CN112250615A - Preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride - Google Patents
Preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of a tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride. The synthesis method is that 3-bromo-4-methylpyridine is used as an initial raw material and undergoes substitution reaction with amine to obtain a compound III, and the compound III is subjected to acetyl or tert-butyloxycarbonyl protection and catalytic hydrogenation to obtain a piperidine compound V. And carrying out reductive amination on the compound V and benzaldehyde or reacting with benzyl halide to obtain a compound VI. And (3) removing the protecting group of the compound VI and simultaneously forming a hydrochloride compound I & 2 HCl. The synthesis method has the advantages of simple operation, high total yield, high product purity and stable quality, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of a tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride, and particularly relates to a preparation method of cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride.
Background
Tofacitinib Citrate (Tofacitinib Citrate, structure shown in formula) was developed by Perey, and was approved by FDA in 11 months of 2012 for sale in the United states under the trade name of Tofacitinib Citrate
The preparation is a tablet, and the specification is 5mg (calculated by tofacitinib). Suitable for the treatment of adult patients with moderate to severe active rheumatoid arthritis who have an inadequate or intolerant response to methotrexate, and which are useful as monotherapy or in combination with methotrexate or other non-biological, disease modifying antirheumatic drugs (DMARDs).
Tofacitinib citrate
As an important intermediate of tofacitinib, cis-1-benzyl-N, 4-dimethylpiperidine-3-amine (I), the development work of the synthesis process is always an important object for research of chemists, and at present, the following synthesis reports mainly exist for the compound.
The literature (Organic process research and development, 2003,7,115-120) reports a preparation method of tofacitinib intermediate (I), and the synthetic route is shown as the following (formula 1).
The route of the formula 1 takes 4-methylpyridine as a starting material, forms pyridinium salt with benzyl chloride, is reduced by sodium borohydride, is oxidized by hydroboration and Parikh-Doering into piperidone, and is subjected to reductive amination to obtain a key intermediate I. In the reaction, anhydrous, anaerobic and ultralow temperature reaction is needed in the hydroboration oxidation reaction process, the reaction conditions are harsh, and the requirements on production operation are high.
The literature (Organic process research and development, 2005,9,51-56) reports a preparation method of tofacitinib intermediate (I), and the synthetic route is as follows (formula 2).
The route of the formula 2 is that 3-amino-4-methylpyridine is used as an initial raw material, and rhodium carbon is reduced into a piperidine ring through an amine ester exchange reaction, and then the piperidine ring and benzaldehyde are subjected to reductive amination and lithium aluminum hydride reduction to obtain a key intermediate I. The use of lithium aluminum hydride in the process undoubtedly increases the safety risk in industrial production.
WO2007012953 discloses a preparation method of tofacitinib intermediate (I), and the synthetic route is as follows (formula 3)
The scheme of formula 3 is similar to the above scheme, and the final reduction step also requires the use of hazardous lithium aluminum hydride.
The literature (Organic Process Research & Development 2014,18, 1714-.
The route of formula 4 also uses 3-amino-4-methylpyridine as starting material, protected by aminoacetyl group, and reacts with benzyl chloride to form pyridinium salt, which is reduced by sodium borohydride and then hydrolyzed by acid to obtain piperidone, and then the key intermediate I is obtained by reductive amination. Although the method avoids the use of expensive noble metal catalyst and the use of lithium aluminum hydride, the method has long route and also has the problem of expensive raw materials.
Patent WO2014097150 discloses a preparation method of tofacitinib intermediate (i), which has a synthetic route as follows (formula 5):
patent CN201810822703 discloses a preparation method of tofacitinib intermediate (i), and the synthetic route thereof is as follows (formula 6):
formula 5 and formula 6 both start with 4-methylpyridine, differing in the sequence of the Ullman coupling reaction with methylamine and the formation of the pyridinium salt with the benzyl halide.
