Process for the preparation of ortho-carboxybenzaldehyde

Abstract

The application discloses a preparation method of o-carboxybenzaldehyde, which comprises the following steps: S1, reacting a phthalide with a potassium hydrogen peroxysulfate complex salt and an alkali in a polar protic solvent to prepare an intermediate; S2, hydrolyzing the intermediate obtained in the step S1 by using a strong protic acid aqueous solution to obtain a product o-carboxybenzaldehyde; and S3, adjusting the pH of the product obtained in the step S2 to 3-4 by using a sodium hydroxide aqueous solution, quenching excessive potassium hydrogen peroxysulfate complex salt by using a saturated sodium sulfite solution, cooling, recrystallizing, filtering and vacuum drying to obtain a final product o-carboxybenzaldehyde. The preparation method of the o-carboxybenzaldehyde can effectively reduce the synthesis cost, avoids the use of dangerous and toxic reagents, effectively reduces the generation of industrial three wastes, and is simple in process, convenient in operation, low in raw material cost, high in yield and beneficial to large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing o-carboxybenzaldehyde. Background Technology

[0002] AZD2281 (Ku-0059436), also known as Olaparib, has the following structure:

[0003]

[0004] Olaparib is an orally effective PARP inhibitor with IC50 values ​​of 5 and 1 nM for inhibiting PARP-1 and PARP-2, respectively. When osparib is applied to SW620 cells at concentrations of 30-100 nM, it inactivates PARP-1. Compared to BRCA1 and BRCA2-sufficient cell lines (Hs578T, MDA-MB-231, T47D), BRCA1-deficient cell lines (MDA-MB-463 and HCC1937) are oversensitive to osparib. Olaparib inhibits PARP, blocking base excision repair, resulting in strong sensitivity of KB2P cells to osparib. This leads to the transformation of single-strand breaks into double-strand breaks during DNA replication, thereby activating the BRCA2-dependent recombination pathway.

[0005] Olaparib is currently primarily used to treat tumors with BRCA gene mutations, such as ovarian cancer, breast cancer, and prostate cancer. PARP enzymes are involved in normal cellular functions, such as DNA transcription and DNA repair. Clinical studies by the US FDA have shown that olaparib, whether used as monotherapy or in combination with platinum-based chemotherapy, can inhibit the growth of tumor cells in vitro and reduce the growth of human tumors. An important starting material intermediate in the industrial production of olaparib is o-carboxybenzaldehyde.

[0006] Existing methods for preparing o-carboxybenzaldehyde typically use o-xylene as a starting material, synthesized under high temperature and pressure with manganese dibromide catalysis and hydrogen peroxide. However, this route places excessive demands on equipment, and the hydrogen peroxide used lacks thermal stability, easily decomposing into oxygen upon heating, potentially leading to explosions or fires. Scale-up operations are unsafe, the overall yield is low, and a significant amount of phthalic acid is produced as a byproduct. Alternatively, o-aldehyde benzonitrile can be used as a starting material, undergoing hydrolysis of the cyano group under sulfuric acid conditions to obtain the target product. However, this route uses expensive starting materials, and the post-processing generates substantial amounts of highly acidic industrial wastewater. Another option is to use phthalide as a starting material, undergoing a free radical substitution reaction with liquid bromine or NBS to obtain a 3-bromophthalide intermediate, followed by hydrolysis to obtain the target product. However, this reaction requires or generates liquid bromine, a toxic and volatile substance, posing a significant safety hazard to production personnel. It is also costly, and the solvents used, such as chloroform or carbon tetrachloride, can cause severe liver damage.

[0007] Therefore, it is now necessary to improve existing technologies to provide more reliable solutions. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a method for preparing o-carboxybenzaldehyde, which addresses the shortcomings of the prior art.

[0009] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is: a method for preparing o-carboxybenzaldehyde, comprising the following steps:

[0010] S1. The intermediate is prepared by reacting phthalide with potassium persulfate complex salt and base in a polar protic solvent.

