CN117682945B - Preparation method of polidocanol and intermediate thereof - Google Patents

Abstract

The present invention relates to a preparation method of polydocanol and an intermediate thereof, the preparation method comprising: step S3: reacting a compound of formula (III) with a compound of formula (II) in the presence of a base to obtain a compound of formula (I-1); step S4: deprotecting the compound of formula (I-1) obtained in step S3 to obtain polydocanol; wherein _R1 is a halogen, a p-toluenesulfonyl ester group or a methanesulfonyl ester group; and _R2 is a methyl group, an ethyl group, a formyl group, an acetyl group, a methanesulfonyl group, a benzyl group, a benzyloxycarbonyl group, a benzoyl group, a benzoyl group or a benzenesulfonyl group. The preparation method provided by the present invention has the advantages of simple operation, mild reaction conditions, stable process and high purity.

Description

A kind of preparation method of polydocanol and intermediate thereof

Technical Field

The present invention relates to the field of medical technology, and in particular to a preparation method of polydocanol and its intermediates.

Background technique

Varicose veins are the most common disease of the venous system. Varicose veins often occur in the lower limbs. Red or blue twisted blood vessels like spider webs or worms, or hard nodules like tree tumors appear on the skin of the legs, and the veins become abnormally enlarged, swollen and varicose. Varicose veins can be treated mainly by injection of sclerosants and surgical removal, among which injection of sclerosants is a simple and efficient method. Commonly used sclerosants include anhydrous ethanol, tetracycline injection, 5% sodium morrhuate injection, 10% sodium chloride injection, hypertonic glucose injection, polidocanol injection, etc.

Polidocanol 400 is a dialkyl alcohol monoether of polyethylene glycol with a molecular weight of about 400. It is an amphiphilic molecule and a membrane active compound. Polidocanol 400 is mainly prepared by ring-opening polymerization of ethylene oxide. Due to the limited controllability of the ring-opening polymerization process, Polidocanol 400 is a mixture of multiple components, the main active ingredient of which is dodecyl alcohol monoether of nona polyethylene glycol, which also includes a series of dodecyl alcohol monoether derivatives of homologues of nona polyethylene glycol, namely dodecyl alcohol monoethers of penta to penta polyethylene glycol. The polydispersity of the components of Polidocanol leads to the non-uniformity of the drug's physicochemical properties, physiological behavior and pharmacodynamic behavior, which leads to a series of problems in drug production, quality control, drug approval and controllability of drug efficacy. The best way to solve this problem is to replace the current Polidocanol mixture used in clinical practice with a single-component Polidocanol, in which efficient, economical and large-scale preparation of dodecyl alcohol monoether of nona polyethylene glycol is the key.

At present, the conventional route of polydocanol is to prepare it by polymerization reaction of lauryl alcohol and ethylene oxide. This method has the following disadvantages: 1) Ethane has a low boiling point, and the reaction conditions are high temperature and high pressure, requiring special reaction equipment and harsh reaction conditions; 2) Ethane is a highly toxic and carcinogenic substance, and it is difficult to control the residue in the raw material drug; 3) Many kinds of by-products are generated in the reaction, and most of these by-products have the following characteristics: high boiling point, difficult to vaporize, no ultraviolet absorption, and high requirements for the development of analytical instruments and analytical methods; 4) The raw material drug is a high boiling point, low melting point substance, and the purification method is single.

Summary of the invention

In view of the defects of the prior art, the present invention provides a method for preparing polydocanol with simple operation, mild reaction conditions, stable process and high purity.

In order to solve the above technical problems, the technical solution adopted by the present invention is:

In a first aspect, the present invention provides a method for preparing polydocanol as shown in formula (I), the preparation method comprising the following steps:

Step S3: the compound of formula (III) reacts with the compound of formula (II) in the presence of a base to obtain a compound of formula (I-1);

Step S4: The compound of formula (I-1) obtained in step S3 is deprotected to obtain polydocanol;

Wherein, R ₁ is halogen, p-toluenesulfonyl ester or methanesulfonyl ester;

_R2 is methyl, ethyl, formyl, acetyl, methylsulfonyl, benzyl, benzyloxycarbonyl, benzoyl, benzoyl or benzenesulfonyl.

Preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:(0.1-3).

Preferably, the base is an inorganic base or an organic base.

Further preferably, the organic base is selected from one or more of triethylamine, diisopropylethylamine and pyridine.

Further preferably, the inorganic base is selected from one or more of sodium hydride, lithium hydride, potassium hydride, calcium hydride, cesium carbonate, sodium carbonate, potassium carbonate and calcium carbonate.