By analyzing the synthetic route for preparing the tofacitinib intermediate (I) reported in the literature, raw materials used directly in the preparation process are not easy to obtain, or lithium aluminum hydride with extremely high safety risk needs to be used, or lithium aluminum hydride and benzyl halide form pyridinium salt and then are reduced by sodium borohydride, the reaction system is complex, the yield is low, the three wastes are huge, a large amount of reagent solvents are wasted, the environment is greatly polluted, the competitiveness is weak, and the preparation of I in an economic mode is not facilitated.
With the further development of the pharmaceutical industry in China, the quality requirement on the pharmaceutical intermediates is higher and higher, and the existing production process cannot meet the requirement. The repeated purification will increase the cost greatly and produce a large amount of waste solvent, which will cause environmental pollution. How to produce high-purity and high-quality intermediates becomes a problem to be solved urgently.
Disclosure of Invention
The invention aims to: aiming at the existing process for producing the tofacitinib intermediate, the purification needs to be carried out for many times, and a large amount of waste solvent is generated; the invention provides a preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride, which has the advantages of simple operation, high yield, high product purity and stable quality and is suitable for large-scale production.
The technical scheme adopted by the invention is as follows:
a preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride comprises the following synthetic route:
the method specifically comprises the following steps:
(1) carrying out Ullmann coupling reaction on the compound II and methylamine under the catalysis of copper to obtain a compound III;
(2) protecting an amino group of the compound III obtained in the step (1) to obtain a compound IV;
(3) carrying out catalytic hydrogenation on the compound IV obtained in the step (2) to obtain a compound V which is mainly cis;
(4) carrying out reductive amination on the compound V obtained in the step (3) and benzaldehyde to obtain a compound VI, or reacting the compound V with benzyl halide under the action of an acid-binding agent to obtain the compound VI;
(5) and (3) dissolving the compound VI obtained in the step (4) in an organic solvent, adding an alcoholic solution of hydrogen chloride or concentrated hydrochloric acid, removing a protecting group, and salifying and purifying to obtain the double hydrochloride of the compound I.
Wherein, the methylamine in the step (1) is methylamine water solution, methylamine alcohol solution, methylamine tetrahydrofuran solution, methylamine hydrochloride or methylamine sulfate; the solvent is water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or any combination of the above solvents. The reaction temperature range is 80-150 ℃.
Wherein, the protecting group in the step (2) is acetyl or tert-butyloxycarbonyl; the base is sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, N-dimethylaminopyridine, triethylamine, diisopropylethylamine or pyridine; the reaction solvent is methanol, ethanol, toluene, tetrahydrofuran, dichloromethane or N, N-dimethylformamide.
Wherein, the catalyst in the step (3) is platinum dioxide, palladium carbon, rhodium carbon, ruthenium carbon or platinum carbon; the reaction solvent is methanol, ethanol, ethyl acetate, tetrahydrofuran, glacial acetic acid or any combination of the above solvents; the reaction pressure is 0.2-6.5 MPa; the reaction temperature range is 30-80 ℃.
Wherein, the reducing agent in the step (4) comprises alkali metal borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride; the reaction solvent is toluene, tetrahydrofuran, methanol, ethanol, isopropanol or any combination of the above solvents; the temperature of the reaction system is-10-60 ℃; the benzyl halide is benzyl chloride or benzyl bromide; the acid-binding agent is triethylamine, diisopropylethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; the reaction solvent is toluene, tetrahydrofuran, ethyl acetate, acetonitrile, dichloromethane or N, N-dimethylformamide.
Wherein the organic solvent in the step (5) is methanol, ethanol, isopropanol, toluene, dichloromethane, dioxane, tetrahydrofuran, ethyl acetate or any combination of the above solvents.