[0011] S2. The intermediate obtained in step S1 is hydrolyzed with a strong protic acid aqueous solution to obtain the product o-carboxybenzaldehyde.

[0012] Preferably, the alkali in step S1 is any one of sodium ethoxide, potassium tert-butoxide, sodium tert-amyloxide, and sodium methoxide.

[0013] Preferably, the polar protic solvent used in step S1 is any one of methanol, ethanol, isopropanol, and tert-butanol.

[0014] Preferably, the molar ratio of alkali to phthalide in step S1 is 4.5:1 to 4.05:1.

[0015] Preferably, the volume ratio of the polar protic solvent to phthalide in step S1 is 5 to 15:1, and the molar ratio of the potassium persulfate complex salt to phthalide in step S1 is 1.5:1 to 1.05:1.

[0016] Preferably, the strong protic acid in step S2 is any one of sulfuric acid, hydrochloric acid, or trifluoroacetic acid.

[0017] Preferably, the mass fraction of the strong protic acid aqueous solution in step S2 is 10% to 40%, and the volume of the strong protic acid aqueous solution is 5 to 8 times that of phthalide.

[0018] Preferably, the method for preparing o-carboxybenzaldehyde further includes the following steps:

[0019] S3. Adjust the pH of the product obtained in step S2 to 3-4 with sodium hydroxide aqueous solution, then quench the excess potassium peroxymonosulfate complex salt with saturated sodium sulfite solution, cool and recrystallize, filter, and vacuum dry to obtain the final product o-carboxybenzaldehyde.

[0020] Preferably, the method for preparing o-carboxybenzaldehyde includes the following steps:

[0021] S1. The intermediate is prepared by reacting phthalide with potassium persulfate complex salt and base in a polar protic solvent for 6-12 hours.

[0022] S2. Add the intermediate obtained in step S1 to an aqueous solution of a strong protic acid and react at 50-70℃ for 1-3 hours to obtain the product;

[0023] S3. Adjust the pH of the product obtained in step S2 to 3-4 with sodium hydroxide aqueous solution, then quench the excess potassium peroxymonosulfate complex salt with saturated sodium sulfite solution, concentrate the methanol, cool to 5-10℃ for recrystallization, filter, and vacuum dry the obtained solid to obtain the final product o-carboxybenzaldehyde.

[0024] Preferably, the method for preparing o-carboxybenzaldehyde includes the following steps:

[0025] S1. Add phthalide to methanol solvent, then add sodium methoxide. During the feeding process, pay attention to controlling the temperature not to exceed 10℃. After the feeding is completed, react at 0℃ for 30 minutes.

[0026] Then, the temperature is naturally raised to room temperature and reacted for 30 minutes. The temperature is then lowered to below 0°C in an ice bath. Potassium persulfate complex salt is added in batches. During the feeding process, the temperature should be controlled not to exceed 10°C. After the feeding is completed, the temperature is naturally raised to room temperature and reacted for 8 hours to obtain the intermediate.

[0027] S2. Lower the temperature of the intermediate obtained in step S1 to -2 to 2℃, and then add a 30% sulfuric acid aqueous solution dropwise. During the addition process, control the temperature not to exceed 20℃. After the addition is complete, raise the temperature to 65℃ and react for 2 hours.

[0028] S3. Adjust the pH of the product obtained in step S2 to 3-4 with sodium hydroxide aqueous solution, then quench the excess potassium peroxymonosulfate complex salt with saturated sodium sulfite solution, concentrate the methanol, cool to 5-10℃ for recrystallization, filter, and vacuum dry the obtained solid at 50℃ to obtain the final product o-carboxybenzaldehyde.