Preferably, the reaction in step S3 is carried out in the presence of solvent 1, and the solvent 1 is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether.

Preferably, the reaction temperature in step S3 is controlled to be -10~50°C.

Preferably, in step S4, the deprotection is carried out under acid or base or Pd/C/ _H2 conditions.

Preferably, the reaction in step S4 is carried out in the presence of solvent 2, and the solvent 2 is selected from one or more of methanol, ethanol, propanol, butanol, tetrahydrofuran, 2-methyltetrahydrofuran, formic acid, acetic acid and propionic acid.

Preferably, the method for preparing the compound of formula (III) comprises:

Step S1: nonaglycone is reacted in the presence of a hydroxyl protecting agent and an acid binding agent to obtain a compound of formula (III);

Wherein, _R2 is methyl, ethyl, formyl, acetyl, methylsulfonyl, benzyl, benzyloxycarbonyl, benzyl ester or benzyl sulfonate.

Further preferably, the acid binding agent is selected from one or more of triethylamine, silver oxide, pyridine, cesium carbonate, sodium carbonate and potassium carbonate.

Further preferably, the hydroxyl protecting agent is selected from one or more of methyl halides, ethyl halides, dimethyl sulfate, diethyl sulfate, dimethyl carbonate, diethyl carbonate, methyl sulfonyl chloride, ethyl sulfonyl chloride, methyl sulfonic acid, ethyl sulfonic acid, acetic anhydride, methyl acetate, ethyl acetate, benzyl halides, benzyloxycarbonyl halides, benzyloxycarbonyl alkane esters, benzoyl halides, benzoyl alkane esters, benzoyl halides, benzoyl alkane esters, benzyl halides and benzenesulfonyl halides.

Preferably, the method for preparing the compound of formula (II) comprises:

Step S2: lauryl alcohol reacts in the presence of an activating agent to obtain a compound of formula (II);

Wherein, _R1 is halogen, p-toluenesulfonyl ester group or methanesulfonyl ester group.

Further preferably, the activation reagent is selected from one or more of p-toluenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonic acid, methanesulfonic acid, thionyl chloride, phosphorus oxychloride, phosphorus tribromide, phosphorus trichloride, phosphorus pentoxide and polyphosphoric acid.

On the other hand, the present invention provides an intermediate compound for synthesizing polydocanol, wherein the structural formula of the intermediate compound is as shown in formula (I-1),

Wherein, _R2 is methyl, ethyl, formyl, acetyl, methanesulfonyl, benzyl, benzyloxycarbonyl, benzoyl, benzoyl or benzenesulfonyl.

Compared with the prior art, the present invention has the following beneficial effects:

The present invention prepares the polydocanol shown in formula (I) by reacting the compound of formula (III) with the compound of formula (II), and the reaction is simple in operation, mild in reaction conditions and high in yield after two steps. The properties of the impurities in the synthetic route of the present invention vary greatly, which is conducive to purification, and the prepared polydocanol has high purity; at the same time, the present invention effectively avoids the use of reagents with potential safety hazards, is safe in operation, has low raw material costs in each step, is suitable for industrial production, and has good economic benefits.

Detailed ways

In order to make the technical solutions and beneficial effects of the present invention more clearly understood, the following is a detailed description by listing specific embodiments. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs.

In a first aspect, the present invention provides a method for preparing polydocanol as shown in formula (I), the preparation method comprising the following steps:

Step S3: the compound of formula (III) reacts with the compound of formula (II) in the presence of a base to obtain a compound of formula (I-1);

Step S4: The compound of formula (I-1) obtained in step S3 is deprotected to obtain polydocanol;

Wherein, R ₁ is halogen, p-toluenesulfonyl ester or methanesulfonyl ester;

_R2 is methyl, ethyl, formyl, acetyl, methylsulfonyl, benzyl, benzyloxycarbonyl, benzoyl, benzoyl or benzenesulfonyl.

In certain embodiments, R ₁ is toluenesulfonyl ester.

In certain embodiments, _R2 is methyl, acetyl, or benzyl.

In certain embodiments, _R2 is benzyl.

In certain embodiments, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:(0.1-3), for example, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0, 1:3, etc.

In certain embodiments, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:(0.1-1).

In certain embodiments, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:(0.5-1).

In certain embodiments, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:0.67.

In certain embodiments, the base is an inorganic base or an organic base.

In certain embodiments, the organic base is selected from one or more of triethylamine, diisopropylethylamine and pyridine.