In summary, due to the adoption of the technical scheme, the invention has the beneficial effects that:
for the reported synthetic method of the tofacitinib intermediate (I), the raw materials used in the invention are more easily available and economical, and the rhodium-carbon metal catalyst which can be recycled is used; the use of dangerous reagents is not involved, the amount of three wastes is small, and the process is safe and environment-friendly; the process is simple and convenient to operate, and has low requirements on reaction equipment; the reaction yield and the product purity are improved, the quality is stable, and the process is more suitable for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
A tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride has the following chemical structural formula:
the synthetic route is as follows:
the synthesis method comprises the following steps:
taking 3-bromo-4-methylpyridine as a starting material, carrying out substitution reaction with methylamine to obtain a compound III, and carrying out acetyl or tert-butyloxycarbonyl protection and catalytic hydrogenation on the compound III to obtain a piperidine compound V; the compound V and benzaldehyde are subjected to reductive amination or react with benzyl halide to obtain a compound VI; and removing the protecting group of the compound VI and simultaneously forming hydrochloride to obtain a compound I & 2 HCl.
Example 1
Preparation of Compound III
Adding a compound II (100g, 0.58mol) and 40% methylamine water solution (350g) into a high-pressure autoclave, adding a catalytic amount of copper powder while stirring, slowly heating to 100-; the temperature was reduced to room temperature, and the mixture was extracted three times with three portions of dichloromethane (500mL), dried and concentrated to obtain compound III (66g, yield 93%).
Preparation of Compound IV
To a reaction flask were added compound III (60g,0.49mol) and dichloromethane (480mL), N-dimethylaminopyridine (73g,0.60mol) was added, followed by dropwise addition of di-tert-butyl dicarbonate (123g,0.56 mol); heating to 50-55 ℃, stirring for reaction for 20h, cooling to room temperature, separating an organic phase by water, drying and concentrating to obtain a compound IV (95g, yield 87%).
Preparation of Compound V
The autoclave was charged with Compound IV (95g, 0.43mol), glacial acetic acid (950mL) was added, and after nitrogen substitution three times, 5% rhodium on charcoal (48g) was added; replacing with nitrogen and hydrogen in sequence, charging hydrogen to 0.4-0.45MPa, heating to 50-55 deg.C, stirring for reaction for 10h, cooling, filtering and recovering catalyst. The resulting compound V was concentrated under reduced pressure from the filtrate and used directly in the next reaction.
Preparation of Compound VI
To the reaction flask was added the crude compound V and toluene (1300mL) was added. Adding benzaldehyde (50g, 0.47mol) under stirring at room temperature, continuing stirring for more than 30min, and adding sodium triacetoxyborohydride (100g,0.47mol) in batches; the reaction was stirred for an additional 2 hours. The reaction was quenched with 30% sodium hydroxide solution, the organic phase was separated, dried and concentrated under reduced pressure to give Compound VI (115g, 84%).
Preparation of Compound I.2HCl
To a reaction flask, Compound VI (100g,0.31mol) and ethanol were added, and an ethanol solution of hydrogen chloride (125mL, 1.0mol) was added dropwise. Heating to reflux, and stirring for 5 h. The reaction solution was cooled to 5-10 deg.C, filtered, the filter cake was washed with a small amount of glacial ethanol and dried to obtain compound I.2HCl (59.6g, 88% yield).
Example 2
Preparation of Compound III
To the autoclave were added compound II (100g, 0.58mol) and water (350g), followed by methylamine hydrochloride (196g, 2.90mol) and sodium hydroxide (120g, 3.0 mol). Adding catalytic amount of copper powder while stirring. Slowly heating to 120 ℃ and 130 ℃, and stirring for reaction for 24 hours. The temperature was lowered to room temperature, and the mixture was extracted with dichloromethane (500mL) three times, dried and concentrated to obtain Compound III (61.6g, yield 87%).
Preparation of Compound IV
To a reaction flask, compound III (60g,0.49mol) and tetrahydrofuran (480mL) were added, followed by the addition of sodium hexamethyldisilazide (600mL,0.60mol,1.0M), followed by the dropwise addition of di-tert-butyl dicarbonate (123g,0.56 mol); heating to 50-55 ℃, stirring for reaction for 24h, concentrating under reduced pressure to recover tetrahydrofuran, adding dichloromethane and water into the residue, separating out an organic phase, drying, and concentrating to obtain a compound IV (98g, yield 90%).
