CN112724091B - Method for industrially producing clobazam - Google Patents

Abstract

The invention discloses a method for industrially producing clobazam, belonging to the technical field of drug synthesis. The method takes 5-chloro-2-nitrobenzidine as a raw material, and prepares the clobazam raw material drug through the processes of acylation, reduction ring closing, methylation and refining. The invention solves the problems that the prior art uses a reagent with higher toxicity; the pollution is serious; the potential safety hazard of the pressure hydrogenation reaction reduces the production cost and improves the quality and the economic benefit of the product.

Description

Method for industrially producing clobazam

Technical Field

The invention relates to an industrial production method of an antiepileptic drug clobazam, belonging to the technical field of drug synthesis.

Background

Clobazam, chemical name: 1-methyl-5-phenyl-7-chloro-1, 2,4, 5-tetrahydro-1, 5-benzodiazepine-2, 4-dione. Clobazam was found in the Maestretti research laboratory in milan and was first introduced in 1969 and has been approved for the treatment of epilepsy in more than 100 countries. Day 21/10/2011, clobazam was approved by the U.S. Food and Drug Administration (FDA) for the adjuvant treatment of seizures in adults and children older than 2 years of age with Lennox-Gastaut syndrome (LGS, diffuse slow spine-slow wave (petit-seizure variant) epileptic encephalopathy) who is a severe form of epilepsy and is refractory to treatment, and may therefore become incapacitated.

Epilepsy is a chronic brain disease caused by various reasons, the prevalence rate is 5-10 per mill, and the epilepsy is the second most common disease in neurology. Children are in the high-incidence stage of epilepsy and children under 18 years of age account for over 60% of all epileptic patients. 40 ten thousand cases of epilepsy are newly developed in China every year, about 900 ten thousand epileptics are currently used, and the use of antiepileptic drugs is the main treatment method.

At present, the like products are used for treating epilepsy in the market, such as phenytoin sodium, phenobarbital, carbamazepine, sodium valproate and the like. Compared with other medicines for treating epilepsy, the clobazam has the following advantages:

(1) the structure is advantageous: the diazepam has the advantages that the diazepam has the diazepam groups on the positions 1 and 5, and has no 1-4 nitrogen groups, so that the diazepam has strong hydrophobicity, and therefore, the affinity with GABAa is low, and the tranquilizing effect and psychomotor adverse reaction of the chlorepam are smaller compared with 1, 4-benzodiazepine medicines such as diazepam.

(2) The curative effect is definite: the clinical study of clobazam shows that the seizure frequency of more than half of patients is reduced by more than 50%; the benefits of more than 1 year are achieved by 42 percent of patients in long-term follow-up patients; approximately 10% of refractory epileptic patients even reach a cure in a retrospective study up to 7 years.

(3) The safety is high: the adverse drug reactions of clobazam are similar to other benzodiazepines, but occur less frequently. Clinical evidence shows that clobazamine is less sedative than 1, 4-benzodiazepines. Periodic therapy is effective in preventing febrile seizures, and causes lower ataxia than diazepam. The clinical efficacy is equivalent to that of carbamazepine, but the side effect of the compound in controlling the early epilepsy is less than that of the carbamazepine.

(4) The tolerance is good: the therapeutic index of clobazam (PI ═ TD50/ED50) is greater than that of 1, 4-benzodiazepines, indicating good tolerance in the development of antiepileptic effects. Published studies report that the development of tolerance varies from 10% to 87% of patients, with up to 70% of patients developing tolerance and that clobazam efficacy recovers after 2-3 months of reinsertion into therapy or increased dose after drug withdrawal. Sustained efficacy was observed for more than 1 year in 85% of patients with improved seizure control, and seizures were completely controlled in many patients during this period. Gabapentin monotherapy also showed good tolerability when it was effective in the treatment of motor epilepsy.

(5) The half-life period is long: clobazam is a long-acting antiepileptic drug that is converted in vivo to the active 1/5 metabolite, N-desmethylclobazam, with elimination half-lives (t1/2) of 36-42h and 71-82h, respectively.

(6) The medical cost is reduced: a retrospective longitudinal queue research abroad shows that the Lombardon adjuvant therapy of the LGS can reduce epileptic seizure, thereby reducing medical cost.