In certain embodiments, the inorganic base is selected from one or more of sodium hydride, lithium hydride, potassium hydride, calcium hydride, cesium carbonate, sodium carbonate, potassium carbonate and calcium carbonate.

In certain embodiments, the reaction in step S3 is carried out in the presence of solvent 1, wherein solvent 1 is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether.

In certain embodiments, the solvent 1 is selected from one or more of toluene, tetrahydrofuran and 2-methyltetrahydrofuran.

In certain embodiments, the reaction temperature in step S3 is controlled to be -10 to 50°C.

In certain embodiments, the reaction temperature in step S3 is controlled to be 20-30°C.

In certain embodiments, in step S4, the deprotection is carried out under acid or base or Pd/C/ _H2 conditions.

In certain embodiments, the reaction in step S4 is carried out in the presence of solvent 2, wherein solvent 2 is selected from one or more of methanol, ethanol, propanol, butanol, tetrahydrofuran, 2-methyltetrahydrofuran, formic acid, acetic acid and propionic acid.

In certain embodiments, the method for preparing the compound of formula (III) comprises:

Step S1: nonaglycone is reacted in the presence of a hydroxyl protecting agent and an acid binding agent to obtain a compound of formula (III);

Wherein, _R2 is methyl, ethyl, formyl, acetyl, methanesulfonyl, benzyl, benzyloxycarbonyl, benzoyl, benzoyl or benzenesulfonyl. The starting material nonaethylene glycol can be synthesized by directing the triethylene glycol with high market purity and stable quality, which reduces the difficulty of purifying nonaethylene glycol and reduces the number of impurities. The starting material nonaethylene glycol can also be obtained through commercial channels.

In certain embodiments, _R2 is methyl, acetyl, or benzyl.

In certain embodiments, _R2 is benzyl.

In certain embodiments, the acid binding agent is selected from one or more of triethylamine, silver oxide, pyridine, cesium carbonate, sodium carbonate and potassium carbonate.

In certain embodiments, the hydroxyl protecting agent is selected from one or more of methyl halides, ethyl halides, dimethyl sulfate, diethyl sulfate, dimethyl carbonate, diethyl carbonate, methyl sulfonyl chloride, ethyl sulfonyl chloride, methyl sulfonic acid, ethyl sulfonic acid, acetic anhydride, methyl acetate, ethyl acetate, benzyl halides, benzyloxycarbonyl halides, benzyloxycarbonyl alkane esters, benzoyl halides, benzoyl alkane esters, benzoyl halides, benzoyl alkane esters, benzyl halides, benzyl alkane esters, benzyl halides and benzyl sulfonyl alkane esters.

In certain embodiments, the hydroxyl protecting agent is a benzyl halide, preferably benzyl bromide.

In certain embodiments, the reaction in step S1 is carried out in the presence of a solvent 3, and the solvent 3 is selected from dichloromethane.

In certain embodiments, the method for preparing the compound of formula (II) comprises:

Step S2: lauryl alcohol reacts in the presence of an activating agent to obtain a compound of formula (II);

Wherein, _R1 is halogen, p-toluenesulfonyl ester group or methanesulfonyl ester group.

In certain embodiments, R ₁ is toluenesulfonyl ester.

In certain embodiments, the activation reagent is selected from one or more of p-toluenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonic acid, methanesulfonic acid, thionyl chloride, phosphorus oxychloride, phosphorus tribromide, phosphorus trichloride, phosphorus pentoxide and polyphosphoric acid.

In certain embodiments, the activation reagent is selected from one or more of p-toluenesulfonyl chloride and methanesulfonyl chloride.

In certain embodiments, the activating reagent is selected from p-toluenesulfonyl chloride.

In certain embodiments, the reaction in step S2 is carried out in the presence of a solvent 4, and the solvent 4 is selected from toluene.

In view of the polydispersity problem of polidocanol, the present invention provides a method for preparing monodisperse nonapolyethylene glycol dodecyl alcohol monoether, and the synthesis route of the present invention is:

.

The preparation method provided by the present invention has low requirements on equipment, and the entire synthetic route does not require harsh conditions such as ultra-low temperature, ultra-high temperature, and high pressure, and the reaction conditions are mild. Moreover, the reagents used are all conventional reagents, which can be effectively removed during the purification process of the intermediates and can be well controlled in the raw materials. The process impurities in the route have large differences in properties, which is convenient for purification.

