WO2022222019A1 - Total synthesis of varenicline - Google Patents
Total synthesis of varenicline Download PDFInfo
- Publication number
- WO2022222019A1 WO2022222019A1 PCT/CN2021/088288 CN2021088288W WO2022222019A1 WO 2022222019 A1 WO2022222019 A1 WO 2022222019A1 CN 2021088288 W CN2021088288 W CN 2021088288W WO 2022222019 A1 WO2022222019 A1 WO 2022222019A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- acid
- compound
- chloride
- varenicline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
Definitions
- the present invention relates to a process for preparing varenicline or a pharmaceutically acceptable salt thereof.
- the present invention also relates to intermediate compounds which are useful in such process and to the preparation of such intermediate compounds.
- Varenicline chemically known as 7, 8, 9, 10-Tetrahydro-6, 10-methano-6H-pyrazino [2, 3-h] [3] benzazepine, is represented by formula (1) .
- Varenicline and its pharmaceutically salts such as varenicline tartrate is marketed by Pfizer under the trade name of CHANTIX TM as a partial agonist selective for certain subtypes of nicotinic receptors and indicated for smoking cessation.
- varenicline The synthesis of varenicline and its pharmaceutically salts were described in US6410550B1, US6890927B2, US2008/0275051A1, US8314235B2 and WO2018163190 A1. Most of the reported methods involve the following process:
- the nitration of formula (2) to form of formula (3) is followed by reduction and cyclization.
- the nitration reaction is vigorously exothermic, which can cause some safety issues in industrial production. Also it takes several steps for this process to construct the pyrazine ring.
- varenicline or a pharmaceutically acceptable salt thereof, in higher yield using cheaper and less toxic reagents.
- room temperature refers to a temperature ranging from about 15 °C to 35 °C, preferably to a temperature ranging from about 20 °C to 30 °C, more preferably to a temperature of 25 °C.
- salts includes, for example salts with an inorganic acid, e.g. hydrochloric acid, hydroiodic acid, phosphoric acid, phosphonic acid, sulfuric acid, hydrobromic acid or an organic acid, e.g. a carboxylic acid such as formic acid, acetic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, salicylic acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid, benzoic acid or a sulfonic acid such as p-toluene sulfonic acid or methanesulfonic acid.
- an inorganic acid e.g. hydrochloric acid, hydroiodic acid, phosphoric acid, phosphonic acid, sulfuric acid, hydrobromic acid or an organic acid, e.g. a carboxylic acid such as formic acid, acetic acid, citric acid, malic acid, maleic acid, tartaric acid, succ
- varenicline of Formula (1) In one aspect, a method for manufacturing varenicline of Formula (1) ,
- R is selected from the group consisting of H, –CH 3 , -CH 2 CH 3 , -C (CH 3 ) 3 .
- the above process is preferably carried out by isolating all intermediate compounds, namely intermediate compounds of formula (8) , (9) , (10) and (11) . Also preferably, the process is carried out without isolating intermediate compound of formula (8) , (9) , (10) and (11) . Even more preferably, the above process is carried out as a one-pot reaction, that is, without the need to isolate any of the intermediate compounds of formula (8) , (9) , (10) and (11) , but completing the whole conversion directly to varenicline, or a pharmaceutically acceptable salt thereof.
- the present application is based on the discovery of a novel, alternative approach to synthesizing varenicline.
- the synthesis described herein allows for the cost-effective preparation of varenicline by reducing production time and cost.
- R is selected from the group consisting of H, –CH 3 , -CH 2 CH 3 , -C (CH 3 ) 3 .
- the first step is a double Mannich reaction which is an effective method for the construction of C-N bond.
- This reaction can proceed under both acidic and basic conditions, but acidic conditions are more common.
- the base herein is selected from any organic and inorganic base such as TEA, DBU, DIPEA, KOH, K 2 CO 3 , NaOH, Na 2 CO 3, Cs 2 CO 3 , CsOH, K 3 PO 4 , K 2 HPO 4 , Na 3 PO 4 , and Na 2 HPO 4 .
- the acid herein is selected from any organic and inorganic acid such as HCl, H 2 SO 4 , H 3 PO 4 , KH 2 PO 4 , NaH 2 PO 4 , HBr, HClO 4 , HBF 4 , AcOH, Tartaric acid, Lactic acid, Citric acid, trifluoromethanesulfonic acid, trifluoroacetic acid and
- ester groups of formula (8) is hydrolyzed to carboxylic acid groups, which are then removed to form formula (9) .
- R is H
- formula (8) is directly converted to formula (9) by decarboxylation.
- a compound of formula (9) reacts with a Wittig reagent to incorporate a methylene group, leading to the formation of formula (10) .