The synthesis method of clobazam reported in the literature at present mainly comprises two main types, one type is that 5-chloro-2-nitrobenzidine is used as a raw material, and a clobazam finished product (CN106243050A, WO2016193482A, CN106946802A, WO2016151464A) is obtained after Pt or Ni catalytic hydrogenation or metal (Zn powder or Fe powder) and acid reduction, acyl chloride acylation, cyclization and methylation of methylation reagents (methyl iodide, dimethyl sulfate, methyl trifluoromethanesulfonate and the like) are carried out, and the method mainly has the defects that hydrogenation reaction has potential safety hazards, metal residues, Fe sludge pollution is serious, toxicity of used benzene and partial methylation reagents is high, Pt using cost is high, and the yield of a cyclization process is low (less than 40%). The other type is that 5-chloro-2-nitrobenzidine is taken as a raw material, acyl chloride acylation is carried out firstly, then Ni catalytic hydrogenation or reduction of Zn powder and acid, cyclization and methyl iodide methylation are carried out, and a clobazam finished product (Eur.J. Med.Gem.1983,23,417-420.CN106749052A) is obtained, and the method mainly has the defects of potential safety hazard, metal residue, higher cost of using 4-pyrrolidinylpyridine, low total yield (less than 33.7%) and the like in hydrogenation reaction. The currently reported industrial synthesis methods of clobazam are few, and the defects exist, so that the industrial application of the clobazam is limited. Therefore, the development of a new method for industrially producing the clobazam, which is simple, efficient and environment-friendly, has important significance and application value.

Disclosure of Invention

The invention aims to provide a simple, efficient, green and environment-friendly method for industrially producing clobazam.

The technical scheme provided by the invention is that the industrial production method of clobazam comprises the following reaction synthetic route, wherein the target product is clobazam I,

the method comprises the following specific steps:

dissolving an initial raw material II (5-chloro-2-nitrobenzidine) in an organic solvent, adding an acylation reagent, namely, methyl malonyl chloride and an acid-binding agent, reacting completely, filtering, washing with water, concentrating under reduced pressure, recrystallizing, filtering and drying to obtain a light yellow to yellow solid, namely an intermediate III (N-phenyl-N- (2-nitro-5-chlorophenyl) -2-methoxycarbonylacetamide);

dissolving the intermediate III in a solvent, adding a reducing agent and an acid, after the reaction is completed, cooling and crystallizing, filtering and drying to obtain a white solid, namely the intermediate IV (8-chloro-1-phenyl-1, 2,4, 5-tetrahydro-1, 5-benzodiazepine-2, 4-diketone);

dissolving the intermediate IV in an organic solvent, adding alkali and a methylating agent, carrying out sealing reaction, cooling and crystallizing after complete reaction, filtering, washing and drying to obtain a white solid crude product, namely the crude product V (1-methyl-5-phenyl-7-chloro-1, 2,4, 5-tetrahydro-1, 5-benzodiazepine-2, 4-dione) of clobazam;

and (4) adding the crude product V of the clobazam into a solvent, heating, stirring, clarifying, adding activated carbon, decoloring, filtering, cooling, crystallizing, filtering, washing and drying to obtain a white solid finished product (the clobazam I).

Further, the organic solvent in the step (1) is one or more of dichloromethane, toluene or xylene, and toluene is preferred.

Further, the acid-binding agent in the step (1) is one or more of triethylamine, sodium carbonate and sodium bicarbonate, preferably triethylamine.

Further, in the step (1), the mass ratio of the starting material II to the acylating reagent to the triethylamine is 1: 0.60-2.20: 0.44-1.63, and the reaction temperature is 60-70 ℃; the recrystallization solvent is acetonitrile, and the mass ratio of the initial raw material II to the acetonitrile is 1: 2.35-6.28.

Further, the solvent in the step (2) is one or more of water, methanol, toluene, tert-butyl alcohol or dichloromethane; a mixed solution of methanol-water is preferred.

Further, the acid in the step (2) is sulfuric acid, hydrochloric acid, glacial acetic acid, acetic anhydride, or an ethanol solution of hydrogen chloride, preferably hydrochloric acid.

Further, in the step (2), the reducing agent is zinc powder, sodium hydrosulfite or iron powder, the mass volume ratio of the intermediate III, the reducing agent and the acid is 1: 0.8-1.8: 3.0-6.0, and the intermediate III, the reducing agent and the acid are calculated by volume according to mass.

