CN113801089A - Preparation method of Cliborol intermediate - Google Patents

Preparation method of Cliborol intermediate Download PDF

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CN113801089A
CN113801089A CN202010543041.0A CN202010543041A CN113801089A CN 113801089 A CN113801089 A CN 113801089A CN 202010543041 A CN202010543041 A CN 202010543041A CN 113801089 A CN113801089 A CN 113801089A
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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 Cliborol intermediate. MED is used for replacing glycol in the prior art for 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 prior art, the preparation process has higher product yield and purity, and is more suitable for industrial production.

Description

Preparation method of Cliborol intermediate
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a Cliborol intermediate.
Background
Crisaborole (Crisabiole), developed by Anaicor pharmaceutical, is a phosphodiesterase 4(PDE4) inhibitor that results in increased intracellular cyclic adenosine monophosphate (cAMP) levels, is used in the topical treatment of mild to moderate allergic dermatitis in patients 2 years of age and older, and has broad prospects. 12/14/2016, and approved by the U.S. Food and Drug Administration (FDA) for marketing, under the trade name Eucrisa, which has the following chemical structure:
Figure BDA0002539607510000011
the preparation methods of kreb is reported IN the patents of CN109456347A, IN201821000974, WO2019138422a1, US2019241585a1, WO2019120637a1, IN201741016807, CN109517003A, CN108864160A, WO2018224923a1, WO2018216032a1, WO2018207216a1, CN108659024A, WO2018150327a1, WO2018115362a1, CN108047261A, CN107759625A, US20170305936a1, CN106928264A, US20070286822a1, WO2009111676a2, WO2007095638a2, WO2007078340a 2.
CN102014927A discloses a synthetic route using 2-bromo-5-hydroxybenzaldehyde as a starting material, first performing aldehyde group protection with ethylene glycol, then reacting with a halogenated carbonitrile substance, removing an ethylene glycol protecting group under an acidic condition to obtain a key intermediate, introducing a boron atom through Miyaura coupling reaction, and performing reactions such as sodium borohydride reduction to obtain kreb, which is as follows:
Figure BDA0002539607510000012
X＝F，Cl；Y，Z＝CH，N；R1h, halogen.
In CN108659025A, an aldehyde group is protected by triethyl orthoformate or ethylene glycol, then the aldehyde group is reacted with boric acid ester (2-alkoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxolane, triisopropyl borate or trimethyl borate) in the presence of isopropyl magnesium chloride, and finally the aldehyde group is contacted with alkali metal borohydride for reaction to obtain the kreb. The synthetic route is as follows:
Figure BDA0002539607510000021
tsutomu Akama et al, in Bioorganic & Medicinal Chemistry Letters,19(2009)2129-2132, use dihydropyran to replace MOM-Cl to protect benzyl alcohol, introduce isopropyl borate under the condition of n-butyl lithium, and cyclize to obtain the target product. The synthetic route is as follows:
Figure BDA0002539607510000022
the Master thesis "Clarithromol synthesis process and quality standard research" adopts the above strategy to prepare 4- (4-bromo-3- (hydroxymethyl) phenoxy) benzonitrile, after the alcohol is protected by acetyl group, the pinacol ester of boronic acid is introduced into the benzene ring, and finally the target product is prepared by cyclization under acidic condition. The synthetic route is as follows:
Figure BDA0002539607510000023
in summary, to avoid the problem that the aldehyde hydroxyl group itself condenses to make the reaction difficult, acetal protection strategies are used in the preparation of kreb related intermediates, and experiments prove that acetal protection groups have a significant advantage over dialkyl acetal protection groups, 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 kreb in a variety of preparation processes. The chemical structural formula is as follows:
Figure BDA0002539607510000024