- Other possible choice maybe any combination of a methylphosphonium salt and a base.
- a compound of formula (10) under goes an oxidative [4+2] reaction with pyrazine in the presence of a catalyst and an oxidant to form a compound of formula (11) .
- the catalyst is selected from the salts containing rare-earth elements, such as the salts of scandium, yttrium, cerium, lanthanum, samarium and europium.
- the catalyst is selected from Scandium chloride, Scandium nitrate, Scandium triflate, Scandium oxide, Yttrium oxide, Yttrium chloride, Yttrium trifluoromethanesulfonate, Yttrium nitrate, Lanthanum trifluoromethanesulfonate, Lanthanum acetylacetonate, Lanthanum chloride, Lanthanum oxide, Cerium Trifluoromethanesulfonate, Cerium chloride, Ammonium cerium sulfate, Ammonium cerium nitrate, Samarium chloride, Samarium nitrate, Europium chloride, Europium oxide and Europium nitrate.
- the oxidant is selected from dioxygen, hydrogen peroxide, organic peroxides, inorganic persulfate and inorganic peroxymonosulfate.
- Formula (11) is treated by hydrogen in the presence of palladium catalyst to form varenicline of Formula (1) .
- Desired compound of formula (10) was obtained as colorless oil. Yield: 19 g, 84%.
- the aqueous layers were combined and washed with dichloromethane (200 ml) .
- the aqueous layer was basified by adding aqueous sodium carbonate solution (20 g in 300 ml water) .
- the aqueous layer was extracted with dichloromethane (3X 150 mL) .
- the dichloromethane layers were combined, washed with water (300 mL) then with 0.5%EDTA solution (200 ml) and again with water (300 mL) .
- the organic layer was dried over sodium sulphate and concentrated to get oil, which solidified on standing. Yield: 9.5 g, 90%.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Provided is a method for the preparation of varenicline or a pharmaceutically acceptable salt thereof. In addition, Also provided are intermediate compounds which are useful in such method.
Description
The present invention relates to a process for preparing varenicline or a pharmaceutically acceptable salt thereof. The present invention also relates to intermediate compounds which are useful in such process and to the preparation of such intermediate compounds.
Varenicline, chemically known as 7, 8, 9, 10-Tetrahydro-6, 10-methano-6H-pyrazino [2, 3-h] [3] benzazepine, is represented by formula (1) .
Varenicline and its pharmaceutically salts such as varenicline tartrate is marketed by Pfizer under the trade name of CHANTIX
TM as a partial agonist selective for certain subtypes of nicotinic receptors and indicated for smoking cessation.
The synthesis of varenicline and its pharmaceutically salts were described in US6410550B1, US6890927B2, US2008/0275051A1, US8314235B2 and WO2018163190 A1. Most of the reported methods involve the following process:
The nitration of formula (2) to form of formula (3) is followed by reduction and cyclization. Generally, the nitration reaction is vigorously exothermic, which can cause some safety issues in industrial production. Also it takes several steps for this process to construct the pyrazine ring.
The above mentioned process has several disadvantages: high costs inherent to long reaction sequences, expensive reagents and/or catalysts, safety concerns and inconvenient operation conditions.
Therefore, there still remains a need to improve such process and develop an efficient, simple and industrially viable synthetic route, which can overcome the drawbacks of the prior art.
In order to overcome the problems associated with the prior art, it is herein described a new and improved process which provides varenicline, or a pharmaceutically acceptable salt thereof, in higher yield using cheaper and less toxic reagents.
DEFINITIONS
The following definitions are used in connection with the present application, unless it is indicated otherwise.
The term "room temperature" refers to a temperature ranging from about 15 ℃ to 35 ℃, preferably to a temperature ranging from about 20 ℃ to 30 ℃, more preferably to a temperature of 25 ℃.
The term "pharmaceutically acceptable salts" , includes, for example salts with an inorganic acid, e.g. hydrochloric acid, hydroiodic acid, phosphoric acid, phosphonic acid, sulfuric acid, hydrobromic acid or an organic acid, e.g. a carboxylic acid such as formic acid, acetic acid, citric acid, malic acid, maleic acid, tartaric acid, succinic acid, salicylic acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid, benzoic acid or a sulfonic acid such as p-toluene sulfonic acid or methanesulfonic acid.
ABBREVIATIONS
Bn benzyl
TFA trifluoroacetic acid
CAN Diammonium cerium (IV) nitrate
TBHP tert-butyl hydroperoxide
DCM dichloromethane
SUMMARY OF THE INVENTION
In one aspect, a method for manufacturing varenicline of Formula (1) ,
or a pharmaceutically acceptable salt thereof, which comprises the steps of:
(a) Reacting a compound of formula (6) with formaldehyde and benzylamine (7) in the presence of an acid or a base to form the compound of formula (8) ,
wherein R is selected from the group consisting of H, –CH
3, -CH
2CH
3, -C (CH
3)
3.