Further, in the step (3), the organic solvent is one or more of methanol, ethanol and acetonitrile, preferably methanol; the alkali is one or more of sodium carbonate, sodium bicarbonate, sodium methoxide, sodium acetate and the like, and sodium carbonate is preferred.

Further, in the step (3), the methylating agent is methyl iodide, and the molar ratio of the intermediate IV, the alkali and the methyl iodide is 1: 1.0-2.0: 1.3-3.0.

Further, in the step (4), the solvent is one or more of methanol, ethanol, isopropanol, acetonitrile, acetone, dichloromethane, diethyl ether, tetrahydrofuran and water; an ethanol-water mixed solution is preferred.

The invention has the following beneficial effects:

1) in the acylation process, the acylation reagent adopts malonic acid methyl ester acyl chloride, which has higher acylation reaction activity and small steric hindrance, and can improve the yield of acylation cyclization reaction, particularly when methanol aqueous solution is used as a solvent in the cyclization reaction process, the yield can reach more than 60%, the purity of the product is more than 99%, and the total impurity content is less than 0.5%.

2) In the reduction reaction, the reducing agent zinc powder is adopted, and hydrochloric acid is added, so that the problem of high risk in the reaction of directly using hydrogen is solved. In the process of acylation reaction, toluene is adopted as a solvent, so that the reaction yield can be improved.

3) The use of less basic sodium carbonate in the methylation reaction greatly reduces the amount of polymethoxylated byproducts generated in the reaction and which are difficult to remove.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a solid obtained in step (1) in example 1;

FIG. 2 is a nuclear magnetic resonance carbon spectrum of a solid obtained in step (1) in example 1;

FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the solid obtained in step (2) in example 1;

FIG. 4 is a NMR carbon spectrum of a solid obtained in step (2) in example 1;

FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the solid obtained in step (3) of example 1;

FIG. 6 is a NMR carbon spectrum of a solid obtained in step (3) in example 1.

Detailed Description

Example 1

A method for industrially producing clobazam, a target product is clobazam I, and the synthetic route is as follows:

the method comprises the following specific steps:

(1) synthesis of intermediate III

30.0L of toluene was added to a 50L dry reaction vessel, and 3.0kg of the starting material II, 3.8kg of the acylating agent and 2.8kg of triethylamine were added thereto. Stirring is started, the temperature is increased to 60-70 ℃ for reaction, and the internal temperature is kept for reaction for 8 hours. Sampling for HPLC rapid detection. After complete reaction, cooling to 20-30 ℃, filtering, soaking and washing a filter cake with a small amount of toluene, merging filtrates, washing with 15.0L of water, separating liquid, adding a proper amount of anhydrous sodium sulfate into an organic layer, drying for 2h, filtering to remove a drying agent, washing the filter cake with a small amount of toluene, merging the filtrates, concentrating under reduced pressure to dryness, cooling to room temperature, adding 10.0kg of acetonitrile into the system, heating to reflux to dissolve out solid, cooling to 0-10 ℃, stirring and crystallizing for 2h, filtering, washing the filter cake with a proper amount of acetonitrile, and drying the solid by blowing at 60 ℃ for 6h to obtain 4.0kg of pale yellow to yellow solid acylate, wherein the yield is 95.2%, the purity is more than 99.0%, the specific single impurity content is less than 0.5%, the other single impurity content is less than 0.15%, and the total impurity content is less than 1.0%.

The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the obtained solid are shown in fig. 1 and fig. 2 respectively, and the specific data are as follows: ¹ H NMR(400MHz, CDCl ₃ )δ＝7.96(d,J＝8.8Hz,1H),7.57-7.47(m,5H),7.39(dd,J ₁ ＝2.0Hz,J ₂ ＝8.8Hz,1H),7.24 (d,J＝2.4Hz,1H),3.74(s,3H),3.43(s,2H). ¹³ C NMR(100MHz,CDCl ₃ )δ＝167.23,166.21, 144.43,140.79,139.60,136.17,130.45,129.67,129.48,128.44,127.87,126.37,52.57,41.67。

(2) synthesis of intermediate IV

To a 100L clean reaction vessel, 29.6L of methanol and 11.0kg of purified water were added and stirred uniformly. 3.7kg of intermediate III were added. 18.5L of hydrochloric acid was slowly dropped into the system while controlling the internal temperature at 30 ℃ or lower. After the dropwise addition, the temperature was controlled at 20 ℃ and 3.9kg of zinc powder was added to the reaction system. And after the zinc powder is added, continuously stirring and reacting for 8 hours. Sampling for HPLC rapid detection. After the reaction is completed, the system is cooled to 5-15 ℃, stirred and crystallized for 2h, filtered, and the filter cake is washed by 3.7L of ethanol to obtain white solid. The solid is dried by blowing at 60 ℃ for 8 hours to obtain 1.8kg of white-like to white solid cyclic compound, the yield is 60.0 percent, the purity is more than 99.8 percent, the single impurity content is less than 0.1 percent, and the total impurity content is less than 0.2 percent.