the Master thesis "Crisbor Synthesis Process and quality Standard research" refers to 4-bromo-3- (1, 3-dioxolan-2-yl) phenol in Bioorganic literature&Reflux reaction of 4-bromo-3-formylphenol and ethylene glycol in Medicinal Chemistry Letters,19(2009)2129-2132 under the catalysis of p-TsOH by using toluene as a solvent for 6h, adding water for quenching, extracting by using ethyl acetate, combining upper organic phases, washing for 3 times, adding anhydrous Na2SO4Drying for 1h, and concentrating under reduced pressure to dryness, wherein the yield of the obtained product is 90%. However, it is found through preliminary experiments that the reaction yield is very low, a large amount of raw materials remain, and a large amount of black oily substances are generated after the reaction, which is not beneficial to the decoloration of the post-treatment. By analyzing the reaction mechanism, water is generated in the reaction, and if the water cannot be removed in time, the reaction is influenced, and further the reaction process is influenced. The reaction temperature greatly affects the yield in order to take out water generated in the reaction by toluene, and the boiling point of toluene is 110 ℃, and the yield is only 52.3% when the reaction temperature is set to 120 ℃ as verified by experiments. Water is generated in the reaction process to influence the reaction, and the toluene is further heated to remove the water generated in the reaction, so that the yield is improved, the reaction energy consumption is undoubtedly greatly increased, and the operation is also extremely inconvenient.
CN108659025A discloses a 4- (4-bromo-3- (1, 3-dioxolan-2-yl) phenoxy) benzonitrile compound, but does not disclose a method for its preparation, and also refers to the above method, when 4- (4-bromo-3-formylphenoxy) benzonitrile is reacted with ethylene glycol under acidic conditions at high temperature for a long time to prepare 4- (4-bromo-3- (1, 3-dioxolan-2-yl) phenoxy) benzonitrile, in addition to the above problems, a small amount of cyano hydrolysis impurities still exist, and purification is difficult.
In conclusion, the preparation method of the related acetal intermediate in the existing krebs preparation process has many defects in the aspects of product purity, yield, experimental operation and the like, so the research and search of the preparation method which has mild reaction conditions, simple and convenient operation process, high product yield and high purity and is suitable for the industrial production of the acetal protective intermediate still needs to solve the problem at present.
Disclosure of Invention
Aiming at the problems of the preparation technology of the acetal intermediate in the existing Kriboron preparation process, the invention provides a novel method for preparing the intermediate by aldehyde group protection. The method has mild reaction conditions and simple and convenient operation process, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
Figure BDA0002539607510000031
a preparation method of a kreb acetal intermediate comprises the following steps:
adding SM-1, butanone ethylene ketal (MED) and a catalyst into a dry reaction solvent at room temperature, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain the target compound.
In a preferable scheme, 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 preferable; wherein the camphorsulfonic acid can be a racemate or a single isomer of 1R- (-) -10-camphorsulfonic acid, 1S- (+) -10-camphorsulfonic acid or a mixture thereof.
Preferably, the reaction solvent is one or a combination of benzene, toluene, xylene, dichloromethane and chloroform, wherein dichloromethane is particularly preferred.
Preferably, the feeding molar ratio of SM-1 to MED to the catalyst is 1: 1.1-2.0: 3.0% to 10.0%, of which 1: 1.3: 5.0 percent.
In a preferable scheme, the reaction temperature is 0-40 ℃, and particularly preferably 20-25 ℃.
Preferably, the post-treatment method comprises the following steps: and after the reaction is finished, adding a saturated sodium bicarbonate solution, separating liquid, taking 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 that the solvent is obtained by a conventional means such as molecular sieve water removal or rectification.
The invention has the beneficial effects that:
1. the invention provides a novel method for preparing a related acetal intermediate of krebs, MED is used for replacing glycol for acetal protection, the related intermediate is obtained almost quantitatively at room temperature, 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.
2. The content of hydrolysis of the cyano group can be effectively reduced in the preparation process of the related acetal intermediate containing the cyano group, and the yield and the purity of the product are improved.