[0029] The beneficial effects of this invention are:

[0030] The method for preparing o-carboxybenzaldehyde provided by this invention can effectively reduce synthesis costs, avoid the use of dangerous and toxic reagents, and effectively reduce the generation of industrial waste. The process of this invention is simple, easy to operate, uses inexpensive and readily available raw materials, and has a high yield, which is conducive to large-scale industrial production. Attached Figure Description

[0031] Figure 1 The 1H NMR spectrum of o-carboxybenzaldehyde prepared in Example 1;

[0032] Figure 2 The carbon NMR spectrum of o-carboxybenzaldehyde prepared in Example 1. Detailed Implementation

[0033] The present invention will be further described in detail below with reference to embodiments, so that those skilled in the art can implement it based on the description.

[0034] It should be understood that terms such as “having,” “comprising,” and “including” as used herein do not exclude the presence or addition of one or more other elements or combinations thereof.

[0035] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available. For examples where specific conditions are not specified, conventional conditions or conditions recommended by the manufacturer are followed. For reagents or instruments whose manufacturers are not specified, they are all commercially available products.

[0036] This invention provides a method for preparing o-carboxybenzaldehyde, which involves oxidation under alkaline conditions using potassium persulfate compound salt, followed by hydrolysis under acidic conditions to obtain the final product. The method specifically includes the following steps:

[0037] S1. The intermediate is prepared by reacting phthalide with potassium persulfate complex salt and base in a polar protic solvent. This intermediate does not require separation and purification.

[0038] S2. The intermediate obtained in step S1 is hydrolyzed with a strong protic acid aqueous solution to obtain the product o-carboxybenzaldehyde.

[0039] The reaction route is as follows:

[0040]

[0041] The reaction mechanism is as follows:

[0042]

[0043] In a preferred embodiment, the alkali in step S1 is any one of sodium ethoxide, potassium tert-butoxide, sodium tert-pentoxide, and sodium methoxide, more preferably sodium methoxide.

[0044] In a preferred embodiment, the polar protic solvent used in step S1 is any one of methanol, ethanol, isopropanol, and tert-butanol, more preferably methanol.

[0045] In a preferred embodiment, the reaction time in step S1 can be 6-12 hours, for example, 6, 8, 10, 12 hours or any value formed by any two of them, more preferably 8 hours.

[0046] In a preferred embodiment, the molar ratio of alkali to phthalide in step S1 is 4.5:1 to 4.05:1, for example, it can be 4.5:1, 4.3:1, 4.2:1, 4.1:1, 4.05:1 or any value formed by any two of them, more preferably 4.2:1;

[0047] In a preferred embodiment, the volume of the polar protic solvent in step S1 is 5 to 15 times that of phthalide, for example, it can be 5, 7, 9, 11, 13, 15 times or any value formed by any two of them, more preferably 10 times.

[0048] In a preferred embodiment, the molar ratio of potassium persulfate complex salt to phthalide in step S1 is 1.5:1 to 1.05:1, for example, it can be 1.5:1, 1.3:1, 1.2:1, 1.1:1, 1.05:1 or any value formed by any two of them, more preferably 1.2:1.

[0049] In a preferred embodiment, the strong protic acid in step S2 is any one of sulfuric acid, hydrochloric acid, and trifluoroacetic acid, more preferably sulfuric acid.

[0050] In a preferred embodiment, the mass fraction of the strong protic acid aqueous solution in step S2 is 10% to 40%, for example, it can be 10%, 20%, 30%, 40% or any value between any two of them, more preferably 30%.

[0051] In a preferred embodiment, the volume of the strong protic acid aqueous solution is 5 to 8 times that of phthalide, for example, it can be 5, 6, 7, 8 times or any value formed by any two of them, more preferably 6 times.

[0052] In a preferred embodiment, the reaction temperature in step S2 can be 50-70°C, for example, 50°C, 60°C, 65°C, 70°C or any value formed by any two of them, more preferably 65°C.

