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CN-121974827-A - Synthesis method of N-Boc-N-methylaminoacetone

CN121974827ACN 121974827 ACN121974827 ACN 121974827ACN-121974827-A

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of N-Boc-N-methylaminoacetone, which comprises the following steps of firstly reacting propylene oxide with methylamine to obtain 1-N-methylamino-2-propanol, wherein the reaction temperature is-10-20 ℃; then reacting 1-N-methylamino-2-propanol with Boc anhydride to obtain 1-N-methyl-N-Boc amino-2-propanol, and finally oxidizing 1-N-methyl-N-Boc amino-2-propanol to obtain N-Boc-N-methylaminoacetone. The invention provides a brand-new method for synthesizing N-Boc-N-methylaminoacetone, which has the advantages of easily available raw materials, simple operation, mild reaction conditions, high purity, greatly improved yield and low cost.

Inventors

  • XIONG CHUANHUI
  • YIN HAISHUN
  • XIONG QIYUAN
  • WANG SHENGGUO
  • ZHANG RENYUE
  • WANG FUPING
  • GAO MING

Assignees

  • 北京京宇复瑞科技集团有限责任公司
  • 白银京宇新药业有限公司

Dates

Publication Date
20260505
Application Date
20260126

Claims (10)

  1. 1. A synthesis method of N-Boc-N-methylaminoacetone comprises the following steps: (1) Propylene oxide and methylamine are reacted to obtain 1-N-methylamino-2-propanol, wherein the reaction temperature is-10-20 ℃; (2) Reacting 1-N-methylamino-2-propanol with Boc anhydride to obtain 1-N-methyl-N-Boc amino-2-propanol; (3) Oxidizing 1-N-methyl-N-Boc amino-2-propanol to obtain N-Boc-N-methylaminoacetone.
  2. 2. The synthetic method according to claim 1, wherein the solvent of the reaction in the step (1) is one or more of water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, 2-butanol and tert-butanol.
  3. 3. The synthetic method of claim 1 wherein the solvent of the reaction in step (1) is methanol; and/or the temperature of the reaction in step (1) is 0 ℃ to 10 ℃; and/or, in the step (1), the molar ratio of the propylene oxide to the methylamine is 1:1-1:10.
  4. 4. The synthetic method of claim 1 wherein the molar ratio of propylene oxide to methylamine in step (1) is 1:5; And/or the reaction time in the step (1) is 15-25 h; And/or (1) distilling under normal pressure after the reaction, and collecting the fraction at 140-150 ℃; and/or (3) carrying out reduced pressure distillation after the reaction in the step (1), and collecting 80-90 ℃ and 20-30 mmHg fractions.
  5. 5. The synthetic method according to claim 1, wherein the solvent of the reaction in step (2) is a halogenated hydrocarbon or an alcohol solvent having 4 or less carbon atoms; and/or the temperature of the reaction in step (2) is from 0 ℃ to 80 ℃; And/or the molar ratio of 1-N-methylamino-2-propanol to Boc anhydride in step (2) is 0.9-1.1:1; And/or the reaction in step (2) takes 6-10 h.
  6. 6. The synthetic method according to claim 1, wherein the solvent of the reaction in step (2) is dichloromethane or t-butanol; And/or the temperature of the reaction in step (2) is 20 ℃ to 30 ℃; And/or (2) after the reaction, distilling under reduced pressure, and collecting 85-95 ℃/2mmHg fractions.
  7. 7. The synthesis method according to claim 1, wherein in the step (3), potassium permanganate is adopted as an oxidant, the solvent of the oxidation reaction is acetone, and in the step (3), the mass ratio of the 1-N-methyl-N-Boc amino-2-propanol to the potassium permanganate to the acetone is 1:1-2:15-25.
  8. 8. The method according to claim 1, wherein the reaction time in the step (3) is 4 to 8 hours, and/or the reaction in the step (3) is followed by filtration, fading of the filtrate by adding aqueous sodium sulfite solution, distillation under reduced pressure, and collection of 80-90 ℃ per 2mmHg fraction.
  9. 9. The synthesis method according to claim 1, wherein the step (3) is characterized in that a TEMPO/sodium bromide/sodium hypochlorite method is adopted for oxidation reaction, the specific step in the step (3) comprises the steps of adding dichloromethane, sodium bromide, water, sodium bicarbonate and TEMPO into 1-N-methyl-N-Boc amino-2-propanol, cooling to a temperature of-5 ℃ to 0 ℃, dropwise adding a sodium hypochlorite solution with a concentration of 5wt% to 15wt%, and then reacting.
  10. 10. The synthetic method according to claim 9, wherein the mass ratio of 1-N-methyl-N-Boc amino-2-propanol, dichloromethane, sodium bromide, water, sodium bicarbonate, TEMPO, 5wt% -15wt% sodium hypochlorite solution in step (3) is 1-3:5-10:0.1-0.3:1:1:0.02-0.06:5-15.