3. Compared with the prior art, the preparation process has higher product yield and purity, and is more suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
Data for structure confirmation of 4-bromo-3- (1, 3-dioxolan-2-yl) phenol: ESI-HRMS (m/z): 243.9728[ M + H]+；1H NMR(400MHz,DMSO-d6)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)；13C NMR(101MHz,DMSO-d6)δ:153.21,139.67,134.46,118.14,117.91,111.33,104.20,67.28。
Data for confirming the structure of 4- (4-bromo-3- (1, 3-dioxolan-2-yl) phenoxy) benzonitrile: ESI-HRMS (m/z): 345.0006[ M + H]+；1HNMR(400MHz,DMSO-d6)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)；13C NMR(101MHz,DMSO-d6)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 procedures and methods not described in detail are conventional methods well known in the art.
Example 1
Adding 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), butanone ethylene ketal (MED, 15.10g, 0.13mol), p-toluenesulfonic acid (0.86g, 0.005mol) into dried dichloromethane (300ml) at room temperature, controlling the temperature to be 20-25 ℃ until the reaction is finished, adding saturated sodium bicarbonate solution (150ml), stirring for 10-15 min, separating liquid to obtain an organic layer, washing with purified water (150ml multiplied by 3), washing with saturated saline solution (150ml), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the 4-bromo-3- (1, 3-dioxolan-2-yl) phenol, wherein the yield is 97.5% and the purity is 99.83%.
Example 2
Adding 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), MED (12.78g, 0.11mol) and 1R- (-) -10-camphorsulfonic acid (1.16g, 0.005mol) into dried dichloromethane (300ml), controlling the temperature to be 20-25 ℃ until the reaction is finished, adding saturated sodium bicarbonate solution (150ml), stirring for 10-15 min, separating, taking an organic layer, washing with purified water (150ml × 3), washing with saturated saline (150ml), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry, namely the 4-bromo-3- (1, 3-dioxolan-2-yl) phenol, wherein the yield is 96.9% and the purity is 99.79%.
Example 3
Adding 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), MED (11.62g, 0.10mol) and 1S- (+) -10-camphorsulfonic acid (1.16g, 0.005mol) into dried dichloromethane (300ml), controlling the temperature to be 20-25 ℃ until the reaction is finished, adding saturated sodium bicarbonate solution (150ml), stirring for 10-15 min, separating, taking an organic layer, washing with purified water (150ml multiplied by 3), washing with saturated saline (150ml), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the 4-bromo-3- (1, 3-dioxolan-2-yl) phenol, wherein the yield is 96.7% and the purity is 99.77%.
Example 4
Adding 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), MED (23.23g, 0.20mol) and alpha-naphthalenesulfonic acid (1.04g, 0.005mol) into dried dichloromethane (300ml), controlling the temperature to be 20-25 ℃ until the reaction is finished, adding saturated sodium bicarbonate solution (150ml), stirring for 10-15 min, separating liquid, taking an organic layer, washing with purified water (150ml multiplied by 3), washing with saturated saline solution (150ml), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the 4-bromo-3- (1, 3-dioxolane-2-yl) phenol, wherein the yield is 96.5% and the purity is 99.78%.
Example 5
Adding 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), MED (24.39g, 0.21mol) and beta-naphthalenesulfonic acid (1.04g, 0.005mol) into dried dichloromethane (300ml), controlling the temperature to be 20-25 ℃ until the reaction is finished, adding saturated sodium bicarbonate solution (150ml), stirring for 10-15 min, separating liquid, taking an organic layer, washing with purified water (150ml multiplied by 3), washing with saturated saline solution (150ml), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the 4-bromo-3- (1, 3-dioxolane-2-yl) phenol, wherein the yield is 96.6% and the purity is 99.76%.
