555 mL of crystalline mother was obtained.
  • 12
  • [ 16133-25-8 ]
  • [ 881681-00-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: dmap; N-ethyl-N,N-diisopropylamine / acetonitrile / 2 h / 20 - 30 °C 2.1: hydrogen / methanol / 5 h / 15 - 25 °C / 1520.1 Torr 3.1: 8 h / 65 °C 3.2: 4 h / 0 - 20 °C
Multi-step reaction with 3 steps 1.1: dmap; N-ethyl-N,N-diisopropylamine / acetonitrile / 3 h / 10 - 30 °C 2.1: acetic acid; pyridine; sodium hypophosphite / tetrahydrofuran; water / 4 h / 15 - 25 °C 3.1: methanol; ethanol / 0.75 h / 20 - 30 °C 3.2: 1 h / -10 - 0 °C
Multi-step reaction with 2 steps 1.1: dmap; triethylamine / acetonitrile / 50 °C / Large scale 2.1: methanol / 0.5 h / 25 °C 2.2: 1 h / -10 - -5 °C
Multi-step reaction with 2 steps 1.1: dmap; triethylamine / acetonitrile / 5 - 35 °C 2.1: methanol / 10 - 20 °C 2.2: 1 h / -15 - 0 °C
Multi-step reaction with 3 steps 1: dmap; triethylamine / acetonitrile / 0.5 h / 15 - 35 °C 2: methanol / 10 - 20 °C 3: methanol; sodium tetrahydroborate / -15 - -10 °C
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; dmap / acetonitrile / 15 min / 20 - 30 °C 1.2: 5 h / 30 °C 2.1: N-ethyl-N,N-diisopropylamine / methanol / 10 min / 20 °C 2.2: 4 h / -5 - 5 °C

  • 13
  • [ 1610043-63-4 ]
  • [ 881681-00-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran / 0.5 h / 20 °C / Cooling with ice 2: trifluoroacetic acid; sodium carbonate / dichloromethane / 25 - 30 °C / pH 8 - 9
  • 14
  • [ 1831110-76-9 ]
  • [ 881681-00-1 ]
YieldReaction ConditionsOperation in experiment
86% With anhydrous sodium carbonate; trifluoroacetic acid In dichloromethane at 25 - 30℃; S4 S4: Preparation of 1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (V) 22.3 g of tert-butyl ((5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate was added to 55 ml Dichloromethane, control the internal temperature of 25-30 ° C drop 55ml of trifluoroacetic acid was added dropwise at the same temperature stirring reaction for 0.5-1 hours, the reaction is completed by adding 20% sodium carbonate to adjust the pH of the reaction solution to 8-9, add dichlorine Methane extraction, abandoned waterPhase; organic phase was added 5% hydrochloric acid to adjust the pH to 3-4, discard the organic phase, the aqueous phase with 20% sodium carbonate to adjust the pH to 8-9, dichloromethane extraction, dichloromethane layer dried with anhydrous sodium sulfate, minus Pressure-dissolution gave 1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (V) yellow oil. 19.1g, yield 86%.
With hydrogenchloride In lithium hydroxide monohydrate at 0 - 5℃; 1.4; 2.4; 3.4; 4.4; 5.4 (4) Preparation of vonolax fumarate Compound VII (44.6 g, 0.1 mol) was added to the reaction flask at room temperature, an appropriate amount of hydrochloric acid was added,Stir at 0-5°C under temperature control,Add 20% sodium carbonate solution to adjust pH to 9-10,The organic phase was collected, and the aqueous phase was extracted with dichloromethane once.The organic phases were combined, washed twice with water, and dried over anhydrous sodium sulfate.Concentrated under reduced pressure to obtain Vonola free base,Vonolax free base was added to methanol and stirred to dissolve.Add fumaric acid (11.6g, 0.1mol) at 25-30°C, heat up to reflux, stir, cool down for crystallization and filtration, rinse the filter cake with methanol, blow dry at 40-50°C,41.5 g of Vonola fumarate was obtained, and the yield was about 90%.
