Process for the preparation of (e)-oct-4-ene-1,8-dioic acid

Abstract

This invention provides a method for preparing (E)-octyl-4-en-1,8-diic acid, comprising the steps of reacting diethyl malonate and allyl chloride as raw materials first in the presence of an organic base, then in the presence of a catalyst, and finally obtaining (E)-octyl-4-en-1,8-diic acid through hydrolysis and decarboxylation. The starting materials of this invention are inexpensive and readily available, the reaction operation is simple, the conditions are mild, the safety is good, and the product yield and purity are high, making it of great value for widespread application.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a method for preparing (E)-oct-4-ene-1,8-diocic acid. Background Technology

[0002] Micuronium chloride is a short-acting, non-depolarizing neuromuscular blocking agent of the benzylisoquinoline class, developed by Abbott Lab and first marketed in the United States in 1992. It is a novel short-acting, non-depolarizing muscle relaxant that meets the ideal muscle relaxant concept since its introduction in 1975. Its structural formula I is as follows:

[0003]

[0004] Micuronium chloride is currently the shortest-acting muscle relaxant discovered, with a duration of action only 1 / 3 to 1 / 2 that of cassavasulfuron-methyl and vecuronium bromide. Micuronium chloride has unique advantages such as rapid onset and short duration of action, and is often used to maintain muscle relaxation during endotracheal intubation and surgery.

[0005] The classic preparation method for micudium chloride involves the N-alkylation reaction of the key intermediate (R)-5'-methoxylactansin with 3-chloropropanol under the catalysis of sodium iodide and sodium carbonate, followed by condensation with (E)-oct-4-en-1,8-diacid to obtain micudium chloride. (E)-oct-4-en-1,8-diacid is a key material in the synthesis of micudium chloride, and its synthesis method is receiving increasing attention.

[0006]

[0007] Patent application CN109232222A reports a method for preparing (E)-oct-4-en-1,8-diacid. The method involves a Grignard reaction between magnesium and bromoacetonitrile to generate the Grignard reagent BrMgCH2CN, which then reacts with 1,4-dibromo-(E)-2-butene to produce (E)-oct-4-en-1,8-dianitron, followed by hydrolysis to obtain (E)-oct-4-en-1,8-diacid. This method requires the Grignard reaction to be conducted under strictly aerated and anhydrous conditions, making it difficult to implement industrially. Furthermore, the Grignard reaction may fail due to inadequate moisture control, or the violent gas production and exothermic phenomena caused by initiating and quenching the reaction could pose safety hazards, even leading to explosions. The temporary storage and transportation of the Grignard reagent also require strict control, resulting in extremely high production management costs. Therefore, this method is unsuitable for industrial production.

[0008] Patent application CN 113563180 A reports a method for preparing (E)-oct-4-en-1,8-dicarboxylic acid, the route of which is as follows:

[0009]

[0010] However, the reaction conditions for malonate and 1,4-dibromo-(E)-2-butene in this method are quite harsh. It requires nitrogen protection and lithium hydride condensation under an ice-water bath. Furthermore, lithium hydride is highly reactive and can spontaneously combust when exposed to air. When heated or in contact with moisture or acids, it releases heat and hydrogen, which can cause combustion and explosion. It also forms hydroxides when exposed to moisture, which are highly corrosive. Therefore, controlling the reaction conditions is difficult, and it is not suitable for large-scale industrial production. If the conditions are not strictly controlled, the yield may be significantly reduced.

[0011] Besides the yield, (E)-oct-4-en-1,8-diacid, a key material in the synthesis of micuronium chloride, contains impurities that can easily participate in the reaction or be transferred to micuronium chloride during the reaction, increasing the difficulty of purification and affecting the quality, safety, and efficacy of micuronium chloride. In the preparation of (E)-oct-4-en-1,8-diacid, the isomer impurity (Z)-oct-4-en-1,8-diacid is easily generated. This impurity participates in the preparation of micuronium chloride, reacting with compound II to generate the Z-isomer of micuronium chloride. The Z-isomer of micuronium chloride contains three trans / cis isomers with chiral nitrogen atoms: trans-trans: trans-cis: cis-cis isomers. These three isomers have very similar polarities to the three isomers of micuronium chloride, making separation difficult and affecting the purity and quality of micuronium chloride.