Example 6
Adding 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), MED (15.10g, 0.13mol) and p-toluenesulfonic acid (0.52g, 0.003mol) into dried chloroform (300ml), controlling the temperature to be 30-35 ℃ until the reaction is finished, adding a saturated sodium bicarbonate solution (150ml), stirring for 10-15 min, separating liquid to obtain an organic layer, washing with purified water (150ml multiplied by 3), washing with saturated saline solution (150ml), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dried to obtain the 4-bromo-3- (1, 3-dioxolane-2-yl) phenol, wherein the yield is 96.5% and the purity is 99.78%.
Example 7
Adding 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), MED (15.10g, 0.13mol) and p-toluenesulfonic acid (0.34g, 0.002mol) into dry benzene (300ml), controlling the temperature to be 35-40 ℃ until the reaction is finished, adding saturated sodium bicarbonate solution (150ml), stirring for 10-15 min, separating liquid to obtain an organic layer, washing with purified water (150ml multiplied by 3), washing with saturated saline solution (150ml), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the 4-bromo-3- (1, 3-dioxolane-2-yl) phenol, wherein the yield is 96.1% and the purity is 99.76.
Example 8
At room temperature, adding 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), MED (15.10g, 0.13mol), p-toluenesulfonic acid (1.72g, 0.01mol) into dried dichloromethane (300ml), controlling the temperature to be 10-15 ℃ until the reaction is finished, adding saturated sodium bicarbonate solution (250ml), stirring for 10-15 min, separating liquid to obtain an organic layer, washing with purified water (150ml × 3), washing with saturated saline solution (150ml), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the 4-bromo-3- (1, 3-dioxolane-2-yl) phenol, wherein the yield is 97.7%, and the purity is 99.73%.
Example 9
Adding 2-bromo-5-hydroxybenzaldehyde (SM-1, 20.10g, 0.10mol), MED (15.10g, 0.13mol) and p-toluenesulfonic acid (1.89g, 0.011mol) into dry xylene (300ml), controlling the temperature to be 0-5 ℃ until the reaction is finished, adding saturated sodium bicarbonate solution (300ml), stirring for 10-15 min, separating liquid to obtain an organic layer, washing with purified water (150ml multiplied by 3), washing with saturated saline solution (150ml), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the 4-bromo-3- (1, 3-dioxolane-2-yl) phenol, wherein the yield is 97.6% and the purity is 99.70%.
Example 10
Adding 4- (4-bromo-3-formylphenoxy) benzonitrile (SM-1, 30.21g, 0.10mol), MED (13.94g, 0.12mol), p-toluenesulfonic acid (0.86g, 0.005mol) into dried dichloromethane (300ml), controlling the temperature to be 20-25 ℃ until the reaction is finished, adding saturated sodium bicarbonate solution (150ml), separating to obtain an organic layer, washing with purified water (150ml multiplied by 3), washing with saturated saline solution (150ml), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until no solvent flows out to obtain the 4- (4-bromo-3- (1, 3-dioxolan-2-yl) phenoxy) benzonitrile at the yield of 97.9% and the purity of 99.87%.

Claims (6)

1. A preparation method of a krebs intermediate is characterized in that a target compound is obtained by catalytic reaction of a compound of formula SM-1 and MED, and the route is as follows:
Figure FDA0002539607500000011
2. the preparation method according to claim 1, comprising the following steps: at room temperature, adding SM-1, butanone ethylene ketal MED and catalyst into a dry reaction solvent, controlling the temperature until the reaction is finished, and carrying out post-treatment to obtain the target compound.
3. The method of claim 2, wherein the catalyst is one or a combination of p-toluenesulfonic acid, camphorsulfonic acid, alpha-naphthalenesulfonic acid, and beta-naphthalenesulfonic acid.
4. The method according to claim 2, wherein the reaction solvent is one or a combination of benzene, toluene, xylene, dichloromethane, chloroform.
5. The method of claim 2, wherein the molar ratio of SM-1 to MED to catalyst is 1: 1.1-2.0: 3.0 to 10.0 percent.
6. The method according to claim 2, wherein the reaction temperature is 0 to 40 ℃.
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