With hydrogenchloride In toluene at 30 - 40℃; 1-3 Preparation of compound 4 302.73 g of concentrated hydrochloric acid was added dropwise to the toluene solution of compound 5 obtained in the previous step at 30 to 40° C. After stirring for 1 to 3 h, 500 g of 20% sodium hydroxide solution was added, and the alkalinity was adjusted by stirring, and the solution was separated and decolorized to obtain Compound 4 in toluene.
  • 15
  • [ 881681-00-1 ]
  • [ 1957202-44-6 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In ethanol; water at 40 - 45℃; 1 Example 1: Preparation of Volonarzan bis-hydrochloride (Formula III) and its Form A vonoprazan 3.00 g (8.69 mmol) was dissolved in 6 ml of ethanol, concentrated hydrochloric acid (containing 36% hydrogen chloride) 1.59 g(15.64 mmol, 1.8 eq) was dissolved in 3 ml of ethanol.The ethanolic hydrochloric acid solution was added dropwise to the Volnolat's ethanol solution at 40-45°C, and then 20 ml of ethyl acetate was added dropwise.Cool to about 5°C.Filtration and washing with ethyl acetate afforded vonoprazan bis-hydrochloride.
  • 16
  • [ 881681-00-1 ]
  • [ 2416241-93-3 ]
YieldReaction ConditionsOperation in experiment
With hydrogen bromide In ethanol at 45 - 50℃; 3 Example 3: Preparation of vonoprazan Dihydrobromide (Formula IV) and its Form A vonoprazan 3.00 g (8.69 mmol) was dissolved in 6 ml of ethanol and hydrobromic acid (containing 48% hydrogen bromide) 2.78 g(16.51 mmol, 1.9 eq) was dissolved in 3 ml of ethanol.The ethanol solution of hydrobromic acid was added dropwise to the vonoprazan ethanol solution at 45 to 50°C, and then 20 ml of acetone was added dropwise. Cool to about 10°C.It was filtered, washed with acetone, and dried under reduced pressure at 45 to 50° C. to obtain vonoprazan dihydrobromide.
  • 17
  • [ 881681-00-1 ]
  • [ 1957202-33-3 ]
YieldReaction ConditionsOperation in experiment
With phosphoric acid In ethanol at 50 - 55℃; 19 Example 19: Preparation of Vonoprazam Phosphate (Formula XV) Form A Dissolve 3.00 g (8.69 mmol) of Vonoprazam in 9 ml of ethanol and concentrate 0.90 g of phosphorus (7.82 mmol, 0.9 eq).Soluble in ethanol 3ml.The phosphoric acid ethanol solution was added dropwise to the Volnolat's ethanol solution at 50 to 55°C, and then 20 ml of acetone was slowly added dropwise.Cool to about 10°C.It was filtered, washed with acetone and dried under reduced pressure at 45-50[deg.] C. to obtain Vonoprazam Phosphate Form A.
  • 18
  • [ 881681-00-1 ]
  • [ 1957202-31-1 ]
YieldReaction ConditionsOperation in experiment
With sulfuric acid In water; acetone at 55 - 60℃; 4 Example 4: Preparation of Vonolazan bisulfate (Formula V) and its Form A vonoprazan 3.80 g (8.69 mmol) was dissolved in 9 ml of acetone, and 1.74 g (17.38 mmol, 2.0 eq) of concentrated sulfuric acid (containing sulfuric acid 98%) was dissolved in 3 ml of water.The aqueous sulfuric acid solution was added dropwise to the Vorenza oil acetone solution at 55 to 60°C, and naturally cooled to about 25°C.It was filtered, washed with acetone and dried under reduced pressure at 40-45[deg.] C. to obtain vonoprazan disulfate.