[0053] In a preferred embodiment, the reaction time in step S2 can be 1-3 hours, for example, 1, 1.5, 2, 2.5, 3 hours or any value formed by any two of them, more preferably 2 hours.

[0054] In a preferred embodiment, the method for preparing the o-carboxybenzaldehyde further includes the following steps:

[0055] S3. Adjust the pH of the product obtained in step S2 to 3-4 with sodium hydroxide aqueous solution, then quench the excess potassium peroxymonosulfate complex salt with saturated sodium sulfite solution, cool and recrystallize, filter, and vacuum dry to obtain the final product o-carboxybenzaldehyde.

[0056] In a preferred embodiment, the method for preparing o-carboxybenzaldehyde includes the following steps:

[0057] S1. The intermediate is prepared by reacting phthalide with potassium persulfate complex salt and base in a polar protic solvent for 6-12 hours.

[0058] S2. Add the intermediate obtained in step S1 to an aqueous solution of a strong protic acid and react at 50-70℃ for 1-3 hours to obtain the product;

[0059] S3. Adjust the pH of the product obtained in step S2 to 3-4 with sodium hydroxide aqueous solution, then quench the excess potassium peroxymonosulfate complex salt with saturated sodium sulfite solution, concentrate the methanol, cool to 5-10℃ for recrystallization, filter, and vacuum dry the obtained solid to obtain the final product o-carboxybenzaldehyde.

[0060] The above is the general concept of the present invention. Detailed embodiments are provided below to further illustrate the present invention.

[0061] Example 1

[0062] A method for preparing o-carboxybenzaldehyde includes the following steps:

[0063] Step 1: Preparation of intermediates:

[0064]

[0065] Add 6.7L of methanol to a 20L three-necked flask, then add phthalide (670g, 5mol). After the addition is complete, cool to below 0℃. Slowly add sodium methoxide (1134g, 21mol) in batches, carefully controlling the temperature not to exceed 10℃ during the addition process. After the addition is complete, maintain the temperature at 0℃ for 30 minutes, then allow it to naturally warm to room temperature for another 30 minutes. Cool to below 0℃ in an ice bath, then slowly add potassium persulfate complex salt (3689g, 6mol) in batches, carefully controlling the temperature not to exceed 10℃ during the addition process. After the addition is complete, remove the ice bath and allow it to naturally warm to room temperature for 8 hours. After the TLC reaction is complete, no separation or purification is required; proceed directly to the next step.

[0066] Step 2: Preparation of o-carboxybenzaldehyde

[0067]

[0068] Cool the product solution obtained in step 1 to about 0°C. Slowly add 4.02L of 30wt% sulfuric acid aqueous solution to the product solution. During the addition process, be careful to control the temperature not to exceed 20°C. After the addition is complete, raise the temperature to 65°C and react for 2 hours.

[0069] After the TLC reaction was complete, the pH was adjusted to 3-4 with a 5wt% sodium hydroxide aqueous solution. Then, 126g of sodium sulfite was added to quench excess potassium peroxymonosulfate. After concentrating to remove methanol, the system temperature was slowly lowered to 5-10℃, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was washed with ice water to remove salt. After vacuum drying at 50℃, 685g of o-carboxybenzaldehyde (white solid) was obtained, with a yield of 91.25%. The NMR spectrum of the product is shown below. Figure 1 (H NMR spectrum) and Figure 2 As shown in the (carbon NMR spectrum), the NMR data are as follows:

[0070] 1 H NMR (400MHz, DMSO-d6):

[0071] δ13.09(s,2H),7.66-7.70(m,2H),7.57-7.61(m,2H).