[0012]

[0013] Therefore, it is of great significance to develop a new method for preparing (E)-oct-4-ene-1,8-dicarboxylic acid that is simple in reaction steps, has readily available raw materials, mild conditions, safe operation, high product yield and purity, low impurity content, and is suitable for industrial production. Summary of the Invention

[0014] The purpose of this invention is to provide a method for preparing (E)-oct-4-ene-1,8-dioctic acid with high yield and high purity.

[0015] This invention provides a method for preparing (E)-oct-4-en-1,8-diocic acid, comprising the following steps:

[0016] (1) Diethyl malonate and allyl chloride are reacted in an organic solvent in the presence of an organic base to prepare compound A;

[0017] (2) Compound A was reacted in an organic solvent in the presence of a catalyst to prepare compound B;

[0018] (3) Compound B was hydrolyzed in a solvent in the presence of hydroxide to obtain compound C;

[0019] (4) Compound C undergoes a decarboxylation reaction to obtain;

[0020] The reaction formula is as follows:

[0021]

[0022] Further, the organic base in step (1) is sodium methoxide and / or sodium ethoxide; the organic solvent is an alcohol solvent;

[0023] And / or the catalyst in step (2) is any one or a combination of phenylmethylene bis(tricyclohexylphosphine) ruthenium dichloride, 1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinedimethyl)(dichlorobenzylmethyl)(tricyclohexylphosphine) ruthenium, and (1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(o-isopropoxybenzylmethyl) ruthenium; the organic solvent is any one or a combination of alkane solvents, ester solvents, and benzene solvents;

[0024] And / or the hydroxide in step (3) is any one or a combination of lithium hydroxide or its hydrate, sodium hydroxide, potassium hydroxide; the solvent is a mixed solvent of alcohol and water, wherein the volume ratio of alcohol to water is 1:1.

[0025] Furthermore, the alcohol solvent mentioned in step (1) is any one or a combination of methanol, ethanol, isopropanol;

[0026] And / or the alkane solvent in step (2) is: dichloromethane or dichloroethane;

[0027] The ester solvent is: ethyl acetate, methyl acetate, ethyl formate, or butyl acetate;

[0028] The benzene-based solvent is toluene or xylene;

[0029] And / or the alcohol in step (3) is methanol, ethanol or isopropanol.

[0030] Further, the molar ratio of diethyl malonate, allyl chloride and organic base in step (1) is 1:(1~3):(0.9~3);

[0031] And / or the molar ratio of compound A to catalyst in step (2) is 1:(0.01 to 0.1);

[0032] And / or the molar ratio of compound B to hydroxide in step (3) is 1:(1-10).

[0033] Furthermore, the molar ratio of diethyl malonate, allyl chloride, and organic base in step (1) is 1:(1.1-2):(1-1.5);

[0034] And / or the molar ratio of compound A to catalyst in step (2) is 1:(0.02-0.05);

[0035] And / or the molar ratio of compound B to hydroxide in step (3) is 1:(3-6).

[0036] Further, the mass-to-volume ratio of diethyl malonate to the organic solvent in step (1) is 1:(1~10)g / ml;

[0037] And / or the mass-to-volume ratio of compound A in step (2) to the organic solvent is 1:(3-15)g / ml;

[0038] And / or the mass-to-volume ratio of compound B in step (3) to the organic solvent is 1:(3-20)g / ml.

[0039] Furthermore, the reaction conditions described in step (1) are: reaction temperature 30-80℃, reaction time 1-5 hours;

[0040] And / or the reaction conditions described in step (2) are: reaction temperature 30-80℃, reaction time 1-8 hours;

[0041] And / or the conditions for the hydrolysis reaction described in step (3) are: reaction temperature 30-80℃, reaction time 1-24 hours;

[0042] The conditions for the decarboxylation reaction in step (4) are: reaction temperature of 100-150°C, preferably 110-130°C, and reaction time of 2-5 hours.

[0043] Furthermore, the reaction temperature in step (1) is 78°C, and the reaction time is 2 hours;

[0044] And / or the reaction temperature in step (2) is 40°C and the reaction time is 8 hours;

[0045] And / or the reaction temperature in step (3) is 80°C and the reaction time is 24 hours;

[0046] And / or the reaction temperature in step (4) is 130°C and the reaction time is 2 hours.

[0047] Furthermore, step (4) also includes the step of recrystallizing with a recrystallization solvent; the recrystallization solvent is any one or a combination of ethyl acetate, methyl acetate, butyl acetate.

