CN117800858A

CN117800858A - Preparation method for catalytic cyanation of milbelin

Info

Publication number: CN117800858A
Application number: CN202311834372.XA
Authority: CN
Inventors: 洪声
Original assignee: Nanjing Jinhong Technology Co ltd
Current assignee: Nanjing Jinhong Technology Co ltd
Priority date: 2023-12-28
Filing date: 2023-12-28
Publication date: 2024-04-02

Abstract

The invention relates to milabalin, in particular to a preparation method for catalytic cyanation of milabalin. Taking (1R, 5S) -3-ethyl-bicyclo [3.2.0] heptane-3-alkene-6-ketone as a starting material SM1, diethyl phosphonoacetic acid tert-butyl ester/ethyl ester/methyl ester as a starting material SM2, and condensing into an intermediate M2 under alkaline conditions; performing high-efficiency and safe cyano reaction by using a TMSCN/catalyst system to replace a high-toxicity lethal potassium cyanide or sodium cyanide method to obtain M3, and finally reducing cyano groups into amine to obtain M4, performing chemical resolution to obtain M5, and performing hydrolysis to obtain M6; the invention provides a safe and reliable commercial production route with strong operability and low cost for the drug Milobalin for treating neuralgia.

Description

Preparation method for catalytic cyanation of milbelin

Technical Field

The invention relates to milabalin, in particular to a preparation method for catalytic cyanation of milabalin.

Background

Mirobulin benzenesulfonate (Mirogabalin) is the first three co-developed new drug for treating peripheral neuropathic pain (pnp), which is caused by peripheral nerve injury or dysfunction due to various causes, and typical pnp includes diabetic pnp (dpnp) and post-herpetic neuralgia (phn).

The medicines for treating neuralgia in the current market comprise gabapentin (gabapentin) and pregabalin, and the two medicines have serious defects in clinical treatment.

The synthesis of Milobulin has been reported at present, and an improved synthesis route is reported by Shanghai Hua biological medicine Co., ltd.A.3-ethylbicyclo [3.2.0] hept-3-en-6-one is taken as a starting material, and Milobulin is obtained through 4 steps of reactions and 1 time of chiral resolution. The other route from European patent publication contains two routes, wherein both routes take (1R, 5S) -3-ethyl-bicyclo [3.2.0] heptane-3-alkene-6-ketone as a starting material, and the two routes directly obtain the milabalin through 5 steps of reactions, and the difference is that the second step is divided into two methods, namely one is nitro and the other is cyano.

The first route starts with 3-ethylbicyclo [3.2.0] hept-3-en-6-one, S1: 3-ethylbicyclo [3.2.0] hept-3-en-6-one is taken as a starting material a, and reacts with cyanoacetate and ammonia water to generate ammonium salt B; s2: heating ammonium salt B and sulfuric acid to react to generate diacetic acid compound C; s3: reacting a compound diacetic acid C with urea to generate an imide compound D; s4: the imide compound D is subjected to Hofmann degradation in an alkaline solution of hypohalite to generate racemic milabalin hydrochloride E; s5: the obtained racemic milabalin hydrochloride is resolved in an alcohol solvent through a resolving agent to obtain the milabalin, and the specific synthetic route is as follows:

The second route starts with (1 r, 5S) -3-ethyl-bicyclo [3.2.0] heptane-3-en-6-one, S1: taking (1R, 5S) -3-ethyl-bicyclo [3.2.0] heptane-3-alkene-6-ketone as a starting material 1, and reacting with ester (multiple choices) to generate products 1-2 such as tert-butyl ester/methyl ester/ethyl ester/cross ester; s2: nitro on nitromethane on ester 1-2 to give compound 1-3; s3: reducing the compound 1-3 into an amino compound 1-4 through nickel catalysis hydrogen; s4: forming hydrochloride 1-5 from amino compound 1-4 in acid; s5: the obtained hydrochloride is hydrolyzed under alkaline condition to obtain the milrobulin, and the specific synthetic route is as follows:

the third route starts with (1R, 5S) -3-ethyl-bicyclo [3.2.0] heptane-3-en-6-one, S1: taking (1R, 5S) -3-ethyl-bicyclo [3.2.0] heptane-3-alkene-6-ketone as a starting material 2, and reacting with ester (multiple choices) to generate products 2-2 such as tert-butyl ester/methyl ester/ethyl ester/cross ester; s2: cyano group on ester 2-2 with sodium cyanide to give compound 2-3; s3: hydrolyzing the compound 2-3 under alkaline conditions to obtain a compound 2-4; s4: the compound 2-4 generates hydrochloride in acid and is reduced by nickel catalytic hydrogen to obtain the milobalin, and the specific synthetic route is as follows:

by comparing three routes of the two patent documents, the main difference of the three routes is in the aspect of amino conversion, sodium cyanide is needed to be used for cyano group reduction to amino group in the third route, and the method uses the highly toxic cyanide, is not suitable for scale-up production, and has great risk in experiments; the second route and the third route both use the hydrogenation reduction route, use nickel catalysis and need hydrogen to participate in the reaction, and have a great risk factor in the scale-up production. While the first route avoids the use of some highly toxic drugs and dangerous reactions.

Disclosure of Invention

In order to solve the safety problems of inflammability, explosiveness, high toxicity and the like of nitromethane, potassium cyanide and sodium raw materials in patent and literature routes in the prior art, the invention provides a preparation method for catalytic cyanation of milobalin.