(b) Converting a compound of formula (8) to formula (9) by decarboxylation,
(C) Reacting a compound of formula (9) with Ph
3P=CH
2 to form a compound of formula (10)
(d) Reacting a compound of formula (10) with pyrazine in the presence of a catalyst and an oxidant to form a compound of formula (11) ,
(e) Removing the protecting group -Bn from formula (11) to form varenicline of Formula (1) .
The above process is preferably carried out by isolating all intermediate compounds, namely intermediate compounds of formula (8) , (9) , (10) and (11) . Also preferably, the process is carried out without isolating intermediate compound of formula (8) , (9) , (10) and (11) . Even more preferably, the above process is carried out as a one-pot reaction, that is, without the need to isolate any of the intermediate compounds of formula (8) , (9) , (10) and (11) , but completing the whole conversion directly to varenicline, or a pharmaceutically acceptable salt thereof.
The present application is based on the discovery of a novel, alternative approach to synthesizing varenicline. The synthesis described herein allows for the cost-effective preparation of varenicline by reducing production time and cost.
This approach provides a step-economical method for the low cost production of varenicline. In order to realize a strategy based on cheap, readily available chemical inputs, step economy, and overall efficiency, novel reactions are relied on to build in significant molecular complexity at each synthetic step.
In a first aspect, a synthetic method is provided as outlined below:
The synthesis is started by the reaction of a compound of formula (6) with formaldehyde and benzylamine (7) in the presence of an acid or a base to form the compound of formula (8) . For formula (6) , R is selected from the group consisting of H, –CH
3, -CH
2CH
3, -C (CH
3)
3.
The first step is a double Mannich reaction which is an effective method for the construction of C-N bond. This reaction can proceed under both acidic and basic conditions, but acidic conditions are more common. For a basic condition, the base herein is selected from any organic and inorganic base such as TEA, DBU, DIPEA, KOH, K
2CO
3, NaOH, Na
2CO
3, Cs
2CO
3, CsOH, K
3PO
4, K
2HPO
4, Na
3PO
4, and Na
2HPO
4. For an acidic condition, the acid herein is selected from any organic and inorganic acid such as HCl, H
2SO
4, H
3PO
4, KH
2PO
4, NaH
2PO
4, HBr, HClO
4, HBF
4, AcOH, Tartaric acid, Lactic acid, Citric acid, trifluoromethanesulfonic acid, trifluoroacetic acid and
p-toluenesulfonic acid.
Next, the ester groups of formula (8) is hydrolyzed to carboxylic acid groups, which are then removed to form formula (9) . Alternatively, if R is H, formula (8) is directly converted to formula (9) by decarboxylation.
A compound of formula (9) reacts with a Wittig reagent to incorporate a methylene group, leading to the formation of formula (10) . One of the most straightforward Wittig reagent herein is Ph
3P=CH
2. Other possible choice maybe any combination of a methylphosphonium salt and a base.
A compound of formula (10) under goes an oxidative [4+2] reaction with pyrazine in the presence of a catalyst and an oxidant to form a compound of formula (11) . Herein, the catalyst is selected from the salts containing rare-earth elements, such as the salts of scandium, yttrium, cerium, lanthanum, samarium and europium. More preferably, the catalyst is selected from Scandium chloride, Scandium nitrate, Scandium triflate, Scandium oxide, Yttrium oxide, Yttrium chloride, Yttrium trifluoromethanesulfonate, Yttrium nitrate, Lanthanum trifluoromethanesulfonate, Lanthanum acetylacetonate, Lanthanum chloride, Lanthanum oxide, Cerium Trifluoromethanesulfonate, Cerium chloride, Ammonium cerium sulfate, Ammonium cerium nitrate, Samarium chloride, Samarium nitrate, Europium chloride, Europium oxide and Europium nitrate. The oxidant is selected from dioxygen, hydrogen peroxide, organic peroxides, inorganic persulfate and inorganic peroxymonosulfate.
Formula (11) is treated by hydrogen in the presence of palladium catalyst to form varenicline of Formula (1) .
EXAMPLE
Detailed experimental parameters suitable for the preparation of varenicline or pharmaceutically acceptable salts thereof according to the present invention are provided by the following examples, which are intended to be illustrative and not limiting.
Unless otherwise noted, all materials, solvents and reagents, including anhydrous solvents such as DMF and DCM, were obtained from commercial suppliers, of the best grade, and used without further purification. All reactions involving air-or moisture-sensitive compounds were performed under nitrogen or argon atmosphere, unless otherwise noted.