  • 19
  • [ 881681-00-1 ]
  • [ 2202683-65-4 ]
YieldReaction ConditionsOperation in experiment
With nitric acid In ethanol; acetone at 55 - 60℃; 6 Example 6: Preparation of Volno Lazan's Nitrate (VI) and its Form A vonoprazan 3.80 g (8.69 mmol) was dissolved in 9 ml of acetone, and concentrated nitric acid (containing nitric acid 68%) 0.84 g (8.69 mmol, 1.0 eq) was dissolved in 3 ml of ethanol.The ethanolic nitric acid solution was added dropwise to the vonoprazan phosphate solution at 55-60°C and then 10 ml of acetone was added dropwise. Cool to about 20°C.It was filtered, washed with acetone, and dried under reduced pressure at 45 to 50°C to obtain vonoprazan nitrate.
  • 20
  • [ 881681-00-1 ]
  • [ 1957202-33-3 ]
YieldReaction ConditionsOperation in experiment
With phosphoric acid In methanol at 40 - 45℃; 7 Example 7: Preparation of Vonolazan Bisphosphonate (Formula VII) and its Form A vonoprazan was dissolved in methanol (9 ml) and 3.80 g (phosphoric acid containing 85%) 1.80 g (15.64 mmol, 1.8 eq) was dissolved in 3 ml of methanol.The methanolic solution of phosphoric acid was added dropwise to the vorenza chemistry solution at 40-45°C, followed by dropwise addition of 20 ml of acetone.Cool to about 0°C.It was filtered, washed with acetone and dried under reduced pressure at 50-55°C to obtain vonoprazan bisphosphonate.
  • 21
  • [ 881681-00-1 ]
  • [ 2202683-69-8 ]
YieldReaction ConditionsOperation in experiment
With 1,4-butanedisulphonic acid In methanol; water at 55 - 60℃; 14 Example 14: Preparation of Vonoprazan 1,4-butanedisulfonate (Formula X) and its Form A Vonoprazan dissolved 3.00 g (8.69 mmol) in 20 ml of methanol, and dissolved 3.97 g (10.43 mmol, 1.2 eq) of a 1 ,4-butanedisulfonic acid 60% aqueous solution in 10 ml of methanol.The methanol solution of 1,4-butanedisulfonic acid is added dropwise to the voralaczan solution at 55-60°C.Cool to about 15°C.It is filtered, washed with acetone and dried under reduced pressure at 40-45[deg.] C. to obtain Vonoprazan 1,4-butanedisulfonate.
  • 22
  • [ 881681-00-1 ]
  • [ 98-11-3 ]
  • [ 2202683-67-6 ]
YieldReaction ConditionsOperation in experiment
In ethanol at 40 - 45℃; 10 Example 10: Preparation of vonoprazan Benzene Sulfonate (Formula VIII) and its Form A vonoprazan 3.80 g (8.69 mmol) was dissolved in 9 ml of ethanol and 1.45 g (7.82 mmol, 0.9 eq) of benzenesulfonic acid was dissolved in 5 ml of ethanol.The ethanol solution of benzenesulfonic acid was added dropwise to the vonoprazan ethanol solution at 40 to 45°C, and then 20 ml of ethyl acetate was added dropwise.Cool to about 20°C.It is filtered, washed with ethyl acetate, and dried under reduced pressure at 50-55°C to obtain vonoprazan benzenesulfonate.
  • 23
  • [ 881681-00-1 ]
  • [ 27665-39-0 ]
  • [ 2202683-69-8 ]
YieldReaction ConditionsOperation in experiment
In water; acetone at 40 - 45℃; 11 Example 11: Preparation of Vonoprazan 1,4-butanedisulfonic acid half salt (Formula IX) and its Form A Vonoprazan was dissolved in 3.00 g (8.69 mmol) of acetone (30 ml) and 0.95 g (2.61 mmol, 0.3 eq) of a 1 ,4-butanedisulfonic acid 60% aqueous solution was dissolved in 3 ml of water.This aqueous solution of 1,4-butanedisulfonic acid is added dropwise to the voraragcan solution at 40-45°C and cooled to about 0°C.It is filtered, washed with acetone and dried under reduced pressure at 45-50° C. to obtain Vonoprazan 1,4-butanedisulfonic acid half salt.
