Preparation method of long-chain alkyl diacid mono-tert-butyl ester

Abstract

The invention provides a synthesis method of long-chain alkyl diacid mono-tert-butyl ester, aiming at solving the problems that the process selectivity is poor, a high-purity target product is difficult to obtain, the yield is low and the cost is high when the long-chain alkyl diacid mono-tert-butyl ester is synthesized at present.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drug synthesis and relates to a method for preparing long-chain alkyl diacid monoter-butyl esters. Technical Background

[0002] Most long-chain alkyl diacid monoter-butyl esters are important intermediates in organic synthesis, especially as intermediates for the synthesis of important drugs in the pharmaceutical field. Long-chain alkyl diacid monoter-butyl esters are important intermediates for the synthesis of GLP-1 hypoglycemic drugs. Glucagon-like peptide-1 (GLP-1) receptor agonists (or GLP-1 analogs) are the latest hypoglycemic drugs, which are insulinotropic drugs that can both lower blood sugar and reduce body weight. The application of glucagon-like peptide-1 (GLP-1) analogs has made a breakthrough in the treatment of diabetes. Octadecyl diacid monoter-butyl ester and eicosyl diacid monoter-butyl ester are important intermediates for the GLP-1 hypoglycemic drugs semaglutide and tirzepatide, respectively.

[0003] Currently, the methods reported in the literature for octadecyl diacid monoter-butyl ester and eicosyl diacid monoter-butyl ester have poor process selectivity, making it difficult to obtain high-purity target products, with low yields and high costs. Due to the limitations of the preparation process, large-scale production is restricted.

[0004] The structure of the long-chain alkyl diacid monoter-butyl ester is shown as the following formula (Ⅰ):

[0005]

[0006] where n = 9 - 16,

[0007] When n = 14, the octadecane dicarboxylic acid monoter-butyl ester is shown as the following formula:

[0008]

[0009] When n = 16, the eicosane dicarboxylic acid monoter-butyl ester is shown as the following formula (Ⅲ):

[0010]

[0011] Patent CN114213235A discloses a method for preparing octadecane dicarboxylic acid monoter-butyl ester, using oleic acid as the starting material, and the route is as follows:

[0012]

[0013] This method requires selective monoesterification of long-chain alkane diacids, with poor selectivity and difficult purification.

[0014] Patent CN11875495A discloses a method for preparing monoterbutyl octadecane - dicarboxylate. This method uses sebacic acid as the starting material. The market supply price of sebacic acid is very high, resulting in high production costs. Moreover, the reaction involves the use of concentrated sulfuric acid, which poses risks during the operation process and the purity is not high.

[0015] The research and development of GLP - 1 hypoglycemic drugs involving important intermediates monoterbutyl octadecane - dicarboxylate and monoterbutyl eicosane - dicarboxylate have great market prospects and social and economic benefits. Existing processes have problems such as poor selectivity in the mono - esterification of dicarboxylic acids, difficulty in purification, and high production costs. There is a need for a new synthesis process to solve the deficiencies in the existing technology. Summary of the Invention

[0016] The purpose of the present invention is to provide a method for synthesizing monoterbutyl long - chain alkyl - dicarboxylate to solve the problems of poor process selectivity, difficulty in obtaining a high - purity target product, low yield, and high cost when currently synthesizing monoterbutyl long - chain alkyl - dicarboxylate. The present invention provides a brand - new method for preparing monoterbutyl long - chain alkyl - dicarboxylate.

[0017] The solution of the present invention includes the following steps:

[0018] Compound of formula C undergoes a transesterification reaction with tert - butyl alcohol to obtain a compound of formula D;

[0019]

[0020] Hydrolyze the compound of formula D to obtain monoterbutyl long - chain alkyl - dicarboxylate E.

[0021]

[0022] Wherein, n = 9, 10, 11, 12, 13, 14, 15 or 16.

[0023] Preferably, in the above hydrolysis reaction, first perform alkaline hydrolysis, and then adjust the pH value to 2 - 3 with an acidic reagent to obtain monoterbutyl long - chain alkyl - dicarboxylate E.

[0024] Preferably, the hydrolysis reaction catalyst is potassium hydroxide or sodium hydroxide;

[0025] Preferably, reduce the compound of formula B to obtain the compound of formula C;

[0026]

[0027] Preferably, in this step, a borohydride is used as the reducing agent, preferably sodium borohydride;

[0028] Preferably, condense the compound of formula A with Meldrum's acid to obtain the compound of formula B;

[0029]

[0030] Preferably, a pyridine compound is used as the catalyst in this step, and 4-dimethylaminopyridine is preferred.

[0031] Through the step design of the technical solution of the present invention, on the one hand, it avoids the single esterification reaction with poor selectivity in the prior art, and avoids problems such as difficult product purification and high production costs. On the other hand, it avoids the reaction path of coupling chain extension commonly used in the prior art in the process of preparing long-chain diacids / esters, in which catalysts such as zinc powder and pyridine have high requirements for catalytic safety and are also difficult to remove later. The present invention newly designs a mild synthesis path for long-chain diesters, directly obtaining di-tert-butyl long-chain alkyl diacids without obtaining diacids, with significantly reduced impurities and easy removal, and taking advantage of the high selectivity of the hydrolysis of di-tert-butyl long-chain alkyl diacids under alkaline conditions to preferentially obtain single hydrolysis products. Therefore, the by-products of the present invention have few impurities, greatly reducing the operation difficulty in industrial production and improving the yield of the whole reaction. Each step of the above reaction has fewer impurities, and the separation difficulty and cost are significantly reduced, making it more suitable for industrial production. Description of the Drawings

[0032] Figure 1 It is the NMR spectrum of the compound in Example 4. Detailed Embodiments

[0033] The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention to the scope of the described examples.