The
1H (400MHz) and
13C NMR (100MHz) data were recorded on Bruker AVANCE Ⅱ 400MHz spectrometer using CDCl
3 or DMSO-D
6 as solvent. The chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz.
1H NMR spectra was recorded with tetramethylsilane (δ= 0.00 ppm) as internal reference;
13C NMR spectra was recorded with CDCl
3 (δ = 77.00 ppm) or DMSO-D
6 (δ = 39.5 ppm) as internal reference.
The synthesis of compound of formula (8a) from methyl 4-acetoxy-2, 3-dioxocyclopentane-1-carboxylate (6a) :
A mixture of methyl 4-acetoxy-2, 3-dioxocyclopentane-1-carboxylate (6a) (21.4 g, 100 mmol) , formaldehyde (6.6 g, 220 mmol) , phenylmethanamine (11.8 g, 110 mmol) , TFA (100 mL) , and DCM (100 mL) was refluxed for 8 h. Then the reaction mixture was concentrated to a volume of 50 mL before being partitioned between ethyl acetate (300 mL) and water (100 mL) . The combined organics were dried over MgSO
4, filtered and concentrated in vacuum to give a crude product, which was used directly for next step. Desired compound of formula (8a) was obtained as colorless oil. Yield: 30 g, 88%.
The synthesis of compound of formula (8a) from methyl 4-acetoxy-2, 3-dioxocyclopentane-1-carboxylate (6a) :
A mixture of methyl 4-acetoxy-2, 3-dioxocyclopentane-1-carboxylate (6a) (21.4 g, 100 mmol) , formaldehyde (6.6 g, 220 mmol) , phenylmethanamine (11.8 g, 110 mmol) , AcOH (100 mL) , and DCM (100 mL) was refluxed for 8 h. Then the reaction mixture was concentrated to a volume of 50 mL before being partitioned between ethyl acetate (300 mL) and water (100 mL) . The combined organics were dried over MgSO
4, filtered and concentrated in vacuum to give a crude product, which was used directly for next step. Desired compound of formula (8a) was obtained as colorless oil. Yield: 28 g, 82%.
The synthesis of compound of formula (8b) from 4, 5-dioxocyclopentane-1, 3-dicarboxylic acid (6b) :
A mixture of 4, 5-dioxocyclopentane-1, 3-dicarboxylic acid (6b) (18.6 g, 100 mmol) , formaldehyde (6.6 g, 220 mmol) , phenylmethanamine (11.8 g, 110 mmol) , TFA (50 mL) , and DCM (100 mL) was refluxed for 8 h. Then the reaction mixture was concentrated to a volume of 50 mL before being partitioned between ethyl acetate (300 mL) and water (100 mL) . The combined organics were dried over MgSO
4, filtered and concentrated in vacuum to give a crude product, which was used directly for next step. Desired compound of formula (8b) was obtained as white solid. Yield: 27 g, 85%.
The synthesis of compound of formula (9) from formula (8a) :
A mixture of compound of formula (8a) (34.5 g, 100 mmol) , DMSO (50 mL) , and H
2O (100 mL) was refluxed for 8 h. Then the reaction mixture was partitioned between ethyl acetate (300 mL) and water (100 mL) . The combined organics were dried over MgSO
4, filtered and concentrated in vacuum to give a crude product, which was purified by flash chromatography (hexane/ethyl acetate 5/1 eluent) . Desired compound of formula (9) was obtained as colorless oil. Yield: 19 g, 83%.
1H NMR (400 MHz, CDCl
3) δ 7.26-7.30 (m, 2H) , 7.20-7.24 (m, 3H) , 3.62 (s, 2H) , 2.75 (dd, J= 7.0, 12.4 Hz, 2H) , 2.50 (dd, J= 7.0, 12.4 Hz, 2H) , 2.34-2.38 (m, 2H) , 2.20-2.23 (m, 1H) , 1.98-2.21 (m, 1H) .
13C NMR (100 MHz, CDCl
3) δ 202.0, 138.6, 128.8, 128.4, 127.2, 64.7, 55.0, 44.7, 15.5. ESI-TOF-HRMS calculated for C
14H
15NO
2Na (M+Na) 252.0995, found 252.0987.
The synthesis of compound of formula (9) from formula (8b) :
A mixture of compound of formula (8b) (31.7 g, 100 mmol) , and DMSO (100 mL) , was stirred at 120 ℃ for 5 h. Then the reaction mixture was partitioned between ethyl acetate (300 mL) and water (100 mL) . The combined organics were dried over MgSO
4, filtered and concentrated in vacuum to give a crude product, which was purified by flash chromatography (hexane/ethyl acetate 5/1 eluent) . Desired compound of formula (9) was obtained as colorless oil. Yield: 20 g, 87%.