The invention adopts the technical scheme that:

the preparation method of the milbelin catalytic cyanation is realized by the following steps:

the method comprises the following steps:

s1 Synthesis of intermediate M2

Sequentially adding 1.0-10.0 equivalents of (1R, 5S) -3-ethyl-bicyclo [3.2.0] heptane-3-alkene-6-ketone serving as a starting material SM1, 1.0-10.0 equivalents of diethyl phosphonoacetic acid tert-butyl ester serving as a starting material SM2 and 1-10 times of tetrahydrofuran serving as a solvent into a reaction bottle, controlling the internal temperature of the reaction liquid to be 0-5 ℃ and adding 1-1.5 equivalents of potassium tert-butoxide into the reaction bottle under stirring in ten equal parts, adding 20-25 ℃ to stir and react for 1-10 hours, performing HPLC (high performance liquid chromatography) central control until the SM1 content is less than 0.1%, adding purified water with 5 times of mass volume ratio, extracting for 3 times by using an ethyl acetate solvent with 5 times of mass volume ratio, combining ethyl acetate phases, purifying and washing with 1 time of mass volume ratio, and removing the solvent by decompression to obtain an intermediate M2;

S2 Synthesis of Compounds of formula M2-1

Under the protection of nitrogen, adding an intermediate M2, a catalyst and tetrahydrofuran into a reaction bottle, cooling to-78-0 ℃, adding TMSCN at 30-100ml/min under stirring, carrying out heat preservation reaction for 30-60min, monitoring by TLC until the content of the intermediate M2 is less than 0.1% at a heating rate of 1 ℃/min to 20-30 ℃, and stopping the reaction to obtain a compound reaction solution of a formula M2-1, wherein the catalyst consists of one or more of quaternary ammonium salt, alkali and acid, and the dosage of TMSCN is 1-3 equivalents of the intermediate M2;

s3 Synthesis of Compounds of formula M3

Cooling the reaction solution of the compound of the formula M2-1 to 0-5 ℃, adding a solution of 1-10 equivalent hydrogen chloride at a rate of 30-100ml/min under stirring, reacting for 30-40min under heat preservation, heating to 20-30 ℃, and reacting for 50-60min under heat preservation; monitoring by HPLC until the content of the intermediate M3 is more than 90%, and stopping the reaction; adding sodium bicarbonate solution with the mass volume ratio of 1-5 times into a reaction bottle for quenching reaction, adding ethyl acetate with the mass volume ratio of 1-5 times for extraction three times, merging ethyl acetate phases, purifying and washing twice, washing with 0.1-0.5 times of purified water each time, washing with saturated sodium chloride solution with the mass volume ratio of 0.1-0.5 times, drying with anhydrous sodium sulfate, and removing solvent under reduced pressure to obtain a crude intermediate M3, namely a compound with the formula M3, wherein the yield is 93-98%, and the appearance is as follows: brown yellow oily;

S4, catalyzing and reducing cyano group into amine by using the compound of the formula M3 and Raney nickel to obtain the compound of the formula M4

1.0 to 10.0 equivalents of a compound of the formula M3, 1 to 10 times of ethanol and 25 percent ammonia water in mass volume ratio, 0.1 to 0.5 times of 50 percent aqueous slurry of Raney nickel in mass volume ratio is added into a mixed solution in mass volume ratio of 0.5 to 0.6 times of the mixed solution, 1.0 to 4.0Mpa of hydrogen is introduced into a pressure kettle device, the temperature is 20 to 30 ℃, and the heat preservation and stirring are carried out at 100 to 300rpm for 16 to 20 hours; monitoring the content of M3 below 0.1% by reaction HPLC, stopping the reaction, discharging and filtering, washing a filter cake twice by using ethanol with the mass-volume ratio of 0.1-0.5, decompressing the filtrate at the temperature of 40-50 ℃ to remove the solvent to obtain a crude intermediate M4, namely a compound of formula M4, and obtaining the appearance: brown yellow oily;

s5 Synthesis of Compounds of formula M5

Taking 1-10 equivalent of M4 compound, adding 15-20 times of methanol with mass volume ratio, stirring at 100-300rpm, dissolving, heating to an internal temperature of 35-45 ℃, adding 0.2-0.3 equivalent of L-mandelic acid, continuously stirring at 100-300rpm for 1-2h, cooling to 15-25 ℃ for 0.1-0.5h, stirring at 100-300rpm for 1-20h, cooling to 0-5 ℃ for 100-300rpm, continuously stirring for 1-2h, filtering, washing with methanol, drying at 40-45 ℃ under reduced pressure to obtain an intermediate M5 compound, and the appearance: white solid;

s6 Synthesis of Compounds of formula M6

1 to 10.0 equivalents of the compound of the formula M5 are proportioned according to the parts by weight, 15 to 20 parts of water and 0.4 to 0.6 equivalent of sodium hydroxide are added, after stirring and dissolving at 100 to 300rpm, stirring is continued for reaction for 1 to 2 hours, the content of the compound of the formula M5 monitored by the reaction HPLC is less than 0.1 percent, and the reaction is stopped; 3-4 parts of 4M hydrochloric acid is added into the reaction liquid at 30-100ml/min while stirring at an internal temperature of 5-15 ℃, the pH value is adjusted to 3-4, stirring crystallization is continued for 2-4h, and after filtration, the solution is dried at 40-45 ℃ under reduced pressure to obtain the Milobulin M6, namely the compound of the formula M6, and the appearance is shown: white solid.

