Novel synthetic method for tofacitinib intermediate (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine and oxalate hydrates of (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine

A technology of tofacitinib and intermediates, applied in the field of medicinal chemistry, can solve the problems of poor stereoselectivity, poor atom economy, and low overall yield, and achieve high reaction yield, high optical purity, and cheap and easy-to-obtain raw materials Effect

Active Publication Date: 2019-03-22
内蒙古京东药业有限公司
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AI-Extracted Technical Summary

Problems solved by technology

[0023] After investigating various routes, in order to overcome the deficiencies in the preparation of compound I in the prior art (such as the poor stereoselectivity in the preparation of (3R, 4R-rel-) isomers in the process of (II-c) in route one and Cause total yield is not high, atom economy is poor; Need to use very dangerous and expensive aluminum tetrahydrogen lithium or relatively safe some but equally expensive Red-Al) in...
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Abstract

The invention relates to a novel synthetic method for tofacitinib intermediate (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine and oxalate hydrates of (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine. The method comprises the following steps: 3-amino-4-methylpyridine is taken as a starting material, amino of 3-amino-4-methylpyridine is subjected to a reaction with ortho-formate, imino formate is generated, and after simple concentration, an N-methyl derivative is obtained by reduction with metal borohydride; after Boc protection, quaternary ammonium salt is generated from a product and benzyl halide and reduced by metal borohydride, a product is subjected to selective hydrogenation with an Rh catalyst, a compound with rich (3R,4R-rel-) configuration is formed, deprotection, salifying and resolution are performed by a hydrochloric acid/alcohol system for removing a (3R,4S-rel-) isomer pair, an obtained (3R,4R-rel-) configuration product is subjected to free treatment and resolved by L-DTTA, and a 3R,4R- configuration product is obtained; after free treatment of salt obtained after resolution, oxalate is formed and purified, a small quantity of remaining 3S,4S-isomers are further removed, and corresponding (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine with high purity and high optical purity is obtained. Through the adoption of the method, safe, simple and industrial large-scale preparation of the tofacitinib intermediate (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine oxalate hydrates is better facilitated.

Application Domain

Technology Topic

BorohydrideOxalate salt +13

Image

  • Novel synthetic method for tofacitinib intermediate (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine and oxalate hydrates of (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine
  • Novel synthetic method for tofacitinib intermediate (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine and oxalate hydrates of (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine
  • Novel synthetic method for tofacitinib intermediate (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine and oxalate hydrates of (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine

Examples

  • Experimental program(8)

Example Embodiment

[0048] Example 1: Synthesis of N-Boc-N,4-dimethyl-3-aminopyridine (Compound C)
[0049] Add 3-amino-4-methylpyridine (100 g, 924.7 mmol) to the reaction flask, then add triethyl orthoformate (400 g, 2.699 mol), and heat to 130-145° C. to react for about 8-12 hours. After the reaction is completed, the temperature is lowered to about 100°C, and triethyl orthoformate is concentrated under reduced pressure. The obtained residue was distilled under reduced pressure with a high vacuum oil pump to obtain 129 g (785.6 mmol) of a pale yellow to colorless liquid (compound A-x, R=Et) with a yield of 85.0%.
[0050] The compound Ax(R=Et) (120g, 730.8mmol) obtained above was dissolved in 600g of absolute ethanol, cooled to between 5~10℃, and 32g (845.9mmol) of sodium borohydride was added in batches to control the temperature not to exceed 20℃ After the addition, the temperature is returned to 25~30℃ and stirred for about 30~60min, then slowly heated to reflux, and the reaction is continued for about 2~4hr. After the reaction, the ethanol was concentrated under reduced pressure, water (600g) was added to the residue, and THF was added for extraction (360g+180g+120g), and the organic phases were combined without purification and used directly in the next reaction (the resulting compound B) .
[0051] Add 10% sodium hydroxide solution (600g) to the THF solution of compound B obtained above, keep it at 20~30℃, add Boc dropwise while stirring 2 A solution of O (180g, 824.7mmol) dissolved in THF (300g), and the temperature during the dropping process was controlled not to exceed 40°C. Keep the temperature at 35~40℃ and react for about 6~10hr. After the reaction is completed, stand for liquid separation, wash the organic phase with water, concentrate to dryness under reduced pressure, add n-heptane to the residue, heat to 50-60°C, cool and crystallize, filter, collect the solid, and dry to obtain compound C (132g, 593.8mmol), the yield is 81.3%.

Example Embodiment

[0052] Example 2: Synthesis of N-Boc-N,4-dimethyl-3-aminopyridine (Compound C)
[0053] Add 3-amino-4-methylpyridine (120g, 1.110mol) to the reaction flask, then add trimethyl orthoformate (450g, 3.036mol), and heat to 120-130°C to react for about 10-16hr. After the reaction is completed, the temperature is lowered to about 100°C, and trimethyl orthoformate is concentrated under reduced pressure. The obtained residue (compound A-x, R=Me) (182.2 g in theoretical amount) was directly used in the next reaction.
[0054] The compound Ax (R=Me) obtained above was dissolved in 1080g isopropanol, cooled to between 5-10°C, and sodium borohydride 45g (1.190mol) was added in batches to control the temperature not to exceed 20°C. After the addition, return to Stir at 25~30℃ for about 1~1.5hr, then slowly heat to reflux, continue the reaction for about 2~4hr. After the reaction, the isopropanol was concentrated under reduced pressure, water (1000g) was added to the residue, and THF was added for extraction (600g+300g+300g), and the organic phases were combined without purification and used directly in the next reaction (the resulting compound B).
[0055] Add 10% sodium hydroxide solution (900g) to the THF solution of compound B obtained above, keep it at 20~30℃, add Boc dropwise with stirring 2 A solution of O (260g, 1.191mmol) dissolved in THF (500g), and the temperature during the dropping process was controlled not to exceed 40°C. Keep the temperature at 35~40℃ and react for about 6~10hr. After the reaction is completed, stand still for liquid separation, wash the organic phase with water, concentrate to dryness under reduced pressure, add n-heptane to the residue, heat to 50-60°C for about 20-30 minutes, cool and crystallize, filter, collect the solid, and bake After drying, compound C (152 g, 683.8 mmol) was obtained with a yield of 61.6%.

Example Embodiment

[0056] Example 3: Synthesis of 1-benzyl-N-Boc-N,4-dimethyl-1,2,5,6-tetrahydropyridin-3-amine (Compound E)
[0057] The obtained compound C (150g, 674.8mmol) was added to 600g of toluene, then benzyl chloride (94g, 742.6mmol) was added, heated to 100~110℃, and reacted for 10~16hr; after the reaction, cooled to 20~ At 30°C, add 600g of water, stir evenly, stand still, separate the liquid, separate the lower aqueous phase (the aqueous solution of compound Dx, X - =Cl - ),spare.
[0058] Dissolve 0.1g of sodium hydroxide in 100g of water, then add sodium borohydride (26g, 687.3mmol) to dissolve in the sodium hydroxide aqueous solution; slowly add the sodium borohydride aqueous solution to the above quaternary ammonium salt aqueous solution, dropwise The process temperature is controlled between 15~25℃. After the dropping is completed, the reaction is kept for 2~4hr; after the reaction is completed, ethyl acetate is added for extraction, liquid separation, and ethyl acetate is concentrated to obtain compound E (169g, 534.1mmol) , Yield: 79.1%.
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