On the other hand, the present invention provides an intermediate compound for synthesizing polydocanol, wherein the structural formula of the intermediate compound is as shown in formula (I-1),

Wherein, _R2 is methyl, ethyl, formyl, acetyl, methanesulfonyl, benzyl, benzyloxycarbonyl, benzoyl, benzoyl or benzenesulfonyl.

In certain embodiments, _R2 is methyl, acetyl, or benzyl.

In certain embodiments, _R2 is benzyl.

The method of the present invention is described below by means of specific examples. It should be understood that these examples are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following examples; the implementation conditions adopted in the examples can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in routine experiments.

In the following examples, ¹ H NMR measurements were made using a Bruker instrument (400 MHz) and chemical shifts are expressed in ppm. Tetramethylsilane was used as an internal standard (0.00 ppm). ¹ H NMR notation: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplet. Coupling constants, when provided, are in Hz.

The mass spectra were measured using a Quattro MicroTM API triple quadrupole mass spectrometer, and the ionization mode was ESI.

TLC: Thin layer chromatography. The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications of the silica gel plate used in thin layer chromatography (TLC) are 0.2mm~0.3mm, and the specifications of the thin layer chromatography separation and purification products are 0.4mm~0.5mm.

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise indicated, commercial manufacturers include but are not limited to Sinopharm Group, J&K Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Bid Pharmaceutical Technology Co., Ltd. and Shanghai Myrel Chemical Technology Co., Ltd.

Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the eluent system of column chromatography or the developing solvent system of thin layer chromatography used for purifying the compound includes: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; wherein the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine, can also be added for adjustment.

Example 1 Preparation of the compound of formula (III) (1-phenyl-2,5,8,11,14,17,20,23,26-nonyloxyoctane-28-ol)

Add 10g nonaethylene glycol, 8.34g silver oxide, 1.6g potassium iodide, and 100mL dichloromethane to a 250mL three-necked flask, stir to dissolve, and react at 25±5℃ for 0.5h. Add 4.62g benzyl bromide dropwise, control the addition time to 1.5h, and react at 25±5℃ for 16h. Filter the reaction solution, and purify the filtrate by column chromatography to obtain 7.23g of the target product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 – 7.14(m, 5H), 4.58 (s, 2H), 3.93 – 3.58 (m, 37H). ESI-MS(m/z):505[M+1] ⁺ .

Example 2 Preparation of the compound of formula (III) (1-phenyl-2,5,8,11,14,17,20,23,26-nonyloxyoctane-28-ol)

Add 10g of nonaethylene glycol, 11.73g of cesium carbonate and 100mL of dichloromethane to a 250mL three-necked flask, stir to dissolve, and react at 25±5℃ for 0.5h. Add 4.62g of benzyl bromide dropwise, control the addition time to 1.5h, and react at 25±5℃ for 16h. Filter the reaction solution, and purify the filtrate by column chromatography to obtain 7.62g of the target product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 – 7.14 (m, 5H),4.58 (s, 2H), 3.93 – 3.58 (m, 37H). ESI-MS(m/z):505[M+1] ⁺ .

Example 3 Preparation of the compound of formula (II) (dodecyl 4-methylbenzenesulfonate)

Add 10g of lauryl alcohol and 100mL of toluene to a 250mL reaction bottle, stir and dissolve, add 6.48g of triethylamine, slowly drop 12.28g of p-toluenesulfonyl chloride, stir at room temperature for 2h after the addition is complete. Filter the reaction solution, concentrate the filtrate and purify it by column chromatography, add 20mL of n-heptane after purification, stir and cool to -10~0℃, precipitate a white solid, filter, collect the filter cake, and dry under reduced pressure to obtain 16.55g of the target product with a yield of 90%.

Example 4 Preparation of the compound of formula (II) (dodecyl 4-methylbenzenesulfonate)

Add 10g of lauryl alcohol and 100mL of toluene to a 250mL reaction bottle and stir to dissolve. Add 10.8g of triethylamine and slowly drop 20.47g of p-toluenesulfonyl chloride. After the addition is complete, stir at room temperature for 2h. Filter the reaction solution, concentrate the filtrate and purify it by column chromatography. After purification, add 20mL of n-heptane, stir and cool to -10~0℃, precipitate a white solid, filter, collect the filter cake, and dry under reduced pressure to obtain 17.47g of the target product with a yield of 95%.