Preferably, the quaternary ammonium salt used in step S2 is one or more of tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetramethylammonium fluoride, tetraethylammonium fluoride, tetramethylammonium chloride, tetraethylammonium chloride, tetramethylammonium iodide, tetraethylammonium iodide, tetramethylammonium bromide, tetraethylammonium bromide; the quaternary amine salt is used in an amount of 1 to 100mol% based on the intermediate M2.

Preferably, the alkali used in the synthesis in the step S2 is one or more of cesium carbonate, cesium fluoride, cesium chloride, lithium carbonate, lithium fluoride, lithium chloride, zinc carbonate, zinc fluoride and zinc chloride; the amount of base is 1 to 100mol% based on the intermediate M2.

Preferably, the acid used in the synthesis of the step S2 is one or more of hydrochloric acid, hydrogen chloride, sulfuric acid, carbonic acid, hydrobromic acid, dioxane solution of 4M hydrogen chloride, methanol solution of 4M hydrogen chloride, ethyl acetate solution of 4M hydrogen chloride, hydroiodic acid, nitric acid, phosphoric acid and hypochlorous acid; the amount of acid used is 1-10 equivalents of intermediate M2.

Preferably, in the step S3, the temperature of the reaction solution of the compound M2-1 in the formula is reduced to 0 ℃, 177ml of solution of 21.3mol of hydrogen chloride is added, the reaction is carried out for 30min at the temperature of 25 ℃ and the reaction is carried out for 60min; monitoring by HPLC until the content of the intermediate M3 is more than 90%, and stopping the reaction; the reaction flask was quenched by adding 5L of 10% sodium bicarbonate solution, extracting three times with ethyl acetate each time by adding 5L of ethyl acetate, mixing ethyl acetate phases, washing with 500mL of purified water twice, washing with 500mL of saturated sodium chloride solution once, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 543.8g of crude intermediate M3 in 97.5% yield and appearance: brown yellow oily.

Preferably, intermediate M3 in step S4 is used in an amount of 2.081mol, 543.8g; the ethanol dosage is 5000ml; the dosage of 25% ammonia water is 50ml; the dosage of 50% water slurry of Raney nickel is 300ml, hydrogen is introduced into the autoclave device, and the autoclave device is stirred for 18 hours at 30 ℃ and 300rpm under heat preservation; the filter cake was washed with 500ml x 2 ethanol and the filtrate at 40 ℃ was desolventized under reduced pressure to yield 543.9g crude intermediate M4, 98.5% yield, appearance: brown yellow oily.

Preferably, the crude intermediate M4 in step S5 is used in an amount of 2.081mol, 543.9g; after the methanol is used for 5000ml and stirred and cleared at 100-300rpm, the temperature is raised to 40 ℃ at the inner temperature, 158.2g of 1.04mol L-mandelic acid is added, the stirring is continued for 1h at 100-300rpm, the temperature is reduced for 0.5h, the stirring is continued for 12h at 100-300rpm, the stirring is continued for 2h at 300rpm after cooling to 0 ℃, the filtering is carried out, 284.3g of intermediate M5 is obtained after washing with methanol, the yield is 40.5 percent, and the appearance is obtained after drying under 45 ℃ under reduced pressure: white solid.

Preferably, the crude product of the intermediate M5 in the step S6 has the dosage of 0.681mol, 284.3g, the dosage of water is 5000ml, the dosage of sodium hydroxide is 2.724mol, 108.9g, after stirring and dissolving at 300rpm, stirring and reacting for 2h, controlling the temperature of the internal temperature to 10 ℃, the dosage of 4M hydrochloric acid to 885ml, stirring and crystallizing for 3h, filtering, and drying at 45 ℃ under reduced pressure to obtain 100.9g of the intermediate M6, the yield is 70.8 percent, and the appearance is as follows: white solid.

Compared with the prior art, the invention adopts the technical scheme and has the following concrete beneficial technical effects:

1. the invention reduces reaction steps, improves reaction yield and product purity, is more suitable for industrial mass production or can improve product stability, is easy to store, improves bioavailability of the medicine in the body, reduces hepatotoxicity and the like:

2. The cyanation reagent is replaced by a cyanation reaction by using a TMSCN/catalyst system with low toxicity, so that the method has the advantages of safety, high efficiency, low cost, complete commercial scale production route and great advantages;

3. solves the safety problems of inflammability, explosiveness, high toxicity and the like of nitromethane and potassium cyanide and sodium raw materials in patent and literature routes in the prior art;

4. the commercial production line with safer, more convenient and lower cost is obtained, the serious potential safety hazard defects in the two routes of nitromethane and sodium cyanide are perfectly avoided, and the yield is higher.

Detailed Description

The following specific examples are provided to further illustrate the present invention in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. The experimental methods in the invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.