The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the obtained solid are respectively shown in fig. 3 and 4, and the specific data are as follows: ( ¹ H NMR(400 MHz,DMSO)δ＝10.64(s,1H),7.48-7.44(m,2H),7.38-7.36(m,1H),7.29(d,J＝2.4Hz,1H), 7.26-7.25(m,2H),7.21-7.18(m,2H),7.14-7.10(m,1H),6.84(d,J＝7.6Hz,1H),3.73-3.60(m, 1H),3.15-3.13(m,1H). ¹³ C NMR(100MHz,DMSO)δ＝166.92,164.67,141.88,134.56,132.55, 129.72,128.69,127.87,126.59,126.11,125.49,123.02,45.63.)

(3) Synthesis of crude Lorbazem V

30.0L of methanol and 1.5kg of intermediate IV were added to a 100L clean reaction vessel and stirred at room temperature. Sodium carbonate (1.0 kg) was added. And adding 3.2kg of methyl iodide, sealing the reaction kettle, and stirring and reacting for 8-10 h at the temperature of 30-40 ℃. Sampling for HPLC rapid detection. And filtering after complete reaction, washing a filter cake with a small amount of methanol, combining filtrates, concentrating until obvious solids appear, stopping concentrating, cooling the system to 0-10 ℃, stirring and crystallizing for 1h, filtering, washing the filter cake with a small amount of methanol, and drying the solids in a drying oven at 60 ℃ for 6h to obtain 1.4kg of a white solid crude product, wherein the yield is 95.0%, the purity is more than 99.5%, the content of single impurities is less than 0.2%, and the content of total impurities is less than 0.5%.

The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the obtained solid are respectively shown in fig. 5 and 6, and the specific data are as follows: ( ¹ H NMR(400 MHz,DMSO)δ＝7.51-7.47(m,2H),7.42-7.38(m,1H),7.35-7.21(m,4H),7.21-7.18(m,2H),6.81 (d,J＝2.4Hz,1H),3.42(s,3H),2.56(s,2H). ¹³ C NMR(100MHz,DMSO)δ＝166.78,164.66, 141.44,135.60,131.82,129.95,128.76,128.30,126.58,125.36,124.74,45.59,40.85.)

(4) Refining of clobazam crude product V

6.5L of ethanol and 6.5L of purified water were added to a 50L clean decolorizer, and 1.3kg of crude product V were added, and stirring was started. Heating to reflux to dissolve the system, adding 52.0g of active carbon, continuing to perform heat preservation and decoloration for 15min, filtering to remove the active carbon, cooling the filtrate to 0-10 ℃, stirring and crystallizing for 2h, filtering, washing the material with a proper amount of ethanol, and drying the solid in a drying oven at 60 ℃ for 8h to obtain 1.17kg of the finished product of the clobazam I, wherein the yield is 92.3%, the purity is more than 99.8%, the content of known impurities is less than 0.15%, the content of other single impurities is less than 0.10%, and the content of total impurities is less than 0.20%.

And (3) a central control HPLC method: agilent 1260 high performance liquid chromatograph, chromatographic column (Agilent ZORBAX Bonus-RP, 4.6X 250mm, 5.0 μm), 40 deg.C ultrapure water/acetonitrile ratio 60/40, running for 20 minutes, flow rate of 3.0ml/min, detection wavelength of 230 nm.

Comparative example 1:

in the operation of step (1), the acylating agent was ethyl malonyl chloride, and the rest was the same as in example 1.

The yield of the solid acylate obtained after the step (1) is 94.9 percent, and the purity is more than 99.0 percent. However, in step (2), the yield of the solid cyclic compound obtained is only 35.4%, the purity is > 99.5%, and the yield is much lower than that of example 1.