1H NMR (400 MHz, CDCl
3) δ 7.26-7.30 (m, 2H) , 7.20-7.24 (m, 3H) , 3.62 (s, 2H) , 2.75 (dd, J= 7.0, 12.4 Hz, 2H) , 2.50 (dd, J= 7.0, 12.4 Hz, 2H) , 2.34-2.38 (m, 2H) , 2.20-2.23 (m, 1H) , 1.98-2.21 (m, 1H) .
13C NMR (100 MHz, CDCl
3) δ 202.0, 138.6, 128.8, 128.4, 127.2, 64.7, 55.0, 44.7, 15.5. ESI-TOF-HRMS calculated for C
14H
15NO
2Na (M+Na) 252.0995, found 252.0987.
The synthesis of compound of formula (10) from (9)
To a solution of compound of formula (9) (22.9 g, 100 mmol) in THF (200 mL) , was added dropwise a solution of Ph
3P=CH
2 (60.8 g, 220 mmol) in THF (200 mL) . The reaction mixture was stirred at room temperature for 20 h before being quenched by water (100 mL) . The resulted solution was partitioned between ethyl acetate (300 mL) and water (100 mL) . The combined organics were dried over MgSO
4, filtered and concentrated in vacuum to give a crude product, which was purified by flash chromatography (hexane/ethyl acetate 8/1 eluent) . Desired compound of formula (10) was obtained as colorless oil. Yield: 19 g, 84%.
1H NMR (400 MHz, CDCl
3) δ 7.26-7.30 (m, 2H) , 7.20-7.24 (m, 3H) , 5.06 (d, J=2.4 Hz, 2H) , 5.03 (d, J= 2.4 Hz, 2H) , 3.62 (s, 2H) , 2.46 (dd, J= 7.0, 12.4 Hz, 2H) , 2.21 (dd, J= 7.0, 12.4 Hz, 2H) , 2.17-2.21 (m, 2H) , 1.61-1.64 (m, 1H) , 1.36-1.39 (m, 1H) .
13C NMR (100 MHz, CDCl
3) δ 149.6, 138.6, 128.8, 128.4, 127.2, 103.5, 65.7, 59.0, 41.7, 35.5. ESI-TOF-HRMS calculated for C
16H
19N
9Na (M+Na) 248.1410, found 248.1433.
The synthesis of compound of formula (11) from (10) with CAN and O
2:
To a stirring mixture of compound of formula (10) (22.5 g, 100 mmol) and pyrazine (8.8 g, 110 mmol) in MeCN (100 mL) , was added CAN (1.6 g, 3 mmol) . The reaction mixture was stirred at 80 ℃ for 5 h before being connected to an O
2 balloon. The reaction mixture was stirred for another 8 h in the presence of O
2. Finally, the mixture was cooled and partitioned between ethyl acetate (300 mL) and water (100 mL) . The combined organics were dried over MgSO
4, filtered and concentrated in vacuum to give a crude product, which was purified by flash chromatography (hexane/ethyl acetate 4/1 eluent) . Desired compound of formula (11) was obtained as colorless oil. Yield: 26 g, 86%.
1H NMR (400 MHz, CDCl
3) δ 8.77 (s, 2H) , 7.79 (s, 2H) , 7.06-7.16 (m, 3H) , 6.79-6.89 (m, 2H) , 3.48 (s, 2H) , 3.30-3.41 (m, 2H) , 2.94-3.06 (m, 2H) , 2.57 (d, J= 10.2 Hz, 2H) , 2.28-2.39 (m, 1H) , 1.86 (d, J= 10.8 Hz, 1H) ,
13C NMR (100 MHz, CDCl
3) δ150.86 143.31, 143.25, 138.08, 128.23, 127.93, 126.59, 20.38 61.45, 57.32, 43.08, 41.2. ESI-TOF-HRMS calculated for C
20H
19N
3Na (M+Na) 324.1471, found 324.1460.
The synthesis of compound of formula (11) from (10) with Scandium triflate and TBHP:
To a stirring mixture of compound of formula (10) (22.5 g, 100 mmol) and pyrazine (8.8 g, 110 mmol) in MeCN (100 mL) , was added Scandium triflate (1.5 g, 3 mmol) . The reaction mixture was stirred at 80 ℃ for 5 h before TBHP (9.9 g, 110 mmol) was added. The reaction mixture was stirred for another 8 h at 80 ℃
. Finally, the mixture was cooled and partitioned between ethyl acetate (300 mL) and water (100 mL) . The combined organics were dried over MgSO
4, filtered and concentrated in vacuum to give a crude product, which was purified by flash chromatography (hexane/ethyl acetate 4/1 eluent) . Desired compound of formula (11) was obtained as colorless oil. Yield: 24 g, 79%.