  • 24
  • 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine [ No CAS ]
  • [ 107-36-8 ]
  • vonoprazan 2-hydroxyethanesulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In water; acetone; at 40 - 45℃; vonoprazan 3.80 g (8.69 mmol) was dissolved in 30 ml of acetone, and <strong>[107-36-8]2-hydroxyethanesulfonic acid</strong> 0.55 g (9.56 mmol, 1.1 eq) was dissolved in 3 ml of water.The aqueous solution of <strong>[107-36-8]2-hydroxyethanesulfonic acid</strong> is added dropwise to the Venola Zinc acetone solution at 40-45C and cooled to about 20C.It is filtered, washed with acetone and dried under reduced pressure at 50-55[deg.] C. to obtain vonoprazan 2-hydroxyethanesulfonate.
  • 25
  • [ 881681-00-1 ]
  • [ 87-69-4 ]
  • [ 2202683-71-2 ]
YieldReaction ConditionsOperation in experiment
In water; acetone at 45 - 50℃; 16 Example 16: Preparation of vonoprazan L-Tartartrate (Formula XII) and its Form A vonoprazan 3.00 g (8.69 mmol) was dissolved in acetone 20 ml, 1.30 g L-tartaric acid (8.69 mmol,1.0 eq) dissolved in 3 ml of water.The aqueous L-tartaric acid solution was added dropwise to the vorarabicon acetone solution at 45-50°C.Cool to about 25°C.It was filtered, washed with acetone, and dried under reduced pressure at 55-60°C to obtain vonoprazan L-tartrate.
  • 26
  • [ 881681-00-1 ]
  • [ 110-16-7 ]
  • [ 2202683-72-3 ]
YieldReaction ConditionsOperation in experiment
In ethyl acetate at 50 - 55℃; 17 Example 17: Preparation of Form A of vonoprazan Maleate (Formula XIII) vonoprazan 3.80 g (8.69 mmol) was dissolved in 15 ml of ethyl acetate.3.50 g (7.82 mmol, 0.9 eq) of maleic acid was added to the Volnozan ethyl acetate solution at 50-55°C.Then 15 ml of anisole was added dropwise and cooled to about 5°C.It is filtered, washed with anisole and dried under reduced pressure at 40-45° C. to obtain Formola maleate salt form A.
  • 27
  • [ 881681-00-1 ]
  • [ 75-75-2 ]
  • [ 1957202-36-6 ]
YieldReaction ConditionsOperation in experiment
In ethanol at 55 - 60℃; 18 Example 18: Preparation of vonoprazan methanesulfonate (Formula XIV) Form A vonoprazan 3.80 g (8.69 mmol) was dissolved in 9 ml of ethanol and methanesulfonic acid 0.67 g (6.95 mmol, 0.8 eq) was dissolved in 3 ml of ethanol.The methanesulfonic acid ethanol solution was added dropwise to the vorolatach ethanol solution at 55 to 60°C, and then 20 ml of ethyl acetate was added dropwise.Cool to about 15°C.It was filtered, washed with ethyl acetate, and dried under reduced pressure at 45 to 50° C. to obtain vonoprazan mesylate salt form A.
  • 28
  • [ 881681-00-1 ]
  • [ 26811-96-1 ]
  • [ 1621259-50-4 ]
YieldReaction ConditionsOperation in experiment
In ethyl acetate at 55 - 60℃; 21 Example 21: Preparation of Formola A of vonoprazan L-lactate (Formula XVII) Dissolve 3.00 g (8.69 mmol) of vonoprazan in 20 ml of ethyl acetate.L-lactic acid 0.74 g (6.95 mmol, 0.8 eq) was dissolved in 10 ml of ethyl acetate.The acetic acid solution of L-lactic acid in acetic acid was added to the Vonolazan ethyl acetate solution at 55-60°C.Cool to about 10°C.It was filtered, washed with ethyl acetate and dried under reduced pressure at 45-50[deg.] C. to obtain vonoprazan L-lactate form A.