The preparation method of the intermediate M2 comprises the following steps:

sequentially adding 1.0-10.0 equivalents of (1R, 5S) -3-ethyl-bicyclo [3.2.0] heptane-3-alkene-6-ketone serving as a starting material SM1, 1.0-10.0 equivalents of diethyl phosphonoacetic acid tert-butyl ester serving as a starting material SM2 and 1.0-10.0 times of tetrahydrofuran serving as a solvent into a reaction bottle, controlling the internal temperature of the reaction liquid to be 0-5 ℃, adding 1.0-1.5 equivalents of potassium tert-butoxide into the reaction bottle under stirring in ten equal parts, stirring at 20-25 ℃ for reaction for 1-10 hours, performing HPLC (high performance liquid chromatography) central control reaction until the SM1 content is less than 0.1%, adding purified water with 1-5 times of mass volume ratio, extracting for 3 times by using ethyl acetate solvent with 1-5 times of mass volume ratio, mixing ethyl acetate phases, performing 1-5 purification water washing, and removing the solvent by decompression of the organic phase to obtain an intermediate M2;

Example 1:

the embodiment 1 of the invention provides a preparation method for the catalytic cyanation of milbelin, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

under the protection of nitrogen, adding an intermediate M2 (500.0 g,2.134mol,1.0 eq), tetrahydrofuran 5L, cesium carbonate (695.29 g,2.134mol,1.0 eq) and TBAF (211.7 g,2.134mol,1.0 eq) into a reaction bottle, cooling to-30 ℃, dripping TMSCN (211.7 g,2.134mol,1.0 eq) at 30-100ml/min under stirring, carrying out heat preservation reaction for 30min, and carrying out reaction at a heating rate of 1 ℃/min to 25 ℃ for 30min; TLC monitoring until the content of the intermediate M2 is less than 0.1%, stopping the reaction, and obtaining a compound reaction solution of the formula M2-1;

cooling the reaction solution of the compound of formula M2-1 to 0 ℃, dropwise adding hydrochloric acid (177 ml,21.3mol,10.0 eq) at a speed of 30-100ml/min under stirring, reacting for 30min under heat preservation, and reacting for 60min at a heating rate of 1 ℃/min to 25 ℃. HPLC monitored to an intermediate M3 content of greater than 90% and the reaction stopped. Adding 10% sodium bicarbonate solution 5L into a reaction bottle to quench reaction, adding ethyl acetate into the reaction bottle for extraction three times, combining ethyl acetate phases, washing 500mL of purified water twice, washing 500mL of saturated sodium chloride solution once, drying by anhydrous sodium sulfate, and removing solvent under reduced pressure to obtain 543.8g of intermediate M3 crude product, wherein the yield is 97.5%, and the appearance is that: brown yellow oily.

Raney nickel (300 ml of 50% aqueous slurry) was added to a solution of crude intermediate M3 (543.8 g;2.081 mol), ethanol 5000ml and aqueous ammonia (25%; 50 ml), and 4MPa hydrogen was introduced into the autoclave apparatus, and the mixture was stirred at 30℃for 18 hours. The reaction HPLC monitors that the M3 content is less than 0.1%, the reaction is stopped, the materials are discharged and filtered, the filter cake is washed with 500ml ethanol for 2 times, the filtrate at 40 ℃ is decompressed and the solvent is removed to obtain 543.9g of intermediate M4 crude product, the yield is 98.5%, and the appearance is that: brown yellow oily.

Crude intermediate M4 (543.9 g;2.081 mol) was dissolved in 5000ml of methanol under stirring at 300rpm, warmed to an internal temperature of 40 ℃, L-mandelic acid (158.2 g;1.04 mol) was added, stirring was continued for 1h,0.5h was cooled to 15-25 ℃, stirring was continued for 12h, cooling to 0 ℃, stirring was continued for 2h, washing with methanol after filtration, and drying under reduced pressure at 45℃gave 284.3g of intermediate M5 compound, yield 40.5%, appearance: white solid.

Adding 5000ml of water and sodium hydroxide (108.9 g; 2.724mol) into an intermediate M5 compound (284.3 g;0.681 mol), stirring at 300rpm to dissolve, continuing stirring to react for 2 hours, monitoring the M5 content by using a reaction HPLC to be less than 0.1%, and stopping the reaction; controlling the internal temperature to be 10 ℃, dropwise adding 885ml of 4M hydrochloric acid into the reaction liquid at the rate of 30-100ml/min, adjusting the pH value to be 3-4, continuously stirring and crystallizing for 3h, filtering, and drying at 45 ℃ under reduced pressure to obtain 100.9g of intermediate M6, wherein the yield is 70.8%, and the appearance is as follows: white solid.

Example 2:

the embodiment 2 of the invention provides a preparation method of the catalytic cyanation of milbelin, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

under the protection of nitrogen, adding the intermediate M2 (500.0 g,2.134mol,1.0 eq), tetrahydrofuran 5L, cesium fluoride (324.15 g,2.134mol,1.0 eq) and TBACl (211.7 g,2.134mol,1.0 eq) into a reaction bottle, cooling to-30 ℃, dripping TMSCN (211.7 g,2.134mol,1.0 eq) at 30-100ml/min under stirring, keeping the temperature for 30min, and heating to 25 ℃ at a speed of 1 ℃/min for 30min. TLC monitoring is carried out until the content of the intermediate M2 is less than 0.1%, and the reaction is stopped to obtain a compound reaction liquid of the formula M2-1.

Raney nickel (300 ml of 50% aqueous slurry) was added to a solution of intermediate M3 (543.8 g;2.081 mol), ethanol 5000ml and aqueous ammonia (25%; 50 ml), and 4MPa hydrogen was introduced into the autoclave apparatus, and the mixture was stirred at 30℃for 18 hours. The reaction HPLC monitors that the M3 content is less than 0.1%, the reaction is stopped, the materials are discharged and filtered, the filter cake is washed with 500ml ethanol for 2 times, the filtrate at 40 ℃ is decompressed and the solvent is removed to obtain 543.9g of intermediate M4 crude product, the yield is 98.5%, and the appearance is that: brown yellow oily.