[0048] Furthermore, the mass-to-volume ratio of compound C to recrystallization solvent is 1:(1-10) g / ml, preferably 1:(3-5) g / ml.

[0049] The beneficial effects of this invention are as follows: The method for preparing (E)-oct-4-en-1,8-diic acid provided by this invention uses inexpensive and readily available starting materials, involves simple reaction operations, operates under mild conditions, has good safety, and produces high product yield and purity: the overall yield is over 81%, and the purity of the obtained (E)-oct-4-en-1,8-diic acid is ≥99.9%, with impurities of (Z)-oct-4-en-1,8-diic acid ≤0.1%. Even if this level of impurity participates in the preparation of micuronium chloride, it will not affect the quality, safety, or efficacy of micuronium chloride, making it highly valuable for widespread application.

[0050] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0051] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0052] Figure 1 This is the 1H NMR spectrum of the product obtained in Example 1.

[0053] Figure 2 This is the carbon NMR spectrum of the product obtained in Example 1. Detailed Implementation

[0054] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0055] Example 1

[0056] (1) Weigh 102.1 g of sodium ethoxide and add it to 750 mL of anhydrous ethanol. Then add 241.0 g of diethyl malonate and stir for 0.5 hours. Add 127.0 g of allyl chloride and react at 78 °C for 2 hours. The reaction was detected by TLC as complete (iodine fuming color development). Concentrate to dryness under reduced pressure at 45 °C, cool to room temperature, add 300 mL of water to disperse, adjust the pH to 7.0 with 10% sulfuric acid, add 500 mL of diethyl ether to extract and separate the layers. Wash the organic layer once with saturated sodium bicarbonate solution, separate the layers, dry the organic layer with anhydrous sodium sulfate, and concentrate to dryness under reduced pressure at 35 °C to obtain 290.0 g of compound A.

[0057] (2) Take 290.0 g of compound A and 30.5 g of phenylmethylene bis(tricyclohexylphosphine) ruthenium dichloride, add them to 1.5 L of dichloromethane, and reflux at 40 °C for 8 h. The reaction was detected by TLC (iodine fuming for color development). Concentrate to dryness under reduced pressure. Purify by column chromatography with petroleum ether:ethyl acetate = 10:1 as the eluent to obtain 239.2 g of compound B.

[0058] (3) Take 239.2 g of compound B, 164.8 g of lithium hydroxide monohydrate, and 1.2 L of methanol / water mixed solvent (1:1, V / V), and reflux at 80 °C for 24 h. Concentrate the methanol under reduced pressure, cool to room temperature, adjust the pH to 1 with hydrochloric acid, extract with dichloromethane to separate the layers, dry the organic layer with anhydrous sodium sulfate, and concentrate under reduced pressure at 35 °C to dryness to obtain 167.0 g of white powder solid. Add the white solid to 500 mL of ethyl acetate and stir for 1 hour, filter, and dry the filter cake under reduced pressure to obtain 163.8 g of compound C.

[0059] (4) 163.8 g of compound C was taken and stirred at 130 °C for 2 h until it was in a molten state. After cooling, a white solid was obtained. The white solid was recrystallized from 800 mL of ethyl acetate to give 105.0 g of (E)-oct-4-en-1,8-diacid. The overall yield was 81%.

[0060] The obtained compound was analyzed using a microTOF-Q II mass spectrometer, yielding a molecular ion peak at m / z of 173.2 [M+H]. + .

[0061] The compound was analyzed using nuclear magnetic resonance spectroscopy, and its proton nuclear magnetic resonance spectrum was obtained. Figure 1 ) and carbon spectrum ( Figure 2 The results are as follows:

[0062] 1 H NMR (400MHz, CDCl3), δ=5.462~5.445(t, 2H); 2.277~2.238(m, 4H); 2.201~2.159(m, 4H).

[0063] 13 C NMR (400MHz, CDCl3), δ=179.11, 134.47~134.25, 39.06~38.51, 32.59.

[0064] The product is (E)-oct-4-ene-1,8-dicarboxylic acid.

[0065] Purity testing:

[0066] (1) Chromatographic conditions

[0067] Column: Sulfonated cross-linked styrene-divinylbenzene copolymer, strong cation exchange column Carbomix H-NP5, 7.8 × 300 mm, 5 μm, cross-linking degree 8%.

