A kind of synthetic method of anagrelide key intermediate, analog or its salt

A synthetic method and technology of analogues, applied in the synthesis of analogues and their salts, analogues and salts and their synthesis, key intermediates of anagrelide, N-glycine ester fields, can solve the complicated operation and the yield is only 75% % and other problems to achieve the effect of overcoming the long route, high total yield and simple operation

Active Publication Date: 2016-01-20
SHANGHAI PUKANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] This method has simple steps, but the content of components and water content must be strictly controlled during the process, the operation is cumbersome, and the yield is only 75%.

Method used

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  • A kind of synthetic method of anagrelide key intermediate, analog or its salt
  • A kind of synthetic method of anagrelide key intermediate, analog or its salt
  • A kind of synthetic method of anagrelide key intermediate, analog or its salt

Examples

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Effect test

Embodiment 1

[0046] The preparation of embodiment 1N-(6-nitro-2,3-dichlorobenzyl) glycine

[0047] After mixing 35kg of methanol and 39kg of 2mol / l sodium hydroxide aqueous solution, add 9.2kg of glycine, stir for 20min, dissolve 15.4kg of 2,3-dichloro-6-nitrobenzaldehyde in 35kg of methanol, drop the solution Add it to the above reaction system, control the temperature at 20-25°C, stir for 40min after the dropwise addition, cool down to 0-5°C, and add 120kgNaBH in batches 4 , heated up to 20-25°C and stirred until the reaction was complete, evaporated the methanol under reduced pressure, adjusted the pH to 5 with 2mol / l hydrochloric acid, spin-dried and recrystallized with 30kg of water to obtain 20.78kg of off-white solid with a yield of 97.2%.

Embodiment 2

[0048] The preparation of embodiment 2N-(6-nitro-2,3-dichlorobenzyl) glycine methyl ester

[0049] In a 100L reactor, add 10.0kg N-(6-nitro-2,3-dichlorobenzyl)glycine to 50kg methanol, add 5kg concentrated sulfuric acid, heat and reflux until the reaction is complete, recover methanol under reduced pressure, add 10kg saturated NaHCO 3 The aqueous solution was extracted with ethyl acetate, the organic layer was dried, and the solvent was recovered to obtain 99.8 kg of N-(6-nitro-2,3-dichlorobenzyl) glycine methyl ester, with a yield of 95%.

Embodiment 3

[0050] The preparation of embodiment 3N-(6-nitro-2,3-dichlorobenzyl) glycine methyl ester hydrochloride

[0051] In a 100L reaction kettle, add 10kg of N-(6-nitro-2,3-dichlorobenzyl)glycine to 50kg of methanol, cool down to 0-5°C, add 4.7kg of thionyl chloride dropwise, and the dropwise addition is completed , heated to reflux until the reaction was complete, methanol was reclaimed under reduced pressure, the residue was added to 20 kg of ethyl acetate for beating, filtered to obtain 11.46 kg of N-(6-nitro-2,3-dichlorobenzyl) glycine hydrochloride, collected The rate is 97%.

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Abstract

The invention provides a synthesis method for a key intermediate, analogue or salt of ticlopidine. The synthesis method comprises the following steps of: (1) adding 6-nitro-2,3-dichlorobenzaldehyde and glycine or corresponding substituted glycine into a solution and adding a reducing agent to completely react to obtain N-(6-nitro-2,3-dichlorobenzyl) glycine and an analogue thereof; and (2) completely reacting the N-(6-nitro-2,3-dichlorobenzyl) glycine and the analogue thereof under the action of a catalyst to obtain the key intermediate, analogue or salt of the ticlopidine, wherein the solution in the step (1) is a mixed solution of a protic solvent and an inorganic base, and the reducing agent is one or a mixture of sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride and acetic sodium borohydride. The method is simple in operation, mild and easily-controlled in condition, convenient for aftertreatment, environment-friendly and higher in yield, and is a brand new efficient industrial synthesis method for the key intermediate, analogue or salt of the ticlopidine.

Description

technical field [0001] The present invention relates to quinazoline compounds, in particular to anagrelide key intermediates, analogues, salts and synthesis methods thereof, namely N-(6-nitro-2,3-dichlorobenzyl)glycinate, Synthesis of analogues and their salts. Background technique [0002] Anagrelide hydrochloride (IV) was developed by Roberts Pharmaceuticals and was approved by the FDA in 1997 as a drug marketed in the United States. This drug can be used to treat essential thrombocythemia and polycythemia vera complicated with thrombocytosis. It can also be used For other myeloid proliferative diseases, such as myelofibrosis and osteodysplastic syndrome accompanied by abnormal platelet increase, its mechanism of action is an inhibitor of cyclic adenosine monophosphate phosphodiesterase III, which can inhibit the formation and aggregation of platelets at high concentrations. This drug was originally used to inhibit platelet aggregation and has antithrombotic effect, but i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/18C07C229/14
Inventor 汪迅李新涓子李勇刚高艳吕兴红沈小良俞翔施乐乐
Owner SHANGHAI PUKANG PHARMA
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