Preparation of Compound V
The compound IV (95g, 0.43mol), ethanol (950mL) and glacial acetic acid (95mL) were added to the autoclave, and palladium acetate (4.8g, 21.5mmol) was added after three nitrogen replacements; replacing with nitrogen and hydrogen in sequence, charging hydrogen to 0.4-0.45MPa, heating to 50-55 deg.C, stirring and reacting for 10 h. Cooling, filtering with diatomite, and vacuum concentrating the filtrate to obtain compound V for the next reaction.
Preparation of Compound VI
To the reaction flask was added the crude compound V and toluene (1300mL) was added. Benzaldehyde (50g, 0.47mol) is added under stirring at room temperature, stirring is continued for more than 30min, and sodium cyanoborohydride (29.5g,0.47mol) is added in batches; the reaction was continued for 3 hours with stirring and quenched with 30% sodium hydroxide solution, the organic phase separated, dried and concentrated under reduced pressure to give compound VI (119g, 87%).
Preparation of Compound I.2HCl
To a reaction flask was added compound VI (100g,0.31mol) and isopropanol (800mL), and concentrated hydrochloric acid (83mL, 1.0mol) was added dropwise. Heating to reflux, and stirring for reaction for 3 h. The reaction solution is cooled to 5-10 ℃, filtered, the filter cake is washed by a small amount of isopropanol and dried to obtain the compound I.2HCl (60.9g, yield 90%).
Example 3
Preparation of Compound III
Adding a compound II (100g, 0.58mol) and a 40% methylamine water solution (300g) into an autoclave, and adding a catalytic amount of copper powder under stirring; slowly heating to 110 ℃ and 120 ℃, and stirring for reaction for 24 hours. The temperature was reduced to room temperature, and the mixture was extracted with dichloromethane (500mL) three times, dried and concentrated to give compound III (65g, 92% yield).
Preparation of Compound IV
To a reaction flask, Compound III (60g,0.49mol) and methylene chloride (480mL) were added, and triethylamine (60.7g, 0.60mol) and a catalytic amount of N, N-dimethylaminopyridine were successively added, followed by dropwise addition of acetic anhydride (57.2g,0.56 mol). The reaction was stirred at room temperature for 4 h. Water was added to quench the reaction, and the organic phase was separated, dried and concentrated to give compound IV (80.5g, yield 100%).
Preparation of Compound V
Compound IV (80g, 0.49mol) was charged into an autoclave, methanol (800mL) was added, nitrogen was replaced three times, and 10% ruthenium charcoal (10g) was added. Replacing with nitrogen and hydrogen in sequence, charging hydrogen to 5.0-6.0MPa, heating to 60-65 deg.C, stirring for reaction for 20h, cooling, filtering and recovering catalyst. The filtrate is decompressed and concentrated to obtain a compound V which is used for the next reaction.
Preparation of Compound VI
To the reaction flask was added the crude compound V and acetonitrile (800 mL). Anhydrous potassium carbonate (88g, 0.64mol) and benzyl bromide (101g,0.59mol) were added with stirring at room temperature, and the reaction was continued with stirring for 18 hours. The solvent was recovered by concentration under reduced pressure, ethyl acetate and water were added to the residue to separate the organic phase, which was dried and concentrated under reduced pressure to give Compound VI (116g, 91%).
Preparation of Compound I.2HCl
To a reaction flask was added compound VI (100g,0.38mol) and 6M hydrochloric acid (300 mL). Heating to reflux, and stirring for reaction for 8 h. Concentrating under reduced pressure to remove water, adding anhydrous ethanol (500mL) into the residue, heating to reflux and stirring for 30min, cooling to 5-10 deg.C, filtering, washing the filter cake with a little ethanol, and oven drying to obtain compound I.2HCl (76g, yield 92%).