  • 29
  • [ 881681-00-1 ]
  • [ 2231651-93-5 ]
YieldReaction ConditionsOperation in experiment
71.2% Stage #1: 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine With trichlorophosphate In acetonitrile at 0 - 35℃; for 6.5h; Stage #2: With water In acetonitrile at 0℃; 1 Example 1: Preparation of 5-(2-fluorophenyl)-N-methyl-1-(3-sulfonylpyridinyl)-1H-pyrrole-3-methylamine phosphate Take 1L three-necked bottle, weigh 100g of 5-(2-fluorophenyl)-N-methyl-1-(3-sulfonylpyridyl)-1Η-pyrrole-3-methylamine, add to the bottle, add 100ml of acetonitrile In the middle, stir, cool in ice water bath, control temperature 0 °C, add 10g of phosphorus oxychloride, stir for 30min, heat up to 25-35 °C for 6 hours, then cool to 0 °C, slowly add water 20ml, add up After that, the pH was adjusted to 4.0 with a sodium hydroxide solution, evaporated to dryness under reduced pressure at 60 ° C, and then 100 ml of anhydrous ethanol was added thereto, and the mixture was stirred for 30 minutes, filtered, and the filtrate was evaporated to dryness to give 64.6 g of white solid, yield was 71.2%
  • 30
  • [ 2169271-28-5 ]
  • [ 74-89-5 ]
  • [ 881681-00-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrole-3-methanol With triethylamine In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: With p-toluenesulfonyl chloride In tetrahydrofuran at 20℃; for 0.5h; Stage #3: methylamine With triethylamine In tetrahydrofuran; water at 20 - 40℃; for 6h; 1.4; 2.4; 3.4; 4.4; 5.4-20.4 Preparation of 1-[5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-N-methylmethylamine Add 5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-methanol to a 250 mL reaction flask (16.6g, 50 mmol), tetrahydrofuran (70 mL) and triethylamine (6.1 g, 60 mmol), stirred at room temperature for 10 min,Tosyl chloride (10.5 g, 55 mmol) was reacted at room temperature for 6 hours. Concentrate under reduced pressure, add water (100 mL), stir at room temperature 0.5After an hour, filtration, the resulting product was directly subjected to the next reaction.The above obtained product, tetrahydrofuran (100 mL) and triethylamine (6.1 g, 60) were added to a 250 mL reaction flask.(mmol), stirred at room temperature for 10 min, added 40% aqueous methylamine solution (4.7 g, 60 mmol), and allowed to react at room temperature for 6 hours. DecompressionThe mixture was stirred, added with water (100 mL), and stirred at room temperature for 0.5 hour, and filtered to give 1-[5-(2-fluorophenyl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-N - Methylmethylamine (ie, Venolazan) (two-step total yield: 93.8%, HPLC purity: 99.88%). Total yield: 85.1%.
  • 31
  • [ 16133-25-8 ]
  • [ 881674-56-2 ]
  • [ 74-89-5 ]
  • 1-[5-(2-fluorophenyl)-1-(pyridin-3-yl-sulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
84.9% Dissolve 37.8g (0.20mol, 1.0eq) of compound 5- (2-fluorophenyl)-1H-pyrrole-3-carboxaldehyde in 150ml (4v / m) of DMF,Add 22.4g (0.40mol, 2.0eq) potassium hydroxide,1.6 g (5.0 mmol, 2.5%) of tetrabutylammonium bromide and 33.6 g (0.21 mol, 1.05 eq) of 3-pyridinesulfonyl chloride,After stirring the reaction at 50 55 for 1-2 hours, cool to room temperature.Add 31.1 g (0.40 mol, 2.0 eq) of a 40% methylamine in ethanol solution and 15.1 g (0.4 mol, 2.0 eq) of sodium borohydride, and react for 2 to 3 hours.Add 200ml ethyl acetate and water to extract,The ethyl acetate layer was adjusted to pH 2 to 3 by adding 0.5 M hydrochloric acid to obtain an organic layer a.The aqueous layer was added with 1M sodium hydroxide to adjust the pH to 9-10, and 200 ml (5v / m) of ethyl acetate was added for extraction to obtain an organic layer b.After mixing the organic layer a and the organic layer b, the organic layer obtained is stirred and dried with sodium sulfate,Add 400ml (10v / m) n-hexane, stir and crystallize at 0 10 , suction filter,The filter cake was washed with n-hexane, and dried under reduced pressure at 40 to 45 C for 3 to 4 hours.Vacuum degree ?-0.08Mpa,58.6 g of 1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl) -N-methylmethanamine was obtained in a yield of 84.9% , Purity 99.63%.