[0072] 13 C NMR (101MHz, DMSO-d6):

[0073] δ169.17,133.30,131.25,128.82,40.57,40.36,40.15,39.94,39.73,39.52,39.31

[0074] Example 2

[0075] A method for preparing o-carboxybenzaldehyde includes the following steps:

[0076] Step 1: Preparation of intermediates:

[0077]

[0078] Add 3.35 L of potassium tert-butoxide to a 20 L three-necked flask, followed by phthalide (670 g, 5 mol). After the addition is complete, cool the flask to below 0 °C. Slowly add potassium tert-butoxide (2272 g, 20.25 mol) in batches, carefully controlling the temperature to not exceed 10 °C during the addition process. After the addition is complete, maintain the temperature at 0 °C for 30 min, then allow the temperature to rise naturally to room temperature for another 30 min. Cool the flask to below 0 °C in an ice bath, then slowly add potassium persulfate complex salt (3228 g, 5.25 mol) in batches, carefully controlling the temperature to not exceed 10 °C during the addition process. After the addition is complete, remove the ice bath and allow the flask to rise naturally to room temperature for 6 h. After the TLC reaction is complete, no separation or purification is required; proceed directly to the next step.

[0079] Step 2: Preparation of o-carboxybenzaldehyde

[0080]

[0081] Cool the product solution obtained in step 1 to about 0°C. Slowly add 3.85L of 30wt% sulfuric acid aqueous solution to the product solution. During the addition process, be careful to control the temperature not to exceed 20°C. After the addition is complete, raise the temperature to 65°C and react for 2 hours.

[0082] After the TLC reaction was complete, the pH was adjusted to 3-4 with a 5wt% sodium hydroxide aqueous solution. Then, 126g of sodium sulfite was added to quench the excess potassium peroxymonosulfate. After the methanol was concentrated, the system temperature was slowly lowered to 5-10℃, and a white solid precipitated out. The solid was filtered, and the filter cake was washed with ice water to remove salt. The solid was then dried under vacuum at 50℃ to obtain 645g of o-carboxybenzaldehyde as a white solid, with a yield of 85.92%.

[0083] Example 3

[0084] A method for preparing o-carboxybenzaldehyde includes the following steps:

[0085] Step 1: Preparation of intermediates:

[0086]

[0087] Add 10L of ethanol to a 20L three-necked flask, then add phthalide (670g, 5mol). After the addition is complete, cool to below 0℃. Slowly add sodium ethoxide (1530g, 22.5mol) in batches, carefully controlling the temperature not to exceed 10℃ during the addition process. After the addition is complete, maintain the temperature at 0℃ for 30 minutes, then allow it to naturally warm to room temperature for another 30 minutes. Cool to below 0℃ in an ice bath, then slowly add potassium persulfate complex salt (4605g, 7.5mol) in batches, carefully controlling the temperature not to exceed 10℃ during the addition process. After the addition is complete, remove the ice bath and allow it to naturally warm to room temperature for 12 hours. After the TLC reaction is complete, no separation or purification is required; proceed directly to the next step.

[0088] Step 2: Preparation of o-carboxybenzaldehyde

[0089]

[0090] Cool the product solution obtained in step 1 to about 0°C. Slowly add 4.20L of 30wt% sulfuric acid aqueous solution to the product solution. During the addition process, be careful to control the temperature not to exceed 20°C. After the addition is complete, raise the temperature to 65°C and react for 2 hours.

[0091] After the TLC reaction was complete, the pH was adjusted to 3-4 with a 5wt% sodium hydroxide aqueous solution. Then, 126g of sodium sulfite was added to quench the excess potassium peroxymonosulfate. After the methanol was concentrated, the system temperature was slowly lowered to 5-10℃, and a white solid precipitated out. The solid was filtered, and the filter cake was washed with ice water to remove salt. The solid was then dried under vacuum at 50℃ to obtain 680g of o-carboxybenzaldehyde as a white solid, with a yield of 90.58%.

[0092] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details.