Intermediate M5 (284.3 g;0.681 mol) was added with 5000ml of water and sodium hydroxide (108.9 g; 2.724mol), after stirring to dissolve the clear, the reaction was continued with stirring at 300rpm for 2h, with the reaction HPLC monitoring that the M5 content was less than 0.1%, and the reaction stopped. Controlling the internal temperature to be 10 ℃, dropwise adding 885ml of 4M hydrochloric acid into the reaction liquid at the rate of 30-100ml/min, adjusting the pH value to be 3-4, continuously stirring and crystallizing for 3h, filtering, and drying at 45 ℃ under reduced pressure to obtain 100.9g of intermediate M6, wherein the yield is 70.8%, and the appearance is as follows: white solid.

Example 3:

the embodiment 3 of the invention provides a preparation method for the catalytic cyanation of milbelin, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

under the protection of nitrogen, adding the intermediate M2 (500.0 g,2.134mol,1.0 eq), tetrahydrofuran 5L, cesium fluoride (324.15 g,2.134mol,1.0 eq) and TBAF (211.7 g,2.134mol,1.0 eq) into a reaction bottle, cooling to-30 ℃, dripping TMSCN (211.7 g,2.134mol,1.0 eq) into the reaction bottle at 30-100ml/min under stirring, keeping the temperature for 30min, and heating to 25 ℃ at a heating rate of 1 ℃/min for 30min. TLC monitoring is carried out until the content of the intermediate M2 is less than 0.1%, and the reaction is stopped to obtain a compound reaction liquid of the formula M2-1.

Intermediate M5 (284.3 g;0.681 mol) was added with 5000ml of water and sodium hydroxide (108.9 g; 2.724mol), after stirring the solution at 300rpm, the reaction was continued for 2h with stirring, and the reaction was stopped with HPLC monitoring of M5 content less than 0.1%. Controlling the internal temperature to be 10 ℃, dropwise adding 885ml of 4M hydrochloric acid into the reaction liquid at the rate of 30-100ml/min, adjusting the pH value to be 3-4, continuously stirring and crystallizing for 3h, filtering, and drying at 45 ℃ under reduced pressure to obtain 100.9g of intermediate M6, wherein the yield is 70.8%, and the appearance is as follows: white solid.

Example 4:

the embodiment 4 of the invention provides a preparation method of the catalytic cyanation of milbelin, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

under the protection of nitrogen, adding the intermediate M2 (500.0 g,2.134mol,1.0 eq), tetrahydrofuran 5L, lithium fluoride (55.4 g,2.134mol,1.0 eq) and TBACl (211.7 g,2.134mol,1.0 eq) into a reaction bottle, cooling to-30 ℃, dripping TMSCN (211.7 g,2.134mol,1.0 eq) at 30-100ml/min under stirring, keeping the temperature for 30min, heating to 25 ℃ at a heating rate of 1 ℃/min, and reacting for 30min. TLC monitoring is carried out until the content of the intermediate M2 is less than 0.1%, and the reaction is stopped to obtain a compound reaction liquid of the formula M2-1.

Raney nickel (300 ml of 50% aqueous slurry) was added to a solution of intermediate M3 (543.8 g;2.081 mol), ethanol 5000ml and aqueous ammonia (25%; 50 ml), and 4MPa hydrogen was introduced into the autoclave apparatus, and the mixture was stirred at 30℃for 18 hours. Reaction HPLC monitored M3 content below 0.1%, stopped the reaction, discharged and filtered, the filter cake washed with ethanol (500 ml x 2), filtrate at 40 ℃ was desolventized under reduced pressure to yield 543.9g crude intermediate M4, yield 98.5%, appearance: brown yellow oily.

Example 5:

the embodiment 5 of the invention provides a preparation method for the catalytic cyanation of milbelin, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

under the protection of nitrogen, adding the intermediate M2 (500.0 g,2.134mol,1.0 eq), tetrahydrofuran 5L, cesium fluoride (324.2 g,2.134mol,1.0 eq) and TBACl (211.7 g,2.134mol,1.0 eq) into a reaction bottle, cooling to-30 ℃, dripping TMSCN (211.7 g,2.134mol,1.0 eq) at 30-100ml/min under stirring, keeping the temperature for 30min, heating to 25 ℃ at a heating rate of 1 ℃/min, and reacting for 30min. TLC monitoring is carried out until the content of the intermediate M2 is less than 0.1%, and the reaction is stopped to obtain a compound reaction liquid of the formula M2-1.

Continuously cooling the reaction solution of the compound of formula M2-1 to 0 ℃, dropwise adding dioxane solution (177 ml,21.3mol,10.0 eq) of 4M hydrogen chloride at a speed of 30-100ml/min under stirring, reacting for 30min under heat preservation, and reacting for 60min at a heating rate of 1 ℃/min to 25 ℃. HPLC monitored to an intermediate M3 content of greater than 90% and the reaction stopped. Adding 10% sodium bicarbonate solution 5L into a reaction bottle to quench reaction, adding ethyl acetate into the reaction bottle for extraction three times, combining ethyl acetate phases, washing 500mL of purified water twice, washing 500mL of saturated sodium chloride solution once, drying by anhydrous sodium sulfate, and removing solvent under reduced pressure to obtain 543.8g of intermediate M3 crude product, wherein the yield is 97.5%, and the appearance is that: brown yellow oily.