1H NMR (400 MHz, CDCl
3) δ 8.77 (s, 2H) , 7.79 (s, 2H) , 7.06-7.16 (m, 3H) , 6.79-6.89 (m, 2H) , 3.48 (s, 2H) , 3.30-3.41 (m, 2H) , 2.94-3.06 (m, 2H) , 2.57 (d, J= 10.2 Hz, 2H) , 2.28-2.39 (m, 1H) , 1.86 (d, J= 10.8 Hz, 1H) ,
13C NMR (100 MHz, CDCl
3) δ150.86 143.31, 143.25, 138.08, 128.23, 127.93, 126.59, 20.38 61.45, 57.32, 43.08, 41.2. ESI-TOF-HRMS calculated for C
20H
19N
3Na (M+Na) 324.1471, found 324.1460.
The synthesis of compound of formula (11) from (10) with Yttrium triflate and Na
2S
2O
8:
To a stirring mixture of compound of formula (10) (22.5 g, 100 mmol) and pyrazine (8.8 g, 110 mmol) in DMF (100 mL) , was added Yttrium triflate (1.6 g, 3 mmol) . The reaction mixture was stirred at 80 ℃ for 5 h before Na
2S
2O
8 (26.2 g, 110 mmol) was added. The reaction mixture was stirred for another 8 h at 80 ℃
. Finally, the mixture was cooled and partitioned between ethyl acetate (300 mL) and water (100 mL) . The combined organics were dried over MgSO
4, filtered and concentrated in vacuum to give a crude product, which was purified by flash chromatography (hexane/ethyl acetate 4/1 eluent) . Desired compound of formula (11) was obtained as colorless oil. Yield: 25 g, 82%.
1H NMR (400 MHz, CDCl
3) δ 8.77 (s, 2H) , 7.79 (s, 2H) , 7.06-7.16 (m, 3H) , 6.79-6.89 (m, 2H) , 3.48 (s, 2H) , 3.30-3.41 (m, 2H) , 2.94-3.06 (m, 2H) , 2.57 (d, J= 10.2 Hz, 2H) , 2.28-2.39 (m, 1H) , 1.86 (d, J= 10.8 Hz, 1H) ,
13C NMR (100 MHz, CDCl
3) δ150.86 143.31, 143.25, 138.08, 128.23, 127.93, 126.59, 20.38 61.45, 57.32, 43.08, 41.2. ESI-TOF-HRMS calculated for C
20H
19N
3Na (M+Na) 324.1471, found 324.1460.
The synthesis of compound of formula (11) from (10) with Lanthanum triflate and KHSO
5:
To a stirring mixture of compound of formula (10) (22.5 g, 100 mmol) and pyrazine (8.8 g, 110 mmol) in DMF (100 mL) , was added Lanthanum triflate (1.8g, 3 mmol) . The reaction mixture was stirred at 80 ℃ for 5 h before KHSO
5 (16.6 g, 110 mmol) was added. The reaction mixture was stirred for another 8 h at 80 ℃
. Finally, the mixture was cooled and partitioned between ethyl acetate (300 mL) and water (100 mL) . The combined organics were dried over MgSO
4, filtered and concentrated in vacuum to give a crude product, which was purified by flash chromatography (hexane/ethyl acetate 4/1 eluent) . Desired compound of formula (11) was obtained as colorless oil. Yield: 24 g, 79%.
1H NMR (400 MHz, CDCl
3) δ 8.77 (s, 2H) , 7.79 (s, 2H) , 7.06-7.16 (m, 3H) , 6.79-6.89 (m, 2H) , 3.48 (s, 2H) , 3.30-3.41 (m, 2H) , 2.94-3.06 (m, 2H) , 2.57 (d, J= 10.2 Hz, 2H) , 2.28-2.39 (m, 1H) , 1.86 (d, J= 10.8 Hz, 1H) ,
13C NMR (100 MHz, CDCl
3) δ150.86 143.31, 143.25, 138.08, 128.23, 127.93, 126.59, 20.38 61.45, 57.32, 43.08, 41.2. ESI-TOF-HRMS calculated for C
20H
19N
3Na (M+Na) 324.1471, found 324.1460.
