CN113801089B - Preparation method of clenbuterol intermediate - Google Patents

Preparation method of clenbuterol intermediate Download PDF

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CN113801089B
CN113801089B CN202010543041.0A CN202010543041A CN113801089B CN 113801089 B CN113801089 B CN 113801089B CN 202010543041 A CN202010543041 A CN 202010543041A CN 113801089 B CN113801089 B CN 113801089B
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CN113801089A (en
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张乃华
鲍广龙
刘忠
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/20—Free hydroxyl or mercaptan

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a clenbuterol intermediate. The MED is used for replacing glycol in the prior art to carry out acetal protection, so that the reaction temperature and the use of a water separator can be obviously reduced, the reaction operation is simplified, and the energy consumption is reduced. Compared with the product obtained by the prior art, the preparation process provided by the invention has higher yield and purity, and is more suitable for industrial production.

Description

Preparation method of clenbuterol intermediate
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a clenbuterol intermediate.
Background
The clenbuterol (Crisacorole) developed by An Nakao mol (Anacor) pharmaceutical company is a phosphodiesterase 4 (PDE 4) inhibitor, and the inhibition results in increased intracellular cyclic adenosine monophosphate (cAMP) levels, and has broad prospect in the local treatment of mild to moderate allergic dermatitis in patients aged 2 years and older. The chemical formula of the product is shown below, under the trade name Eucrisa, approved by the United states Food and Drug Administration (FDA) for 14 days of 2016:
the preparation method of the clenbuterol has been researched and reported IN patents such as CN109456347A, IN201821000974, WO2019138422A1, US2019241585A1, WO2019120637A1, IN201741016807, CN109517003A, CN108864160A, WO2018224923A1, WO2018216032A1, WO2018207216A1, CN108659024A, WO2018150327A1, WO2018115362A1, CN108047261A, CN107759625A, US20170305936A1, CN106928264A, US20070286822A1, WO2009111676A2, WO2007095638A2 and WO2007078340A 2.
Wherein, CN102014927A discloses a synthetic route which uses 2-bromo-5-hydroxybenzaldehyde as a starting material, uses ethylene glycol to carry out aldehyde group protection, then reacts with halogenated carbonitriles to remove ethylene glycol protecting groups under an acidic condition to obtain a key intermediate, introduces boron atoms through Miyaura coupling reaction, and obtains the clenbuterol through sodium borohydride reduction and other reactions, wherein the synthetic route is as follows:
X＝F，Cl；Y，Z＝CH，N；R 1 =h, halogen.
In CN108659025A, triethyl orthoformate or ethylene glycol is adopted to protect aldehyde group, then the aldehyde group is reacted with boric acid ester (2-alkoxy-4, 5-tetramethyl-1, 3, 2-dioxaborolane, triisopropyl borate or trimethyl borate) in the presence of isopropyl magnesium chloride, and finally the boric acid ester is contacted with alkali metal borohydride to react, so that the clenbuterol is obtained. The synthetic route is as follows:
tsutomu Akama et al in Bioorganic & Medicinal Chemistry Letters,19 (2009) 2129-2132, a method for preparing a target product by introducing isopropyl borate under the condition of n-butyllithium after protecting benzyl alcohol by dihydropyran instead of MOM-Cl. The synthetic route is as follows:
the preparation method comprises the steps of preparing 4- (4-bromo-3- (hydroxymethyl) phenoxy) benzonitrile by adopting the above strategy in Keli borol synthesis process and quality standard research in Shuoshi paper, introducing pinacol borate into benzene ring after acetyl protection of alcohol, and finally cyclizing under acidic condition to obtain the target product. The synthetic route is as follows:
in summary, to avoid the problem that the reaction is difficult to carry out due to the self-condensation of the aldehyde hydroxyl groups, the acetal protection strategy is applied more in the preparation of the intermediate related to the clenbuterol, and experiments prove that the acetal protection group has obvious advantages compared with the dialkyl acetal protection group, such as 4- (4-bromo-3- (1, 3-dioxolan-2-yl) phenoxy) benzonitrile and 4-bromo-3- (1, 3-dioxolan-2-yl) phenol, which are disclosed as key intermediates for preparing the clenbuterol in a plurality of preparation processes. The chemical structural formula is as follows:
reference to 4-bromo-3- (1, 3-dioxolan-2-yl) phenol in the literature Bioorganic in the Studies of Criboro Synthesis Process and quality standards&Under the catalysis of p-TsOH, 4-bromo-3-formylphenol and ethylene glycol in Medicinal Chemistry Letters,19 (2009) 2129-2132 are subjected to reflux reaction for 6h by taking toluene as a solvent, water is added for quenching, ethyl acetate is used for extraction, the upper organic phase is combined, water is used for washing for 3 times, and anhydrous Na is added 2 SO 4 Drying for 1h, and concentrating under reduced pressure to obtain the product with the yield of 90%. However, it was found by preliminary experiments that the reaction yield was very low, a large amount of starting materials remained, and a large amount of black oil was produced after the reaction, which was detrimental to the post-treatment decolorization. By analyzing the reaction mechanism, water is generated in the reaction, and if the water cannot be removed in time, the reaction is affected, and the reaction progress is further affected. In order to bring out the water produced in the reaction by toluene, the reaction temperature had a great influence on the yield, whereas the boiling point of toluene was 110℃and, as proved by experiments, when the reaction temperature was set to 120℃the yield was only 52.3%. During the reaction, water is generated to influence the reaction, toluene is further heated to remove the water generated in the reaction, the yield is improved, the reaction energy consumption is obviously greatly increased, and the operation is very inconvenient.
CN108659025a discloses a 4- (4-bromo-3- (1, 3-dioxolan-2-yl) phenoxy) benzonitrile compound, but does not disclose a process for producing the same, and at the same time, a small amount of cyano hydrolysis impurities are still present and difficult to purify by referring to the above process when 4- (4-bromo-3-formylphenoxy) benzonitrile is reacted with ethylene glycol under acidic conditions for a long period of time at high temperature, in addition to the above problems.
In summary, the existing preparation method of the related acetal intermediate in the preparation process of the clenbuterol has a plurality of defects in terms of product purity, yield, test operation and the like, so that the research and the search of a preparation method which is mild in reaction condition, simple and convenient in operation process, high in product yield and high in purity and suitable for industrialized production of the acetal protection intermediate still have the problems to be solved at present.
Disclosure of Invention
Aiming at the problems of the preparation technology of the acetal intermediate in the current preparation technology of the clenbuterol, the invention provides a novel method for preparing the intermediate by protecting aldehyde groups. The method has mild reaction conditions and simple operation process, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
the preparation method of the intermediate of the clenbuterol Luo Yi diacetal specifically comprises the following steps:
and (3) adding SM-1, ding Tongyi glycol ketal (MED) and a catalyst into a dried reaction solvent at room temperature, controlling the temperature to the end of the reaction, and performing post-treatment to obtain the target compound.
Preferably, the catalyst is one or a combination of p-toluenesulfonic acid, camphorsulfonic acid, alpha-naphthalenesulfonic acid and beta-naphthalenesulfonic acid, wherein the p-toluenesulfonic acid is particularly preferred; wherein camphorsulfonic acid can be racemate or single isomer in 1R- (-) -10-camphorsulfonic acid, 1S- (+) -10-camphorsulfonic acid or mixture thereof.
Preferably, the reaction solvent is one or a combination of benzene, toluene, xylene, methylene chloride and chloroform, wherein methylene chloride is particularly preferred.
In a preferred scheme, the feeding mole ratio of SM-1 to MED to catalyst is 1:1.1 to 2.0:3.0% to 10.0%, of which 1:1.3:5.0%.
Preferably, the reaction temperature is from 0 to 40℃and particularly preferably from 20 to 25 ℃.
Preferably, the post-treatment method comprises the following steps: after the reaction is finished, adding saturated sodium bicarbonate solution, separating to obtain an organic layer, washing with purified water, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dried to obtain the target compound.
In the present invention, the method of drying the solvent refers to the conventional method of removing water or rectifying through molecular sieve.
The invention has the beneficial effects that:
1. the invention provides a novel method for preparing a clenbuterol related acetal intermediate, which uses MED to replace glycol for acetal protection, almost quantitatively obtains the related intermediate at room temperature, can obviously reduce the reaction temperature and the use of a water separator, simplifies the reaction operation and reduces the energy consumption.
2. The method can effectively reduce the content of cyano hydrolysis in the preparation process of the related acetal intermediate containing cyano, and improve the yield and purity of the product.
3. Compared with the product obtained by the prior art, the preparation process provided by the invention has higher yield and purity, and is more suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
Data for structural corroboration of 4-bromo-3- (1, 3-dioxolan-2-yl) phenol: ESI-HRMS (m/z): 243.9728[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d 6 )δ:8.24(s,1H),7.38(d,J＝8.4Hz,1H),6.94(d,J＝2.6Hz,1H),6.72(d,J＝8.2Hz,1H),5.93(s,1H),4.14～3.86(m,4H)； 13 C NMR(101MHz,DMSO-d 6 )δ:153.21,139.67,134.46,118.14,117.91,111.33,104.20,67.28。
Data for structural corroboration of 4- (4-bromo-3- (1, 3-dioxolan-2-yl) phenoxy) benzonitrile: ESI-HRMS (m/z): 345.0006[ M+H ]] + ； 1 HNMR(400MHz,DMSO-d 6 )δ:7.88～7.74(m,3H),7.53(d,J＝2.8Hz,1H),7.48～7.32(m,2H),7.28～7.08(m,1H),5.93(s,1H),4.06～4.13(m,4H)； 13 C NMR(101MHz,DMSO-d 6 )δ:159.58,153.11,140.18,133.31,131.56,120.28,120.01,119.12,117.57,117.20,109.84,104.20,67.28。
In the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
Example 1
2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g,0.10 mol), ding Tongyi glycol ketal (MED, 15.10g,0.13 mol), p-toluenesulfonic acid (0.86 g,0.005 mol) were added to dried dichloromethane (300 ml) at room temperature, after the reaction was completed, saturated sodium bicarbonate solution (150 ml) was added to stir for 10 to 15min, the organic layer was separated and taken out, purified water (150 ml. Times.3) was washed, saturated brine (150 ml) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to give 4-bromo-3- (1, 3-dioxolan-2-yl) phenol in 97.5% yield and 99.83% purity.
Example 2
2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g,0.10 mol), MED (12.78 g,0.11 mol) and 1R- (-) -10-camphorsulfonic acid (1.16 g,0.005 mol) are added into dry dichloromethane (300 ml) at room temperature, the temperature is controlled between 20 and 25 ℃ until the reaction is finished, saturated sodium bicarbonate solution (150 ml) is added and stirred for 10 to 15min, the organic layer is separated and taken out, purified water (150 ml multiplied by 3) is washed, saturated saline (150 ml) is washed, anhydrous sodium sulfate is dried, filtered, and the filtrate is concentrated to dryness under reduced pressure, thus obtaining 4-bromo-3- (1, 3-dioxolan-2-yl) phenol with the yield of 96.9% and the purity of 99.79%.
Example 3
2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g,0.10 mol), MED (11.62 g,0.10 mol) and 1S- (+) -10-camphorsulfonic acid (1.16 g,0.005 mol) are added into dry dichloromethane (300 ml) at room temperature, the temperature is controlled between 20 and 25 ℃ until the reaction is finished, saturated sodium bicarbonate solution (150 ml) is added and stirred for 10 to 15min, the organic layer is separated and taken out after stirring, purified water (150 ml multiplied by 3) is washed, saturated saline (150 ml) is washed, anhydrous sodium sulfate is dried, filtered, and the filtrate is concentrated to dryness under reduced pressure, thus obtaining 4-bromo-3- (1, 3-dioxolan-2-yl) phenol with the yield of 96.7% and the purity of 99.77%.
Example 4
2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g,0.10 mol), MED (23.23 g,0.20 mol) and alpha-naphthalenesulfonic acid (1.04 g,0.005 mol) are added into dry dichloromethane (300 ml) at room temperature, the temperature is controlled to 20-25 ℃ until the reaction is finished, saturated sodium bicarbonate solution (150 ml) is added, stirring is carried out for 10-15 min, an organic layer is separated and taken out after the mixture is stirred for 10-15 min, purified water (150 ml multiplied by 3) is washed, saturated saline (150 ml) is washed, anhydrous sodium sulfate is dried, filtration is carried out, and filtrate is concentrated to dryness under reduced pressure, thus obtaining 4-bromo-3- (1, 3-dioxolan-2-yl) phenol with the yield of 96.5% and the purity of 99.78%.
Example 5
2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g,0.10 mol), MED (24.39 g,0.21 mol), beta-naphthalenesulfonic acid (1.04 g,0.005 mol) were added to dried dichloromethane (300 ml), the temperature was controlled at 20-25 ℃ until the reaction was completed, saturated sodium bicarbonate solution (150 ml) was added, stirred for 10-15 min, the organic layer was separated and taken out, purified water (150 ml. Times.3) was washed, saturated brine (150 ml) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to give 4-bromo-3- (1, 3-dioxolan-2-yl) phenol in 96.6% yield and 99.76% purity.