Description

Synthesis method of N-Boc-N-methylaminoacetone Technical Field The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of N-Boc-N-methylaminoacetone. Background N-Boc-N-methylaminoacetonate is a key raw material for preparing Latifinib (indication advanced ALK+NSCLC brain metastasis). Latification can not only prevent the progress of the existing brain metastasis, but also prevent or delay the appearance of new brain metastasis, and provides a better treatment choice for ALK+advanced NSCLC patients. Latifinib has been marketed in China in 4 months of 2021 and has been incorporated into medical insurance varieties. The structural formula of the Boc-N-methylamino acetonate is as follows: compound I The existing traditional synthetic route of the compound I is as follows: The method takes monochloroacetone as an initial raw material, reacts with N-methylbenzylamine to generate N-methyl-N-benzylaminoacetone, then catalytically hydrogenates and debenzylates to prepare N-methylaminoacetone hydrochloride, and then reacts with Boc anhydride to prepare the compound I. The starting material of the method, namely, monochloroacetone, belongs to a controlled drug, is not easy to obtain, catalytic hydrogenation is needed in the process, N-methyl-N-benzyl amino acetone in the product is not easy to remove, and the product purity is poor. High cost and difficult industrialized production. The Chinese patent CN107162920A discloses that (R) -propylene oxide is used as a raw material, and a one-pot method is adopted to prepare the (R) -1-amino-2-propanol with high optical purity, and the production process is a novel production process for replacing the original production of the (R) -1-amino-2-propanol by utilizing L-threonine reduction. The invention adds (R) -epoxypropane, ammonia gas and ketone into a reaction kettle to react, and the obtained intermediate is hydrolyzed, concentrated, rectified and purified. In addition, U.S. Pat. No. 3, 2167351, german patent DE679281, chinese patent invention CN107226780A and the like disclose a method for synthesizing an intermediate compound 1-N-methyl-N-Boc amino-2-propanol, but all the methods adopt a reaction in a pressure vessel at a higher temperature, the temperature is higher, the industrial production is not facilitated, and the synthetic route of the compound N-Boc-N-methylaminoacetone is not described. Disclosure of Invention Aiming at the defects existing in the prior art, the invention provides a synthesis method of N-Boc-N-methylaminoacetone. Description of the terminology: unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, patent inventions, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definitions of this chapter shall control. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the subject matter of the invention, as claimed. In the present invention, the singular is used to include the plural unless specifically stated otherwise. It should also be noted that the use of "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," as well as other forms, such as "comprising," "including," and "containing," are not limiting. The definition of standard chemical terms can be found in the reference "pharmacopoeia of the people's republic of China (2025 edition) edition 1 of Chinese medical science and technology Press. Unless otherwise indicated, conventional methods within the skill of the art, such as centrifugation, reflux, concentration, resuspension, and the like, are employed. Unless specifically defined, the use of various commercially available products as used herein employs standard techniques. For example, the kit may be used by the manufacturer, or may be implemented in a manner known in the art or in accordance with the description of the invention. The techniques and methods described above may generally be practiced according to conventional methods well known in the art, based on a number of general and more specific descriptions in the literature cited and discussed in this specification. The term "optionally/arbitrarily" or "optionally/arbitrarily" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. The term "atmospheric distillation" as used herein refers to the basic chemical operation of liquid separation and purification by heating and condensation at standard atmospheric pressure. The term "reduced pressure distillation" as used herein refers to a technique for separating and purifying a th