Comparative example 2:

in the operation of step (2), the solvent used was 29.6L of ethanol and 11.0kg of purified water, as in example 1. The acylation reagent was ethyl malonyl chloride, as in example 1. After the cyclization reaction in the step (2), the yield is 47.6%, the purity of the product is 99.0%, and the total impurity content is less than 0.5%.

Claims (1)

1. A method for industrial production of clobazam, the target product is clobazam I, and the synthetic route is as follows:

the method comprises the following specific steps:

(1) synthesis of intermediate III

Adding 30.0L of toluene into a 50L dry reaction kettle, and then adding 3.0kg of the starting material II, 3.8kg of the acylating agent and 2.8kg of triethylamine; stirring, heating to 60-70 ℃ for reaction, and keeping the internal temperature for reaction for 8 h; sampling, carrying out HPLC (high performance liquid chromatography) rapid detection, cooling to 20-30 ℃ after complete reaction, filtering, soaking and washing a filter cake with a small amount of toluene, combining filtrates, washing with 15.0L of water, separating liquid, adding a proper amount of anhydrous sodium sulfate into an organic layer, drying for 2h, filtering to remove a drying agent, washing the filter cake with a small amount of toluene, combining the filtrates, concentrating under reduced pressure to dryness, cooling to room temperature, adding 10.0kg of acetonitrile into a system, heating to reflux to dissolve and clear solid, cooling to 0-10 ℃, stirring and crystallizing for 2h, filtering, washing the filter cake with a proper amount of acetonitrile, and drying the solid by blowing at 60 ℃ for 6h to obtain light yellow to yellow solid acylate, wherein the yield is 95.2%, the purity is more than 99.0%, the specific single impurity content is less than 0.5%, the other single impurity content is less than 0.15%, and the total impurity content is less than 1.0%;

(2) synthesis of intermediate IV

Adding 29.6L of methanol and 11.0kg of purified water into a 100L clean reaction kettle, and uniformly stirring; adding 3.7kg of the intermediate III, controlling the internal temperature below 30 ℃, and slowly dropwise adding 18.5L of hydrochloric acid into the system; controlling the temperature to be 20 ℃ after the dropwise addition is finished, and adding 3.9kg of zinc powder into the reaction system; after the zinc powder is added, continuously stirring and reacting for 8 hours, and sampling for HPLC rapid detection; after the reaction is completed, cooling the system to 5-15 ℃, stirring for crystallization for 2h, filtering, washing a filter cake with 3.7L of ethanol to obtain a white solid, and performing forced air drying on the solid at 60 ℃ for 8h to obtain a white-like to white solid cyclic compound with the yield of 60.0%, the purity of more than 99.8%, the single impurity content of less than 0.1% and the total impurity content of less than 0.2%;

(3) synthesis of crude Lorbazem V

Adding 30.0L of methanol and 1.5kg of intermediate IV into a 100L clean reaction kettle, and stirring at room temperature; adding 1.0kg of sodium carbonate, adding 3.2kg of methyl iodide, sealing the reaction kettle, stirring and reacting at 30-40 ℃ for 8-10 h, and sampling for HPLC rapid detection; filtering after complete reaction, washing a filter cake with a small amount of methanol, combining filtrates, concentrating, stopping concentrating until obvious solids appear, cooling the system to 0-10 ℃, stirring, crystallizing for 1h, filtering, washing the filter cake with a small amount of methanol, and drying the solids in a drying oven at 60 ℃ for 6h to obtain 1.4kg of a white solid crude product, wherein the yield is 95.0%, the purity is more than 99.5%, the content of single impurities is less than 0.2%, and the content of total impurities is less than 0.5%;

(4) refining of clobazam crude product V

Adding 6.5L ethanol and 6.5L purified water into a 50L clean decolorization tank, adding 1.3kg crude product V, and stirring; heating to reflux to dissolve the system, adding 52.0g of active carbon, continuing to perform heat preservation and decoloration for 15min, filtering to remove the active carbon, cooling the filtrate to 0-10 ℃, stirring and crystallizing for 2h, filtering, washing the material with a proper amount of ethanol, and drying the solid in a drying oven at 60 ℃ for 8h to obtain 1.17kg of the finished product of the clobazam I, wherein the yield is 92.3%, the purity is more than 99.8%, the content of known impurities is less than 0.15%, the content of other single impurities is less than 0.10%, and the content of total impurities is less than 0.20%.

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