The synthesis of varenicline from compound of formula (11) :
A mixture of compound of formula (11) (15 g, 50 mmol) , and 10%Pd-C (1.5 g) in MeOH (100 mL) was stirred under hydrogen atmosphere until the absorption of hydrogen ceased (3 h) ; the hydrogenation was carried out on an atmospheric pressure hydrogenator. After the Pd-C catalyst was filtered off, the solvent was removed by rotary evaporation. The resulted crude product was dissolved in dichloromethane (300 mL) and aqueous HCl (Concentrated HCl, 16 ml + water 300 mL) was added, followed by stirring for 30 mins. The separated organic layer was washed with water (200 ml) . The organic layer was discarded. The aqueous layers were combined and washed with dichloromethane (200 ml) . The aqueous layer was basified by adding aqueous sodium carbonate solution (20 g in 300 ml water) . The aqueous layer was extracted with dichloromethane (3X 150 mL) . The dichloromethane layers were combined, washed with water (300 mL) then with 0.5%EDTA solution (200 ml) and again with water (300 mL) . The organic layer was dried over sodium sulphate and concentrated to get oil, which solidified on standing. Yield: 9.5 g, 90%. Mp: 137–139 ℃; IR (KBr, cm
-1) : 3342, 2949, 2924, 2852, 1473, 1354;
1H NMR (400 MHz; CDCl
3) δ 8.75 (s, 2H) , 7.83 (s, 2H) , 3.25 (brs, 2H) , 3.15 (d, J = 13.0 Hz, 2H) , 2.92 (d, J = 13.0 Hz, 2H) , 2.48 (m, 1H) , 2.09 (d, J = 8.8 Hz, 1H) , 1.82 (brs, 1H) ;
13C NMR (100 MHz; CDCl3) δ 149.6, 143.5, 143.6, 121.7, 50.5, 43.1, 42.2; Mass (ESI) : 212 [M+H]
+ ; HRMS (ESI) : calcd for C
13H
14N
3 [M+H]
+ 212.1188, found 212.1196.
Claims (7)
- A method for manufacturing varenicline of Formula (1) ,or a pharmaceutically acceptable salt thereof, which comprises the steps of:Step 1: Reacting a compound of formula (6) with formaldehyde and benzylamine (7) in the presence of an acid or base to form the compound of formula (8) ,wherein R is selected from the group consisting of H, –CH 3, -CH 2CH 3, -C (CH 3) 3.Step 2: Converting a compound of formula (8) to formula (9) by decarboxylation,Step 3: Reacting a compound of formula (9) with a Wittig reagent, such as Ph 3P=CH 2 to form a compound of formula (10)Step 4: Reacting a compound of formula (10) with pyrazine in the presence of a catalyst and an oxidant to form a compound of formula (11) ,Step 5: Removing the protecting group -Bn from formula (11) to form varenicline of Formula (1)
- The method of claim 1, wherein the acid of Step 1 is selected from any organic and inorganic acid such as HCl, H 2SO 4, H 3PO 4, KH 2PO 4, NaH 2PO 4, HBr, HClO 4, HBF 4, AcOH, Tartaric acid, Lactic acid, Citric acid, trifluoromethanesulfonic acid, trifluoroacetic acid and p-toluenesulfonic acid.
- The method of claim 1, wherein the base of Step 1 is selected from TEA, DBU, DIPEA, KOH, K 2CO 3, NaOH, Na 2CO 3, Cs 2CO 3, CsOH, K 3PO 4, K 2HPO 4, Na 3PO 4, and Na 2HPO 4.
- The method of claim 1, wherein the catalyst of Step 4 is selected from Scandium chloride, Scandium nitrate, Scandium triflate, Scandium oxide, Yttrium oxide, Yttrium chloride, Yttrium trifluoromethanesulfonate, Yttrium nitrate, Lanthanum trifluoromethanesulfonate, Lanthanum acetylacetonate, Lanthanum chloride, Lanthanum oxide, Cerium Trifluoromethanesulfonate, Cerium chloride, Ammonium cerium sulfate, Ammonium cerium nitrate, Samarium chloride, Samarium nitrate, Europium chloride, Europium oxide and Europium nitrate.
- The method of claim 1, wherein the oxidant of Step 4 is selected from dioxygen, hydrogen peroxide, organic peroxides, inorganic persulfate and inorganic peroxymonosulfate.