Intermediate M5 compound (284.3 g;0.681 mol) was added with 5000ml of water and sodium hydroxide (108.9 g; 2.724mol),

after stirring the solution at 300rpm, the reaction was continued for 2 hours with the reaction HPLC monitor that the M5 content was less than 0.1% and the reaction was stopped. Controlling the internal temperature to be 10 ℃, dropwise adding 885ml of 4M hydrochloric acid into the reaction liquid at the rate of 30-100ml/min, adjusting the pH value to be 3-4, continuously stirring and crystallizing for 3h, filtering, and drying at 45 ℃ under reduced pressure to obtain 100.9g of intermediate M6, wherein the yield is 70.8%, and the appearance is as follows: white solid.

Example 6:

the example 6 of the present invention provides a method for preparing milobalin by catalytic cyanation, which comprises the following synthetic routes:

the preparation method specifically comprises the following steps:

under the protection of nitrogen, adding the intermediate M2 (500.0 g,2.134mol,1.0 eq), tetrahydrofuran 5L, cesium fluoride (324.2 g,2.134mol,1.0 eq) and TBACl (211.7 g,2.134mol,1.0 eq) into a reaction bottle, cooling to-30 ℃, dripping TMSCN (211.7 g,2.134mol,1.0 eq) at 30-100ml/min under stirring, keeping the temperature for 30min, and heating to 25 ℃ at a speed of 1 ℃/min for 30min. TLC monitoring is carried out until the content of the intermediate M2 is less than 0.1%, and the reaction is stopped to obtain a compound reaction liquid of the formula M2-1.

Continuously cooling the reaction solution of the compound of formula M2-1 to 0 ℃, dropwise adding an ethyl acetate solution (177 ml,21.3mol,10.0 eq) of 4M hydrogen chloride at a speed of 30-100ml/min under stirring, reacting for 30min under heat preservation, and reacting for 60min at a heating rate of 1 ℃/min to 25 ℃. HPLC monitored to an intermediate M3 content of greater than 90% and the reaction stopped. Adding 10% sodium bicarbonate solution 5L into a reaction bottle to quench reaction, adding ethyl acetate into the reaction bottle for extraction three times, combining ethyl acetate phases, washing 500mL of purified water twice, washing 500mL of saturated sodium chloride solution once, drying by anhydrous sodium sulfate, and removing solvent under reduced pressure to obtain 543.8g of intermediate M3 crude product, wherein the yield is 97.5%, and the appearance is that: brown yellow oily.

Example 7:

the invention provides a preparation method of the catalytic cyanation of milbelin, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

under the protection of nitrogen, adding the intermediate M2 (500.0 g,2.134mol,1.0 eq), tetrahydrofuran 5L, cesium fluoride (324.2 g,2.134mol,1.0 eq) and TBACl (211.7 g,2.134mol,1.0 eq) into a reaction bottle, cooling to-30 ℃, dripping TMSCN (635.1 g,6.402mol,3.0 eq) at 30-100ml/min under stirring, keeping the temperature for 30min, and heating to 25 ℃ at a speed of 1 ℃/min for 30min. TLC monitoring is carried out until the content of the intermediate M2 is less than 0.1%, and the reaction is stopped to obtain a compound reaction liquid of the formula M2-1.

Crude intermediate M4 (543.9 g;2.081 mol) was dissolved in 5000ml of methanol under stirring at 300rpm, the temperature was raised to 40℃C, L-mandelic acid (158.2 g;1.04 mol) was added, stirring was continued for 1h,0.5h was cooled to 15-25℃C, stirring was continued for 12h, cooling to 0℃C, stirring was continued for 2h, washing with methanol after filtration, drying under reduced pressure at 45℃C gave 284.3g of crude intermediate M5 in 40.5% yield, appearance: white solid.

The crude intermediate M5 (284.3 g;0.681 mol) was taken up in 5000ml of water and sodium hydroxide (108.9 g; 2.724mol), after stirring the solution, the reaction was continued for 2h at 300rpm, the reaction HPLC monitored M5 content to be less than 0.1%, and the reaction was stopped. Controlling the internal temperature to be 10 ℃, dropwise adding 885ml of 4M hydrochloric acid into the reaction liquid at the rate of 30-100ml/min, adjusting the pH value to be 3-4, continuously stirring and crystallizing for 3h, filtering, and drying at 45 ℃ under reduced pressure to obtain 100.9g of intermediate M6, wherein the yield is 70.8%, and the appearance is as follows: white solid.

Example 8:

the example 8 of the present invention provides a method for preparing milobalin by catalytic cyanation, which comprises the following synthetic routes:

the preparation method specifically comprises the following steps:

under the protection of nitrogen, adding the intermediate M2 (500.0 g,2.134mol,1.0 eq), tetrahydrofuran 5L, cesium fluoride (324.2 g,2.134mol,1.0 eq) and TBACl (211.7 g,2.134mol,1.0 eq) into a reaction bottle, cooling to-30 ℃, dripping TMSCN (423.4 g,2.134mol,2.0 eq) at 30-100ml/min under stirring, keeping the temperature for 30min, and heating to 25 ℃ at a speed of 1 ℃/min for 30min. TLC monitoring is carried out until the content of the intermediate M2 is less than 0.1%, and the reaction is stopped to obtain a compound reaction liquid of the formula M2-1.