Example 6
2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g,0.10 mol), MED (15.10 g,0.13 mol) and p-toluenesulfonic acid (0.52 g, 0.003mol) are added into dry chloroform (300 ml) at room temperature, the temperature is controlled between 30 and 35 ℃ until the reaction is finished, saturated sodium bicarbonate solution (150 ml) is added, the mixture is stirred for 10 to 15 minutes, an organic layer is separated and taken out, purified water (150 ml multiplied by 3) is washed, saturated saline (150 ml) is washed, anhydrous sodium sulfate is dried, filtered, and the filtrate is concentrated under reduced pressure until the filtrate is dried, thus obtaining 4-bromo-3- (1, 3-dioxolan-2-yl) phenol, the yield is 96.5%, and the purity is 99.78%.
Example 7
2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g,0.10 mol), MED (15.10 g,0.13 mol) and p-toluenesulfonic acid (0.34 g,0.002 mol) are added into dry benzene (300 ml) at room temperature, saturated sodium bicarbonate solution (150 ml) is added after the reaction is completed at 35-40 ℃ for 10-15 min, the organic layer is separated and taken after stirring, purified water (150 ml multiplied by 3) is washed, saturated saline (150 ml) is washed, anhydrous sodium sulfate is dried and filtered, and the filtrate is concentrated to dryness under reduced pressure to obtain 4-bromo-3- (1, 3-dioxolan-2-yl) phenol with a yield of 96.1% and a purity of 99.76.
Example 8
2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g,0.10 mol), MED (15.10 g,0.13 mol) and p-toluenesulfonic acid (1.72 g,0.01 mol) are added into dry dichloromethane (300 ml) at room temperature, the temperature is controlled to be 10-15 ℃ until the reaction is finished, saturated sodium bicarbonate solution (250 ml) is added, the mixture is stirred for 10-15 min, an organic layer is separated and taken after the mixture is stirred for 10-15 min, purified water (150 ml multiplied by 3) is washed, saturated saline (150 ml) is washed, anhydrous sodium sulfate is dried, filtered, and the filtrate is concentrated to be dried under reduced pressure to obtain 4-bromo-3- (1, 3-dioxolan-2-yl) phenol, and the yield is 97.7% and the purity is 99.73%.
Example 9
2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g,0.10 mol), MED (15.10 g,0.13 mol) and p-toluenesulfonic acid (1.89 g,0.01 mol) are added into dried xylene (300 ml) at room temperature, the temperature is controlled between 0 and 5 ℃ until the reaction is finished, saturated sodium bicarbonate solution (300 ml) is added, the mixture is stirred for 10 to 15 minutes, an organic layer is separated and taken out, purified water (150 ml multiplied by 3) is washed, saturated saline (150 ml) is washed, anhydrous sodium sulfate is dried, filtered, and filtrate is concentrated to dryness under reduced pressure to obtain 4-bromo-3- (1, 3-dioxolan-2-yl) phenol with the yield of 97.6% and the purity of 99.70%.
Example 10
4- (4-bromo-3-formylphenoxy) benzonitrile (SM-1, 30.21g,0.10 mol), MED (13.94 g,0.12 mol) and p-toluenesulfonic acid (0.86 g,0.005 mol) were added to dry methylene chloride (300 ml) at room temperature, and after the reaction was completed, saturated sodium bicarbonate solution (150 ml) was added to the mixture at a temperature of 20 to 25℃to obtain an organic layer, which was washed with purified water (150 ml. Times.3), washed with saturated brine (150 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure until no solvent was released to obtain 4- (4-bromo-3- (1, 3-dioxolan-2-yl) phenoxy) benzonitrile in a yield of 97.9% and a purity of 99.87%.

Claims (2)

1. A preparation method of a clenbuterol intermediate is characterized in that a target compound is obtained by catalytic reaction of a compound of a formula SM-1 and MED, and the route is as follows:
；
the method specifically comprises the following steps: adding SM-1, ding Tongyi glycol ketal (MED) and a catalyst into a dry reaction solvent at room temperature, controlling the temperature until the reaction is finished, and performing post-treatment to obtain a target compound;
the catalyst is p-toluenesulfonic acid, camphorsulfonic acid,αNaphthalene sulfonic acid,β-one of naphthalene sulfonic acids or a combination thereof;
the reaction solvent is one or a combination of benzene, toluene, xylene, methylene dichloride and chloroform;
the temperature is controlled to be 0-40 ℃.
2. The preparation method of claim 1, wherein the feeding mole ratio of SM-1 to MED to catalyst is 1:1.1 to 2.0:3.0 to 10.0 percent.
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