4-chloro-7H-pyrrolo[2,3-d]pyrimidine synthetic method

A synthesis method and a 3-d technology, applied in the direction of organic chemistry and the like, can solve the problems such as difficulty in removing TRIPO, unfavorable for industrialized production, unfavorable production and purification, etc., and achieve the effects of easy industrialized production, simple operation, and easy-to-control conditions.

Inactive Publication Date: 2018-08-17
EAST CHINA NORMAL UNIVERSITY +1
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  • Abstract
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Problems solved by technology

[0017] This synthetic method has a short route, and the literature reports that the yield per step is high, but the by-product triphenoxyphos in the wittings reaction in the route is difficult to remove, which is not conducive to production and purification
[0018] Regarding the synthetic method of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine intermediate in China, 4,6-dichloro-5-allylpyrimidine is used as the starting material in some literature reports. The initial raw material is subjected to ox

Method used

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  • 4-chloro-7H-pyrrolo[2,3-d]pyrimidine synthetic method

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Embodiment 1

[0039] 1.1 Synthesis of Compound II, 2-(4,6-dichloropyrimidine)acetaldehyde

[0040] In a 50ml three-neck flask equipped with magnetic stirring, add 20ml of dichloromethane and 4,6-dichloro-5-allylpyrimidine (5.0g, 0.026mol), and then add dimethyl sulfoxide (8g, 0.104 mol) and triethylamine (5.5mL, 0.040mol), cooled to -40°C, and passed into O 3 Stop passing O until the reaction solution turns blue. 3 , use N instead 2 Continue to pass through for 30min to remove O in the system 3 . Sodium thiosulfate (4.1 g, 0.026 mol) was added, and the temperature was naturally raised to room temperature, and tested by starch potassium iodide test paper (not blue), to ensure that there was no peroxide in the reaction system. 60ml of water was added for extraction, the dichloromethane layer was washed twice with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.4g of off-white solid with a yield of 68%.

[0041] 1 H NMR (400MHz, DMSO-d6) δ ...

Embodiment 2

[0055] 2.1 Synthesis of compound III namely 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine

[0056] In a 100ml three-neck flask equipped with magnetic stirring, add 2-(4,6-dichloropyrimidine) acetaldehyde (5.4g, 0.028mol), triethyl orthoformate (8.5g, 0.057mol), p-toluenesulfonate Acid (0.27g, 0.028mol) was dissolved in 30mL of dichloromethane, the system was heated to 40°C, and kept for 3h. Add 4 mL of triethylamine to the reaction system, concentrate the reaction system, add ethyl acetate for extraction, wash twice with water, separate the organic phase, dry over anhydrous sodium sulfate, and evaporate to dryness; the ratio of petroleum ether to ethyl acetate is 5:1 Purified by column chromatography to obtain 4.1 g of a colorless oily liquid with a yield of 55%.

[0057] 1 H NMR (400MHz, CDCl3) δ8.60(s, 1H), 4.76(t, J=5.7Hz, 1H), 3.62-3.69(m, 2H), 3.36-3.44(m, 2H), 3.20(d, J=5.7Hz, 2H), 1.08(t, J=7.0Hz, 6H).

[0058] 2.2 Synthesis of compound III, namely 4,6-dichloro-5-(2,...

Embodiment 3

[0068] 3.1 Synthesis of compound IV, 4-amino-6-chloro-5-(2,2-diethoxyethyl)pyrimidine

[0069] In a 100ml three-necked flask equipped with magnetic stirring, 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (5g, 0.019mol) was dissolved in 30mL absolute ethanol, and the temperature was raised to 60°C, continuous feeding of NH 3 Stir for 3h. The reaction solution was concentrated, 30 mL of ethyl acetate was added, the organic phase was washed twice with water, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 3.4 g of the product with a yield of 73%.

[0070] 1 H NMR (400MHz, DMSO) δ8.09(s, 1H), 7.01(br, 2H), 4.67(t, J=5.5Hz, 1H), 3.59-3.68(m, 2H), 3.39-3.47(m, 2H), 2.88 (d, J=5.5Hz, 2H), 1.06 (t, J=7.0Hz, 6H).

[0071] 3.2 Synthesis of compound IV, 4-amino-6-chloro-5-(2,2-diethoxyethyl)pyrimidine

[0072] In a 100ml three-neck flask equipped with magnetic stirring, dissolve 4,6-dichloro-5-(2,2-diethoxyethyl)pyrimidine (5g, 0.019mol) in 30mL methanol, and...

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Abstract

The invention discloses a 4-chloro-7H-pyrrolo[2,3-d]pyrimidine synthetic method. A compound is an important intermediate for synthesizing ruxolitinib and tofacitinib as a JAK inhibitor for treating rheumatoid arthritis. The 4-chloro-7H-pyrrolo[2,3-d]pyrimidine synthetic method comprises the following steps of by taking a compound I (4,6-dichloro-5-allyl pyrimidine) as a starting material, performing oxidation reaction on the compound I and ozone to produce a compound II; then performing nucleophilic substitution reaction on the compound II and triethyl orthoformate to produce a compound III; then performing nucleophilic substitution reaction on the compound III and ammonia gas to produce a compound IV; and finally, performing ring closing on the compound IV self in an acid environment to produce a compound V, i.e., 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, wherein a synthetic route is shown as the following formula (described in the description). The synthetic method disclosed by the invention is cheap and available in raw materials, simple and short in synthetic route, low in cost, high in yield and easy in industrial production.

Description

technical field [0001] The present invention relates to the technical field of compound preparation, in particular to the technical field of intermediate preparation of ruxolitinib and tofacitinib, more specifically, a kind of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine resolve resolution. Background technique [0002] Rheumatoid arthritis (RheumatiodArthritis, RA) is a chronic autoimmune disease characterized by joint synovitis. Worldwide, the prevalence of RA is approximately 1% of the population, and the disease begins with fatigue, anorexia, generalized weakness, and vague musculoskeletal symptoms until it becomes apparent with the onset of synovitis, which causes joint pain , stiffness and swelling. As a chronic autoimmune disease, RA has always seriously affected human health. With the in-depth study of the pathogenesis of RA, JAK / STAT is an important cytokine signaling pathway, which is related to rheumatoid arthritis. Pfizer, USA (Pfizer) has developed a small-molecule J...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 占莉朱皓庭何洋李晓林张玉柳罗宇张五军汤美珍
Owner EAST CHINA NORMAL UNIVERSITY
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