The crude intermediate M5 (284.3 g;0.681 mol) was taken up in 5000ml of water and sodium hydroxide (108.9 g; 2.724mol), and after stirring the solution at 300rpm, the reaction was continued for 2h with stirring, and the reaction was stopped with HPLC monitoring of M5 content of less than 0.1%. Controlling the internal temperature to be 10 ℃, dropwise adding 885ml of 4M hydrochloric acid into the reaction liquid at the rate of 30-100ml/min, adjusting the pH value to be 3-4, continuously stirring and crystallizing for 3h, filtering, and drying at 45 ℃ under reduced pressure to obtain 100.9g of intermediate M6, wherein the yield is 70.8%, and the appearance is as follows: white solid.

Example 9:

the embodiment 9 of the invention provides a preparation method of the catalytic cyanation of milbelin, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

under the protection of nitrogen, adding the intermediate M2 (500.0 g,2.134mol,1.0 eq), tetrahydrofuran 5L, cesium fluoride (324.2 g,2.134mol,2.0 eq) and TBACl (211.7 g,2.134mol,1.0 eq) into a reaction bottle, cooling to-30 ℃, dripping TMSCN (635.1 g,2.134mol,3.0 eq) at 30-100ml/min under stirring, keeping the temperature for 30min, and heating to 25 ℃ at a speed of 1 ℃/min for 30min. TLC monitoring is carried out until the content of the intermediate M2 is less than 0.1%, and the reaction is stopped to obtain a compound reaction liquid of the formula M2-1.

Example 10:

the embodiment 10 of the invention provides a preparation method for the catalytic cyanation of milbelin, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

under the protection of nitrogen, adding the intermediate M2 (500.0 g,2.134mol,1.0 eq), tetrahydrofuran 5L, cesium fluoride (695.2.0 g (), 2.134mol,1.0 eq) and TBACl (211.7 g,2.134mol,1.0 eq) into a reaction bottle, cooling to-30 ℃, dripping TMSCN (211.7 g,2.134mol,1.0 eq) at 30-100ml/min under stirring, keeping the temperature for 30min, and heating to 25 ℃ at a speed of 1 ℃/min for 30min. TLC monitoring is carried out until the content of the intermediate M2 is less than 0.1%, and the reaction is stopped to obtain a compound reaction liquid of the formula M2-1.

Continuously cooling the reaction solution of the compound of formula M2-1 to 0 ℃, dropwise adding dioxane solution (35.4 ml,4.268mol,2.0 eq) of 4M hydrogen chloride at a speed of 30-100ml/min under stirring, reacting for 30min under heat preservation, and reacting for 60min at a heating rate of 1 ℃/min to 25 ℃. HPLC monitored to an intermediate M3 content of greater than 90% and the reaction stopped. Adding 10% sodium bicarbonate solution 5L into a reaction bottle to quench reaction, adding ethyl acetate into the reaction bottle for extraction three times, combining ethyl acetate phases, washing 500mL of purified water twice, washing 500mL of saturated sodium chloride solution once, drying by anhydrous sodium sulfate, and removing solvent under reduced pressure to obtain 543.8g of intermediate M3 crude product, wherein the yield is 97.5%, and the appearance is that: brown yellow oily.

Example 11:

the embodiment 11 of the invention provides a preparation method for the catalytic cyanation of milbelin, which comprises the following synthetic route:

the preparation method specifically comprises the following steps:

under the protection of nitrogen, adding the intermediate M2 (500.0 g,2.134mol,1.0 eq), tetrahydrofuran 5L, zinc fluoride (220.6 g,2.134mol,1.0 eq) and TBACl (211.7 g,2.134mol,1.0 eq) into a reaction bottle, cooling to-30 ℃, dripping TMSCN (211.7 g,2.134mol,1.0 eq) at 30-100ml/min under stirring, keeping the temperature for 30min, and heating to 25 ℃ at a speed of 1 ℃/min for 30min. TLC monitoring is carried out until the content of the intermediate M2 is less than 0.1%, and the reaction is stopped to obtain a compound reaction liquid of the formula M2-1.

Raney nickel (300 ml of 50% aqueous slurry) was added to a solution of intermediate M3 (543.8 g; 2.081mol), ethanol (5000 ml and aqueous ammonia (25%; 50 ml), 4MPa hydrogen was introduced into the autoclave apparatus, the reaction was stopped by monitoring the M3 content below 0.1% by reaction HPLC, the reaction was stopped, the material was discharged and filtered, the filter cake was washed with 500ml ethanol for 2 times, and the filtrate at 40℃was depressurized to remove the solvent to obtain 543.9g of crude intermediate M4 in 98.5% yield and the appearance was a brown yellow oil.

The crude intermediate M5 (284.3 g;0.681 mol) was taken up in 5000ml of water and sodium hydroxide (108.9 g; 2.724mol), after stirring the solution at 300rpm, the reaction was stirred for 2h, the reaction HPLC monitored for M5 content of less than 0.1% and the reaction was stopped. Controlling the internal temperature to be 10 ℃, dropwise adding 885ml of 4M hydrochloric acid into the reaction liquid at the rate of 30-100ml/min, adjusting the pH value to be 3-4, continuously stirring and crystallizing for 3h, filtering, and drying at 45 ℃ under reduced pressure to obtain 100.9g of intermediate M6, wherein the yield is 70.8%, and the appearance is as follows: white solid.