  • 32
  • [ 124-04-9 ]
  • [ 881681-00-1 ]
  • [ 2524458-14-6 ]
YieldReaction ConditionsOperation in experiment
89.9% In methanol; tert-butyl methyl ether at 20℃; for 12h; 5 Comparative Example 5: Preparation of 1 -[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H-pyrrol-3-yl]-N-methylmethanamine (vonoprazan) adipate salt 2.0 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (vonoprazan) was added to 6 mL of methyl alcohol. After complete dissolution, 0.89 g of adipic acid and 12 ml of methyl tert-butyl ether were added to precipitate crystals. After stirring at room temperature for 12 hours, the obtained solid was filtered, washed with a mixture of methyl alcohol and methyl tert-butyl ether, and dried to obtain 2.55 g of vonoprazan adipate. (Yield 89.9%, purity 99.78%)
  • 33
  • [ 881681-00-1 ]
  • [ 65-86-1 ]
  • [ 2524457-98-3 ]
YieldReaction ConditionsOperation in experiment
98% In acetone for 0.5h; Reflux; 1-5 Example 2: Preparation of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H-pyrrol-3-yl]-N-methylmethanamine (vonoprazan)orotate 2.5 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (vonoprazan) was added with 12.5 mL of acetone. After addition, 1.1 g of orotic acid was then added. After stirring at reflux for 30 minutes, the mixture was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with acetone, and dried to obtain 3.53 g of bonofrazan orotate. (Yield 98.0%, purity 99.85%)
  • 34
  • [ 881681-00-1 ]
  • [ 140-10-3 ]
  • [ 2524458-04-4 ]
YieldReaction ConditionsOperation in experiment
87% In ethyl acetate for 0.5h; Reflux; 2 Comparative Example 2: preparation of 1 -[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H-pyrrol-3-yl]-N-methylmethanamine (bonoprazane) of trans-cinnamate 2.0 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (Vonoprazan) was added to 20 mL of ethyl acetate. Then, 0.90 g of trans-cinnamic acid and 20 mL of methyl tert-butyl ether were added. After stirring at reflux for 30 minutes, the mixture was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with a mixture of ethyl acetate and methyl tert-butyl ether, and then dried to obtain 2.49 g of bonofrazan trans-cinnamate. (Yield 87.0%, purity 99.96%)
  • 35
  • [ 881681-00-1 ]
  • [ 5872-08-2 ]
  • [ 1621259-58-2 ]
YieldReaction ConditionsOperation in experiment
85.8% In methanol; ethyl acetate for 0.5h; Reflux; 3 Comparative Example 3:Preparation of camsylate of 1 -[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H-pyrrol-3-yl]-N-methylmethanamine (vonoprazan) 2.0 g of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (vonoprazan) in 6.0 mL of methyl alcohol And 50.0 mL of ethyl acetate were added, followed by addition of 1.35 g of camsylic acid. After stirring at reflux for 30 minutes, the mixture was cooled to room temperature and stirred for 12 hours. The obtained solid was filtered, washed with ethyl acetate, and dried to obtain 2.80 g of vonoprazan camsylate. (Yield 85.8%, purity 99.96%)
Same Skeleton Products
Historical Records

Similar Product of
[ 881681-00-1 ]

Chemical Structure| 881681-01-2

A108580[ 881681-01-2 ]

1-(5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine fumarate

Reason: Free-salt