Example 5 Preparation of the compound of formula (I-1) (1-phenyl-2,5,8,11,14,17,20,23,26,29-decadienyl)

2 g of the compound of formula (III) prepared according to the method of Example 2 was added to a 100 mL single-mouth bottle, and 20 mL of tetrahydrofuran was added thereto to dissolve. Sodium hydride was slowly added in batches and stirred for 0.5 h. 2.04 g of the compound of formula (II) prepared according to the method of Example 4 was dissolved in 5 mL of tetrahydrofuran and then slowly added dropwise to the reaction system. After the addition was completed, the mixture was stirred at room temperature overnight. The reaction solution was quenched with water and then prepared and purified to obtain 2.47 g of the target product with a yield of 92% and a purity of 99.83%.

The compound of formula (I-1) prepared in this example: ¹ H NMR (CDCl ₃ ,400MHz):δ7.38 - 7.34 (d,4H), 7.32 - 7.28 (q,1H), 3.72-3.64 (t ,37H), 3.50 - 3.423.64 (t,3H), 1.64 -1.54 (m,2H), 1.34-1.24 (m,18H), 0.93-0.87(t,3H). ESI-MS (m/z):674[M+1] ⁺ .

Example 6 Preparation of the compound of formula (I) (Polidocarbol)

2 g of the compound of formula (I-1) obtained according to the method of Example 5 was added to a 100 mL three-necked flask, and 20 mL of methanol was added thereto to dissolve, and then 0.5 g of Pd/C and hydrogen were added. The mixture was stirred at room temperature for 2.5 h, filtered, concentrated under reduced pressure, and crystallized by cooling with n-heptane to obtain 1.53 g of the target product with a yield of 88%.

Example 7 Preparation of the compound of formula (I) (Polidocarbol)

2 g of the compound of formula (I-1) obtained according to the method of Example 5 was added to a 100 mL three-necked flask, and 20 mL of methanol was added thereto to dissolve, and then 0.5 g of Pd/C and 2 mL of formic acid were added. The mixture was stirred at room temperature for 2.5 h, filtered, and concentrated under reduced pressure. The sample was distilled twice with 50 mL of n-heptane, and then crystallized by cooling with n-heptane to obtain 1.46 g of the target product with a yield of 85% and a purity of 99.92%.

The compound of formula (I) prepared in this example: ¹ H NMR (CDCl ₃ ,400MHz):δ3.72-3.64(t,37H),3.50-3.423.64(t，3H),1.64-1.54(m,2H), 1.34-1.24(m，18H),0.93-0.87(t,3H).ESI-MS(m/z):583[M+1] ⁺ .

It should be understood that the above embodiments are exemplary and are not intended to include all possible implementations included in the claims. Various modifications and changes may be made on the basis of the above embodiments without departing from the scope of the present invention. Similarly, the various technical features of the above embodiments may be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only express several implementations of the present invention and do not limit the scope of protection of the patent of the present invention.

Claims (4)

1. A method for preparing polydocanol as shown in formula (I), characterized in that the preparation method comprises the following steps: ; Step S1: nonaglycone is reacted in the presence of a hydroxyl protecting agent and an acid binding agent to obtain a compound of formula (III); ; Step S2: lauryl alcohol reacts in the presence of an activating agent to obtain a compound of formula (II); ; Step S3: the compound of formula (III) reacts with the compound of formula (II) in the presence of a base to obtain a compound of formula (I-1); Step S4: The compound of formula (I-1) obtained in step S3 is deprotected to obtain polydocanol; Wherein, R ₁ is a p-toluenesulfonyl ester group; _R2 is benzyl; The hydroxyl protecting agent in step S1 is benzyl bromide; The acid binding agent in step S1 is selected from one or more of silver oxide and cesium carbonate; The activation reagent in step S2 is p-toluenesulfonyl chloride; The base in step S3 is an inorganic base, and the inorganic base is selected from one or more of sodium hydride, lithium hydride, potassium hydride, calcium hydride, cesium carbonate, sodium carbonate, potassium carbonate and calcium carbonate. 2. The preparation method according to claim 1, characterized in that the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:(0.1~3). 3. The preparation method according to claim 1, characterized in that the reaction in step S3 is carried out in the presence of solvent 1, and the solvent 1 is selected from one or more of toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane and ethylene glycol dimethyl ether; And/or, the reaction temperature in step S3 is controlled to be -10~50°C. 4. The preparation method according to claim 1, characterized in that, in step S4, the deprotection is carried out under acid or base or Pd/C/ _H2 conditions; and/or, The reaction in step S4 is carried out in the presence of solvent 2, wherein the solvent 2 is selected from one or more of methanol, ethanol, propanol, butanol, tetrahydrofuran, 2-methyltetrahydrofuran, formic acid, acetic acid and propionic acid.