Comparative example:

table 1 comparison of the main indicators of three routes

The TMSCN/catalyst system in Table 1 was tested using the protocol of example 2. By comparison in table 1, it is concluded that: the total yield of the key intermediate M4 and the purity of the intermediate M4 are higher than those of the other two routes, and the number of M4 impurities is reduced to 6, so that the method has obvious cost and quality advantages.

The foregoing describes in detail preferred embodiments of the present invention. It should be understood that numerous modifications and variations can be made in accordance with the concepts of the invention by one of ordinary skill in the art without undue burden. Therefore, all technical solutions which can be obtained by logic analysis, reasoning or limited experiments based on the prior art by the person skilled in the art according to the inventive concept shall be within the scope of protection defined by the claims.

Claims

1. A preparation method of the catalytic cyanation of milbelin is characterized by comprising the following steps: the method comprises the following steps:

the method comprises the following steps:

s1 Synthesis of intermediate M2

S2 Synthesis of Compounds of formula M2-1

s3 Synthesis of Compounds of formula M3

s5 Synthesis of Compounds of formula M5

s6 Synthesis of Compounds of formula M6

2. The method for preparing the milabalin catalyzed cyanation according to claim 1, which is characterized in that: the quaternary ammonium salt used in the step S2 is one or more of tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetramethyl ammonium fluoride, tetraethylammonium fluoride, tetramethyl ammonium chloride, tetraethylammonium chloride, tetramethyl ammonium iodide, tetraethylammonium iodide, tetramethyl ammonium bromide and tetraethylammonium bromide; the quaternary amine salt is used in an amount of 1 to 100mol% based on the intermediate M2.

3. The method for preparing the milabalin catalyzed cyanation according to claim 1, which is characterized in that: the alkali used in the synthesis of the step S2 is one or more of cesium carbonate, cesium fluoride, cesium chloride, lithium carbonate, lithium fluoride, lithium chloride, zinc carbonate, zinc fluoride and zinc chloride; the amount of base is 1 to 100mol% based on the intermediate M2.

4. The method for preparing the milabalin catalyzed cyanation according to claim 1, which is characterized in that: the acid used in the step S2 synthesis is one or more of hydrochloric acid, hydrogen chloride, sulfuric acid, carbonic acid, hydrobromic acid, 4M hydrogen chloride dioxane solution, 4M hydrogen chloride methanol solution, 4M hydrogen chloride ethyl acetate solution, hydroiodic acid, nitric acid, phosphoric acid and hypochlorous acid; the amount of acid used is 1-10 equivalents of intermediate M2.

5. The method for preparing the milabalin catalyzed cyanation according to claim 1, which is characterized in that: step S3, cooling the reaction solution of the compound M2-1 in the formula to 0 ℃, adding 177ml of solution of 21.3mol of hydrogen chloride, reacting for 30min at a temperature of 25 ℃, and reacting for 60min; monitoring by HPLC until the content of the intermediate M3 is more than 90%, and stopping the reaction; the reaction flask was quenched by adding 5L of 10% sodium bicarbonate solution, extracting three times with ethyl acetate each time by adding 5L of ethyl acetate, mixing ethyl acetate phases, washing with 500mL of purified water twice, washing with 500mL of saturated sodium chloride solution once, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 543.8g of crude intermediate M3 in 97.5% yield and appearance: brown yellow oily.

6. The method for preparing the milabalin catalyzed cyanation according to claim 1, which is characterized in that: the amount of the intermediate M3 in the step S4 is 2.081mol and 543.8g; the ethanol dosage is 5000ml; the dosage of 25% ammonia water is 50ml; the dosage of 50% water slurry of Raney nickel is 300ml, hydrogen is introduced into the autoclave device, and the autoclave device is stirred for 18 hours at 30 ℃ and 300rpm under heat preservation; the filter cake was washed with 500ml x 2 ethanol and the filtrate at 40 ℃ was desolventized under reduced pressure to yield 543.9g crude intermediate M4, 98.5% yield, appearance: brown yellow oily.

7. The method for preparing the milabalin catalyzed cyanation according to claim 1, which is characterized in that: the dosage of the crude intermediate M4 in the step S5 is 2.081mol and 543.9g; after the methanol is used for 5000ml and stirred and cleared at 100-300rpm, the temperature is raised to 40 ℃ at the inner temperature, 1.04mol of L-mandelic acid (158.2 g, continuously stirred at 100-300rpm for 1h, cooled at 0.5h, stirred at 100-300rpm for 12h, cooled to 0 ℃ and continuously stirred at 300rpm for 2h, filtered and washed with methanol, and dried at 45 ℃ under reduced pressure to obtain 284.3g of intermediate M5, yield 40.5% and appearance of white solid.

8. The method for preparing the milabalin catalyzed cyanation according to claim 1, which is characterized in that: the crude intermediate M5 in the step S6 is 0.681mol, 284.3g and 5000ml, sodium hydroxide is 2.724mol, 108.9g, after being stirred and dissolved at 300rpm, the reaction is continued for 2h, the temperature of the internal temperature is controlled to be 10 ℃,4M hydrochloric acid is 885ml, the reaction is stirred and crystallized for 3h, 100.9g of intermediate M6 is obtained after filtration and drying at 45 ℃ under reduced pressure, the yield is 70.8%, and the appearance is that: white solid.