[0068] Mobile phase: 0.1% trifluoroacetic acid solution;

[0069] Column temperature: 75℃;

[0070] Flow rate: 0.5 ml / min;

[0071] Detection wavelength: 205nm;

[0072] Diluent: Mobile phase;

[0073] Injection volume: 20 μl;

[0074] (2) Solution preparation

[0075] Blank solution: diluent.

[0076] Separation solution: Take appropriate amounts of reference standards (E)-oct-4-en-1,8-dioctanoic acid and (Z)-oct-4-en-1,8-dioctanoic acid, accurately weigh them, and dilute them with the mobile phase to a concentration of 5 μg / ml, respectively, to obtain the separation solution.

[0077] Test solution: Weigh 20 mg of (E)-oct-4-en-1,8-dicarboxylic acid prepared in Example 1 of this invention accurately, place it in a 20 ml volumetric flask, add mobile phase to dissolve and dilute to the mark, shake well, and use as the test solution.

[0078] (3) Detection

[0079] Take 20 μl each of the test solution and the resolution solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the results using the peak area normalization method.

[0080] (4) Test results

[0081] (E)-Octo-4-en-1,8-dicarboxylic acid has a purity of 99.94%, impurities (Z)-Octo-4-en-1,8-dicarboxylic acid 0.01%, and other maximum unknown single impurities 0.03%.

[0082] Comparative Example 1

[0083] (E)-oct-4-en-1,8-dicarboxylic acid was prepared by referring to the method disclosed in patent application CN113563180A. However, it was found that the method was difficult to reproduce, and the yield and purity of the target compound (E)-oct-4-en-1,8-dicarboxylic acid were low.

[0084] In summary, this invention provides a method for preparing (E)-oct-4-en-1,8-diic acid, using inexpensive and readily available starting materials, with simple reaction operation, mild conditions, good safety, and high product yield and purity: the overall yield is over 81%, and the purity of the obtained (E)-oct-4-en-1,8-diic acid is ≥99.9%, with impurities of (Z)-oct-4-en-1,8-diic acid ≤0.1%. Even if this level of impurity participates in the preparation of micuronium chloride, it will not affect the quality, safety, or efficacy of micuronium chloride, making it highly valuable for widespread application.

Claims

1. A method for preparing (E)-oct-4-en-1,8-diocic acid, characterized in that, Includes the following steps: (1) Weigh 102.1g sodium ethoxide, add it to 750mL anhydrous ethanol, then add 241.0g diethyl malonate and stir for 0.5 hours; add 127.0g allyl chloride and react at 78℃ for 2 hours; the reaction is complete as detected by TLC and iodine fuming is used for color development; concentrate to dryness under reduced pressure at 45℃, cool to room temperature, add 300mL water to disperse, adjust the pH to 7.0 with 10% sulfuric acid, add 500mL diethyl ether to extract and separate the layers, wash the organic layer once with saturated sodium bicarbonate solution, separate the layers, dry the organic layer with anhydrous sodium sulfate, concentrate to dryness under reduced pressure at 35℃ to obtain 290.0g compound A; (2) Take 290.0 g of compound A and 30.5 g of phenylmethylene bis(tricyclohexylphosphine) ruthenium dichloride, add them to 1.5 L of dichloromethane, and reflux at 40 °C for 8 h; the reaction was detected by TLC and iodine fuming was used for color development; the mixture was concentrated to dryness under reduced pressure; the mixture was purified by column chromatography with petroleum ether: ethyl acetate = 10:1 as the eluent to obtain 239.2 g of compound B; (3) Take 239.2g of compound B, 164.8g of lithium hydroxide monohydrate, 1.2L of methanol / water mixed solvent, 1:1, V / V, reflux reaction at 80℃ for 24h; concentrate methanol under reduced pressure, cool to room temperature, adjust pH=1 with hydrochloric acid, extract with dichloromethane to separate layers, dry the organic layer with anhydrous sodium sulfate, concentrate under reduced pressure at 35℃ to dry to obtain 167.0g of white powder solid; The white solid was added to 500 mL of ethyl acetate and stirred for 1 hour. The mixture was then filtered, and the filter cake was dried under reduced pressure to obtain 163.8 g of compound C. (4) Take 163.8g of compound C, stir at 130℃ for 2h until it is in a molten state, and cool down to obtain a white solid; recrystallize the white solid with 800mL of ethyl acetate to obtain 105.0g of (E)-oct-4-ene-1,8-dicarboxylic acid.

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