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CN-122010730-A - Preparation method of key intermediate of Lutrepah

CN122010730ACN 122010730 ACN122010730 ACN 122010730ACN-122010730-A

Abstract

The invention discloses a preparation method of a key intermediate of rupotpa, which comprises the steps of taking cheap and easily available 2, 6-dichlorobenzaldehyde as a starting material, carrying out a Wittig reaction with phosphorus ylide protected by dioxolane of an ester carbonyl group to obtain an olefin compound, then carrying out a bromination reaction under the catalysis of iron powder to obtain a high-yield brominated compound, carrying out Grignard reaction, carboxylation by carbon dioxide and acidification by hydrochloric acid for synchronous de-esterification protection, and carrying out primary crystallization to obtain the key intermediate of rupotpa. The method does not need strong alkali such as lithium diisopropylamide, the reaction temperature is controlled at-10 ℃ to 30 ℃, the system has loose requirements on moisture, the total yield is high, single impurity (containing Z-type isomer) of the product is less than 0.1%, and the method has the advantages of low material cost, mild reaction condition, high stereoselectivity and easy industrial production, and remarkably reduces the production cost of the rupoppa.

Inventors

  • Xiong Zhengou
  • CHEN LIJUAN

Assignees

  • 重庆常捷医药有限公司
  • 重庆圣华曦药业股份有限公司

Dates

Publication Date
20260512
Application Date
20260204

Claims (7)

  1. 1. A method for preparing a key intermediate of donepezil, which is characterized by comprising the following steps: , Step 1, performing olefination reaction on 2, 6-dichlorobenzaldehyde and phosphorus ylide protected by ester carbonyl in methylene dichloride, step 2, cooling a methylene dichloride layer containing olefin compounds, adding iron powder as a catalyst, dropwise adding bromine for bromination reaction, step 3, dissolving the brominated compounds in tetrahydrofuran, preparing an aryl Grignard reagent with magnesium chips under the protection of nitrogen, introducing carbon dioxide for carboxylation, adding hydrochloric acid for acidification and synchronous de-esterification protection, and performing Grignard reaction-carboxylation-acidification and de-protection to obtain the key intermediate of the runpan.
  2. 2. The method of claim 1, wherein the protected form of the ester carbonyl group in step 1 is a dioxolane structure.
  3. 3. The method of claim 1, wherein the phosphorus ylide ester group in step 1 is t-butyl, isopropyl, ethyl or methyl ester.
  4. 4. A process according to claim 3, wherein the ester group of phosphorus ylide is tert-butyl ester.
  5. 5. The preparation method according to claim 1, wherein the temperature of the bromination reaction in step 2 is controlled to be-5 ℃ to-10 ℃.
  6. 6. The preparation method according to claim 1, wherein the temperature of the grignard reaction in step 3 is controlled to 25-30 ℃.
  7. 7. The process according to claim 1, wherein the Z isomer of the olefin compound in step 1 is <0.5%.

Description

Preparation method of key intermediate of Lutrepah Technical Field The invention relates to a preparation method of a Lutrepah intermediate, belonging to the field of pharmaceutical chemistry. Background Thrombocytopenia has a incidence of over 65% in chronic liver disease patients, not only increasing the risk of bleeding, but also resulting in delayed intervention in about 28% of patients. The Lu-qu-Popa is used as a second-generation small-molecule thrombopoietin receptor agonist, has the advantages of oral administration, low liver metabolism dependence (CYP 2C9/CYP3A4 dependence ratio of 25%), and the like, becomes the clinical first choice after being obtained in Japanese in 2015, and has the increased demand after entering the Chinese market in 2018. Previously, the traditional therapy has obvious limitations that recombinant human thrombopoietin needs to be injected daily and the production rate of neutralizing antibodies reaches 12 percent, and platelet infusion is limited by blood sources and has potential safety hazards. At present, the synthesis core of the rutripopal depends on a key intermediate (E) -3, 5-dichloro-4- (3-ethoxy-2-methyl-3-oxo-prop-1-en-1-yl) benzoic acid (patent document 1 refers to compound (VII'), non-patent document 1 refers to compound 3), and the current main preparation process is a one-pot method. The one-pot method has the advantages of no intermediate separation, short production period and the like, but has serious defects in aspects of materials, reaction conditions, isomer control, yield and the like, and restricts the industrialized development. High material cost and poor safety are the primary problems. The one-pot method uses 3, 5-dichlorobenzoic acid as a raw material and relies on strong alkali such as Lithium Diisopropylamide (LDA), N-formylmorpholine and triethyl 2-phosphonopropionate. LDA is unstable in chemistry and is decomposed violently when meeting water, storage is needed at-20 ℃, purchasing cost is high, a special corrosion-resistant reaction kettle is needed, the dosage of N-formylmorpholine reaches 3.0-3.1 equivalent, cost is high and can not be recovered, and 2-phosphonopropionic acid triethyl is fed in 1.5 equivalent excess. In terms of solvents, the literature-optimized 1, 2-dimethoxyethane is miscible with water, is not easy to recycle, and further increases the cost. The harsh reaction conditions lead to poor commercial suitability. The lithiation reaction needs ultralow temperature of-55 ℃ to-75 ℃ and far exceeds the controllable range (-40 ℃) of conventional equipment, liquid nitrogen is needed for auxiliary refrigeration, the energy consumption cost is high, the water content of the system needs less than or equal to 50ppm, the pretreatment needs nitrogen replacement, and the production efficiency is far lower than that of the conventional process. The process has extremely high requirements on operation consistency, and once refrigeration fails, the process leads to material rejection. The problem of isomers is prominent and the separation costs are high. The target intermediate contains C=C double bond to generate E/Z isomer, Z type is inactive and the medicinal standard is less than or equal to 0.1%. Non-patent document 1 optimizes the E/Z to 98:2, but still requires isolation. The physicochemical properties of the two isomers are close, repeated recrystallization is needed, and not only is the step increased, but also yield loss is caused. In addition, the lithiation and formylation reaction also generates formylated positional isomer accounting for 4 percent and 8 percent of bisformylate, and the formylated positional isomer and the bissubstituted compound can be generated by further reacting the formylated positional isomer and the bisformylate with the triethyl 2-phosphonopropionate, so that the separation difficulty is higher. In patent document 1, the total yield of the one-pot method of non-patent document 1 is only about 51%, and the core is seriously lost due to poor reaction selectivity and repeated crystallization and purification. In conclusion, the current preparation method of the key intermediate of the rupoppa has more defects, so that the production cost of the rupoppa is high. The development of a new process with low material cost, mild reaction conditions, stereoselectivity and high yield becomes a key for breaking through the bottleneck of industrialization, and has great significance for improving the accessibility of medicaments and reducing the cost of medicaments. Prior art literature Patent literature Patent document 1 CN105992761A Non-patent literature Non-patent document 1 Org. Process Res. Dev. 2020,24,11,2651-2656 Non-patent document 2 Synlett 1999, no.07, 1033-1036. Disclosure of Invention The invention aims to overcome a plurality of defects in the existing preparation process of key intermediate of the ruxorpa, and provides a preparation method which has the advantages of low material cost, mild reaction