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, substitutions and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (7)
1. A preparation method of tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride is characterized by comprising the following steps:
(1) performing substitution reaction on a compound II and methylamine in a reaction solvent under the catalysis of copper to obtain a compound III, wherein the reaction temperature is 80-150 DEG C
(2) Protecting amino group of the compound III obtained in the step (1) in a reaction solvent under the action of alkali to obtain a compound IV
(3) Carrying out catalytic hydrogenation on the compound IV obtained in the step (2) by using a catalyst in a reaction solvent to obtain a compound V with cis as a main component, wherein the reaction pressure is 0.2-6.5 MPa; the reaction temperature is 30-80 DEG C
(4) Aminating the compound V obtained in the step (3) with benzaldehyde by a reducing agent in a reaction solvent to obtain a compound VI; or reacting the compound V with benzyl halide in a reaction solvent under the action of an acid-binding agent to obtain a compound VI, wherein the reaction temperature is-10-60 ℃;
(5) dissolving the compound VI obtained in the step (4) in an organic solvent, adding an alcoholic solution of hydrogen chloride or concentrated hydrochloric acid, removing a protecting group, salifying and purifying to obtain a double hydrochloride of the compound I
2. The method for preparing the intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride of tofacitinib as claimed in claim 1, wherein the methylamine in step (1) is an aqueous methylamine solution, an alcoholic methylamine solution, a tetrahydrofuran methylamine solution, a methylamine hydrochloride or a methylamine sulfate; the reaction solvent is one or any combination of water, methanol, ethanol, isopropanol, tetrahydrofuran and dioxane.
3. The process for preparing tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidin-3-amine dihydrochloride according to claim 1, wherein the protected amine group in step (2) is acetyl or tert-butoxycarbonyl; the alkali is sodium hydrogen, sodium tert-butoxide, potassium tert-butoxide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, N-dimethylaminopyridine, triethylamine, diisopropylethylamine or pyridine; the reaction solvent is methanol, ethanol, toluene, tetrahydrofuran, dichloromethane or N, N-dimethylformamide.
4. The method for preparing the intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride according to claim 1, wherein the catalyst in the step (3) is platinum dioxide, palladium-carbon, rhodium-carbon, ruthenium-carbon or platinum-carbon; the reaction solvent is methanol, ethanol, ethyl acetate, tetrahydrofuran, glacial acetic acid or any combination of the above solvents.
5. The method for preparing tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidin-3-amine dihydrochloride according to claim 1, wherein the reducing agent in step (4) comprises alkali metal borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride; the reaction solvent for amination of the reducing agent is toluene, tetrahydrofuran, methanol, ethanol, isopropanol or any combination of the solvents.
6. The process for preparing tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidin-3-amine dihydrochloride according to claim 1, wherein the benzyl halide in step (4) is benzyl chloride or benzyl bromide; the acid-binding agent is triethylamine, diisopropylethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; the reaction solvent of the compound V in the reaction with the benzyl halide in the acid-binding agent is toluene, tetrahydrofuran, ethyl acetate, acetonitrile, dichloromethane or N, N-dimethylformamide.
7. The method for preparing tofacitinib intermediate cis-1-benzyl-N, 4-dimethylpiperidine-3-amine dihydrochloride according to claim 1, wherein the organic solvent in step (5) is methanol, ethanol, isopropanol, toluene, dichloromethane, dioxane, tetrahydrofuran, ethyl acetate or any combination thereof.
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| CN108689915A (en) * | 2018-07-25 | 2018-10-23 | 甘肃皓天医药科技有限责任公司 | A kind of synthetic method for the intermediate being used to prepare tropsch imatinib |
| CN109503462A (en) * | 2019-01-21 | 2019-03-22 | 内蒙古京东药业有限公司 | Support method is for cloth intermediate (3R, 4R)-N, 4- dimethyl -1- benzyl -3- piperidinamine and its new synthetic method of oxalic acid salt hydrate |
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| CN115124455A (en) * | 2022-07-11 | 2022-09-30 | 南通常佑药业科技有限公司 | Preparation method of tofacitinib intermediate |
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