[0034] The reagents used in the present invention can all be purchased from the market or can be prepared by the methods described in the present invention.

[0035] Example 1: Synthesis of Compound of Formula B (n = 14):

[0036]

[0037] Under nitrogen protection, 50.0 g of tetradecanedioic acid, 61.37 g of Meldrum's acid, 70.1 g of 4-dimethylaminopyridine and 1 L of dichloromethane were added to a 2 L three-necked flask and stirred until dissolved. The mixture was cooled to 0 °C, and a solution of N,N'-diisopropylcarbodiimide (87.8 g) in dichloromethane (400 mL) was added dropwise. After reacting at this temperature for 30 minutes, the mixture was allowed to return to room temperature naturally and reacted overnight. The mixture was filtered by suction, and the filter cake was washed with dichloromethane. The filtrate was adjusted to acidic pH with hydrochloric acid, extracted with dichloromethane, and the organic phase was washed successively with saturated sodium carbonate and saturated brine. The solvent was removed by concentration, and the residue was triturated with methyl tert-butyl ether to obtain 85.5 g of the light yellow solid dimeldrum's acid tetradecanedione, with a yield of 86%. 1H NMR (400 MHz, CDCl3) δ 15.29 (s, 2H), 3.06 (t, J = 4, 4H), 1.73 (s, 12H), 1.71–1.64 (m, 4H), 1.43–1.35 (m, 4H), 1.33–1.25 (m, 12H).

[0038] Example 2: Synthesis of Compound C (n = 14):

[0039]

[0040] Dimeldrum's acid tetradecanedione was added to a 250 mL single-necked flask, dissolved in 50 mL of dichloromethane, 6.72 mL of acetic acid was added, and the mixture was cooled in an ice bath. 2.96 g of sodium borohydride was added portionwise. After addition, the mixture was stirred at room temperature overnight. After the reaction was completed, water was added to the reaction flask to quench the reaction, and the pH was adjusted to neutral with saturated sodium bicarbonate, followed by extraction with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the solid was triturated with methyl tert-butyl ether to obtain 6.38 g of cyclopropyl isopropyl tetradecanedipropionate, with a yield of 77%. 1H NMR (400 MHz, CDCl3) δ 3.48 (t, J = 5.0 Hz, 2H), 2.14–2.04 (m, 4H), 1.78 (s, 6H), 1.75 (s, 6H), 1.49–1.40 (m, 4H), 1.34–1.23 (m, 21H).

[0041] Example 3: Synthesis of Compound D (n = 14):

[0042]

[0043] Under nitrogen protection, 3.7 g of cycloisopropyl tetradecanedipropionate, 11.1 mL of tert-butanol, 18.5 mL of toluene, and 3.1 g of triethylamine were added to a 50 mL single-necked flask, and the mixture was heated to 100 °C and reacted overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure. 30 mL of dichloromethane was added, and the mixture was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine. The solvent was removed by concentration to obtain 2.21 g of di-tert-butyl octadecanedioate as a light yellow oil, with a yield of 68%. 1H NMR (400 MHz, DMSO) δ 2.16 (t, J = 7.3 Hz, 4H), 1.51–1.45 (m, 4H), 1.39 (s, 18H), 1.25–1.23 (m, 24H).

[0044] Example 4: Synthesis of Compound E (n = 14):

[0045] 500 mg of di-tert-butyl octadecanedioate, 5 mL of tetrahydrofuran, 3 mL of water, 5 mL of tert-butanol, and 395 mg of potassium hydroxide were added to a 25 mL single-necked flask, and the mixture was heated to 100 °C and reacted overnight. The reaction solution was concentrated, and 2% potassium bisulfate was added to adjust the pH to 2 - 3. The mixture was extracted with ethyl acetate, and silica gel chromatography was used to obtain 229 mg of monoter-butyl eicosenoate, with a yield of 52%. 1H NMR (400 MHz, CDCl3) δ 2.36 (t, J = 7.5 Hz, 2H), 2.22 (t, J = 7.5 Hz, 2H), 1.70–1.54 (m, 4H), 1.46 (s, 9H), 1.42–1.17 (m, 24H).

[0046] The specific embodiments of the present invention and the advantages of the present invention are shown and described above. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention needs to be continuously changed and improved, and these changes and improvements all fall within the scope of the present invention claimed. The scope of protection claimed by the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a long-chain alkyl diacid monoter-butyl ester, the method comprising the following steps: The compound of formula C undergoes a transesterification reaction with tert-butanol to obtain a compound of formula D; The compound of formula D is hydrolyzed to obtain a long-chain alkyl diacid monoter-butyl ester E. Among them, n = 9, 10, 11, 12, 13, 14, 15 or 16.

2. The method according to claim 1, wherein In the hydrolysis reaction, alkaline hydrolysis is first carried out, and then the pH value is adjusted to 2-3 with an acidic reagent to obtain a long-chain alkyl diacid monoter-butyl ester E.

3. The method according to claim 2, wherein The hydrolysis reaction catalyst is potassium hydroxide or sodium hydroxide.

4. The method according to any one of claims 1 to 3, characterized in that, The compound of formula B is reduced to obtain a compound of formula C; 5. The method according to claim 4, wherein In the reduction step, a borohydride is used as a reducing agent.

6. The method according to claim 5, wherein The borohydride is sodium borohydride.

7. The method according to claim 4, wherein The compound of formula A is condensed with Meldrum's acid to obtain a compound of formula B; 8. The method according to claim 7, characterized in that In the condensation step, a pyridine compound is used as a catalyst.

9. The method according to claim 7, wherein The pyridine compound is 4-dimethylaminopyridine.

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