Claims

1. A method for preparing o-carboxybenzaldehyde, characterized in that, Includes the following steps: S1. The intermediate is prepared by reacting phthalide with potassium persulfate complex salt and base in a polar protic solvent. The chemical structural formula of the intermediate is shown below: ； S2. Hydrolyze the intermediate obtained in step S1 with a strong protic acid aqueous solution to obtain the product o-carboxybenzaldehyde. The base in step S1 is any one of sodium ethoxide, potassium tert-butoxide, sodium tert-amyloxide, and sodium methoxide.

2. The method for preparing o-carboxybenzaldehyde according to claim 1, characterized in that, The polar protic solvent used in step S1 is any one of methanol, ethanol, isopropanol, and tert-butanol.

3. The method for preparing o-carboxybenzaldehyde according to claim 1, characterized in that, The molar ratio of alkali to phthalide in step S1 is 4.5:1 to 4.05:

1.

4. The method for preparing o-carboxybenzaldehyde according to claim 1, characterized in that, The volume ratio of the polar protic solvent to phthalide in step S1 is 5~15:1, and the molar ratio of the potassium persulfate complex salt to phthalide in step S1 is 1.5:1~1.05:

1.

5. The method for preparing o-carboxybenzaldehyde according to claim 1, characterized in that, The strong protic acid in step S2 is any one of sulfuric acid, hydrochloric acid, or trifluoroacetic acid.

6. The method for preparing o-carboxybenzaldehyde according to claim 1, characterized in that, The mass fraction of the strong protic acid aqueous solution in step S2 is 10%~40%, and the volume of the strong protic acid aqueous solution is 5~8 times that of phthalide.

7. The method for preparing o-carboxybenzaldehyde according to any one of claims 1-6, characterized in that, It also includes the following steps: S3. Adjust the pH of the product obtained in step S2 to 3-4 with sodium hydroxide aqueous solution, then quench the excess potassium peroxymonosulfate complex salt with saturated sodium sulfite solution, cool and recrystallize, filter, and vacuum dry to obtain the final product o-carboxybenzaldehyde.

8. The method for preparing o-carboxybenzaldehyde according to claim 7, characterized in that, Includes the following steps: S1. The intermediate is prepared by reacting phthalide with potassium persulfate complex salt and base in a polar protic solvent for 6-12 hours. S2. Add the intermediate obtained in step S1 to an aqueous solution of a strong protic acid and react at 50-70℃ for 1-3 hours to obtain the product; S3. Adjust the pH of the product obtained in step S2 to 3-4 with sodium hydroxide aqueous solution, then quench the excess potassium peroxymonosulfate complex salt with saturated sodium sulfite solution, concentrate the methanol, cool to 5-10℃ for recrystallization, filter, and vacuum dry the obtained solid to obtain the final product o-carboxybenzaldehyde.

9. The method for preparing o-carboxybenzaldehyde according to claim 8, characterized in that, Includes the following steps: S1. Add phthalide to methanol solvent, then add sodium methoxide. During the feeding process, pay attention to controlling the temperature not to exceed 10℃. After the feeding is completed, react at 0℃ for 30 minutes. Then, the temperature is naturally raised to room temperature and reacted for 30 minutes. The temperature is then lowered to below 0°C in an ice bath. Potassium persulfate complex salt is added in batches. During the feeding process, the temperature should be controlled not to exceed 10°C. After the feeding is completed, the temperature is naturally raised to room temperature and reacted for 8 hours to obtain the intermediate. S2. Lower the temperature of the intermediate obtained in step S1 to -2 to 2℃, and then add a 30% sulfuric acid aqueous solution dropwise. During the addition process, control the temperature not to exceed 20℃. After the addition is complete, raise the temperature to 65℃ and react for 2 hours. S3. Adjust the pH of the product obtained in step S2 to 3-4 with sodium hydroxide aqueous solution, then quench the excess potassium peroxymonosulfate complex salt with saturated sodium sulfite solution, concentrate the methanol, cool to 5-10℃ for recrystallization, filter, and vacuum dry the obtained solid at 50℃ to obtain the final product o-carboxybenzaldehyde.

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