- The method of claim 1, wherein the Formula (11) is treated by hydrogen in the presence of palladium catalyst to form varenicline of Formula (1) in Step 5
- The method of claim 6, wherein the palladium catalyst of Step 5 is selected from palladium on carbon, Pd (OH) 2, PdCl 2, and Pd (OAc) 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2021/088288 WO2022222019A1 (en) | 2021-04-20 | 2021-04-20 | Total synthesis of varenicline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2021/088288 WO2022222019A1 (en) | 2021-04-20 | 2021-04-20 | Total synthesis of varenicline |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022222019A1 true WO2022222019A1 (en) | 2022-10-27 |
Family
ID=83723679
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2021/088288 Ceased WO2022222019A1 (en) | 2021-04-20 | 2021-04-20 | Total synthesis of varenicline |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2022222019A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1285821A (en) * | 1997-12-31 | 2001-02-28 | 辉瑞产品公司 | Aryl Fused azapolycyclic compounds |
| CN101128462A (en) * | 2005-02-24 | 2008-02-20 | 辉瑞产品有限公司 | Preparation of High Purity Substituted Quinoxalines |
| WO2010023561A1 (en) * | 2008-09-01 | 2010-03-04 | Actavis Group Ptc Ehf | Process for preparing varenicline, varenicline intermediates, and pharmaceutically acceptable salts thereof |
-
2021
- 2021-04-20 WO PCT/CN2021/088288 patent/WO2022222019A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1285821A (en) * | 1997-12-31 | 2001-02-28 | 辉瑞产品公司 | Aryl Fused azapolycyclic compounds |
| CN101128462A (en) * | 2005-02-24 | 2008-02-20 | 辉瑞产品有限公司 | Preparation of High Purity Substituted Quinoxalines |
| WO2010023561A1 (en) * | 2008-09-01 | 2010-03-04 | Actavis Group Ptc Ehf | Process for preparing varenicline, varenicline intermediates, and pharmaceutically acceptable salts thereof |
Non-Patent Citations (1)
| Title |
|---|
| AFSAH A. M., OSMAN A. I., SOFAN M.: "Condensation of 4-phenyl-3,5-dicarboethoxycyclopentane-1,2-dione with primary amines", JOURNAL FüR PRAKTISCHE CHEMIE : PRACTICAL APPLICATIONS AND APPLIED CHEMISTRY : COVERING ALL ASPECTS OF APPLIED CHEMISTRY, WILEY, DE, vol. 331, no. 3, 1 January 1989 (1989-01-01), DE , pages 461 - 465, XP055980269, ISSN: 0021-8383, DOI: 10.1002/prac.19893310317 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5373764B2 (en) | Novel opiate reduction using catalytic hydrogen transfer reaction | |
| HU221609B (en) | A method for preparation of arthropodicidal oxadiazines and intermediers and the intermediers | |
| HU198437B (en) | Process for producing mono- or bis-carbonyl-compounds | |
| JP2008546688A (en) | Synthetic route to 14-hydroxyl opiates via 1-halo-thebaine or analogs | |
| CN114835645A (en) | Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine | |
| KR20090083455A (en) | Imatinib and their intermediates and preparation methods thereof | |
| CN113185513B (en) | Method for synthesizing Vanillan | |
| CN112300072A (en) | High-yield synthesis method of 5-iodoisoquinoline compounds | |
| CN114436873B (en) | Preparation method of tranexamic acid | |
| WO2022222019A1 (en) | Total synthesis of varenicline | |
| KR20240024937A (en) | Method for producing CYP11A1 inhibitors and intermediates thereof | |
| TW202206412A (en) | Methods for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionate and hydrochloric acid salts thereof | |
| JP3929545B2 (en) | Method for producing 3-acetyl-cyclopentanecarboxylic acid ester | |
| KR20180116371A (en) | Process for producing 4-alkoxy-3-hydroxypicolic acid | |
| JP4558709B2 (en) | Novel process for producing 4-aminomethyl-3-alkoxyiminopyrrolidine methanesulfonate | |
| US20040087794A1 (en) | Process for preparing zolpidem | |
| KR20180118054A (en) | Production Method of Intermediate Compound for Synthesizing Medicament | |
| CN113956204A (en) | Synthesis method of anserine | |
| CN119504729A (en) | A preparation method of Beclin1-ATG14L interaction inhibitor | |
| CN121248489A (en) | Preparation method of elegance intermediate 2-chloro-4- (4-fluoro-2-methylphenyl) -5-aminopyridine | |
| JP2003137843A (en) | Alicyclic tetracarboxylic acid compound and method for producing the same | |
| KR100359256B1 (en) | Improved method of preparing lansoprazole | |
| JPH0570434A (en) | Production of novel 2-hydroxymethyl-4-methoxy-3,5-dimethylpyridine and its intermediate and their production | |
| CN113717178B (en) | Intermediate of SHP2 inhibitor and preparation method thereof | |
| CN110003121A (en) | A kind of 3,4- dihydroquinazoline derivatives and preparation method thereof, application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21937270 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 21937270 Country of ref document: EP Kind code of ref document: A1 |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 21937270 Country of ref document: EP Kind code of ref document: A1 |
|
| 32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 10/01/2025) |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 21937270 Country of ref document: EP Kind code of ref document: A1 |