Process for the preparation of bromo-piperonylic carboxylic acids and uses thereof

Abstract

The present application relates to the field of medicine synthesis, and discloses a preparation method and application of brominated piperonal carboxylic acid, wherein the brominated piperonal carboxylic acid compound is prepared from o-vanillin as a starting material through acetyl protection, bromination reaction, deprotection and demethylation reaction, cyclization reaction and Pinnick oxidation reaction.No longer through a brominated piperonal intermediate, and without using a live LDA reagent low-temperature lithiation reaction, the safety and stability are greatly improved.The deprotection and demethylation reaction is carried out in one pot, and the use of boron tribromide and other reagents is avoided;finally, the oxidation step from aldehyde to acid avoids using traditional silver oxide or potassium permanganate oxidation, and adopts Pinnick oxidation, which is economic, environmental protection and cost reduction, and greatly improves the yield.The whole has the advantages of easy-to-obtain raw materials, short steps, mild reaction conditions, low production cost, environmental protection, high yield and high purity, and can meet the high quality requirements of pharmaceutical products.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine synthesis, in particular to a preparation method and application of brominated piperonyl carboxylic acid. BACKGROUND

[0002] Aromatic benzo[c]phenanthridine alkaloids are alkaloid components in many traditional Chinese medicines, which have antiviral, antimalarial, antifungal and antitumor effects, and are widely concerned and studied. For example, sanguinarine (SA), chelerythrine (CHE), nitidine chloride (NC), etc.

[0003] The benzo[c]phenanthridine skeleton is mainly composed of a phenanthridine ring (A, B, C ring) and a benzene ring (D ring), and its chemical synthesis method can be divided according to the order of constructing the above-mentioned A-D four rings. In the prior art, the last construction of the B ring or the C ring is the most common.

[0004]

[0005] The brominated piperonyl carboxylic acid compound is a key intermediate for constructing the B ring of the benzo[c]phenanthridine skeleton of sanguinarine, chelerythrine, nitidine chloride and the like.

[0006]

[0007] At present, the synthesis strategies of the brominated piperonyl carboxylic acid compound mainly include the following two types:

[0008] The first type is via brominated piperonyl ring:

[0009] The brominated piperonyl carboxylic acid is prepared from the brominated piperonyl ring as a starting material, via LDA / THF-78℃ lithiation and Kolbe-Schmitt reaction CO2 carboxylation. The yield is uncertain by using the active LDA reagent and low-temperature lithiation reaction, and the brominated piperonyl ring needs to be prepared separately. Sit et al. (BOMC 2004), yield 81% (literature compound 19); AstraZeneca company Ple et al. (JMC 2004), yield 72% (literature compound 73); AstraZeneca company WO2003008409A1, yield not disclosed; Ning et al. (Advanced Synthesis & Catalysis 2017), yield only 59% (literature compound 4j-1). The brominated piperonyl ring raw material is not easy to prepare, the selectivity of the brominated piperonyl ring prepared from the piperonyl ring is poor, the main product is the ortho-brominated piperonyl ring, and there are isomers, which are difficult to separate; the LDA reagent cost is high in the second step of carboxylation, the LDA is easy to pull the hydrogen on the piperonyl ring, the reaction purity is poor, which leads to low yield, and it is not suitable for industrial production.

[0010] The second type, via 6-bromohomosalen:

[0011] Bernardo et al. (JMC 2008), 6-bromohomosalen (literature compound 9) in acetonitrile, 0.1 eq silver nitrate / NaOH solution oxidation to prepare bromohomosalen carboxylic acid (literature compound 21), yield 98%, purity unknown.

[0012] Bristol-Myers Squibb WO1998038991A1, 3-step reaction of demethylation of bromo-o-vanillin by boron tribromide, cyclization by dibromomethane / KF, oxidation by potassium permanganate to prepare bromohomosalen carboxylic acid (literature compound 16 is methyl ester), 3-step reaction yield is 97%, 31%, 53% respectively. The route is shown in the following formula:

[0013]

[0014] The oxidation reaction uses expensive reagent silver nitrate; potassium permanganate oxidation will destroy the homosalen ring, resulting in low yield and poor selectivity; the raw material of bromo-o-vanillin is not easy to obtain, and the price of boron tribromide demethylation is high.

[0015] In the above-mentioned second type of synthesis strategy, 6-bromohomosalen (CAS 72744-54-8) needs to be prepared first.

[0016] 6-bromohomosalen is prepared by cyclization reaction of 6-bromo-2,3-dihydroxybenzaldehyde with dibromomethane, potassium carbonate, CuO, DMF, yield 62% (Zeitschrift fuer Naturforschung, Teil B: Anorganische Chemie, Organische Chemie 1986); KF / DMF, yield 31% (Bristol-Myers Squibb WO1998038991A1). The yield is low, and the purity of the product is unknown.

[0017] In summary, the disadvantages of the above two types of methods in the prior art are as follows:

[0018] The first type, via bromohomosalen, needs to use the active LDA reagent for lithiation reaction at -78°C, which is not suitable for industrial scale-up, and the process operation safety and stability cannot be guaranteed; bromohomosalen needs to be prepared separately.

[0019] The second type, via oxidation of 6-bromohomosalen, uses silver mirror reaction reagent, which is expensive, needs additional separation operation step to further recover silver salt, and is not suitable for industrial scale-up; or uses potassium permanganate oxidation, which destroys the homosalen ring, resulting in low yield and poor selectivity.

[0020] Therefore, it is necessary to develop a synthetic route of brominated piperonal carboxylic acid with easy availability of raw materials, short preparation process, mild reaction conditions, low production cost, environmental protection, high yield and high purity. SUMMARY

[0021] In order to solve the above technical problems, the present application provides a preparation method of brominated piperonal carboxylic acid and its use. The present application uses o-vanillin as a starting material to obtain compound b by acetyl protection, obtains compound c by bromination, obtains compound d by deprotection and demethylation, obtains 6-bromopiperonal e by cyclization reaction, and finally obtains brominated piperonal carboxylic acid compound II by Pinnick oxidation reaction. The synthetic strategy of the present application is through the 6-bromopiperonal intermediate instead of the brominated piperonal intermediate, without low-temperature lithiation reaction with the active reagent LDA, the operation safety is greatly improved, and it is suitable for industrial scale production. The deprotection and demethylation reaction of the present application is carried out in one pot, avoiding the use of expensive reagents such as boron tribromide, the reaction conditions are mild, the reaction can be carried out smoothly without high temperature, and the product purity is high; the cyclization reaction of the present application uses potassium fluoride / DMF, not only the raw material is easy to obtain, but also the yield is greatly improved, more than 90%; the last step of the present application is the oxidation of aldehyde to acid using Pinnick oxidation, using economical and environmental oxidation reagent, the yield is more than 70%, at the same time avoiding the use of expensive reagents such as silver nitrate and silver oxide in silver mirror reaction, without additional silver salt separation and recovery operation, avoiding the use of potassium permanganate and other oxidizing agents, not only the conditions are mild, but also the yield is high and the product purity is high, suitable for industrial production.

[0022] The specific technical scheme of the present application is as follows:

[0023] In the first aspect, the present application provides a preparation method of brominated piperonal carboxylic acid, which specifically comprises the following steps: using o-vanillin as a starting material to obtain compound b by acetyl protection, obtaining compound c by bromination, obtaining compound d by deprotection and demethylation, obtaining e by cyclization reaction, and finally obtaining brominated piperonal carboxylic acid compound II by Pinnick oxidation reaction, the synthetic route is as follows:

[0024]

[0025] As a preferred, the acetyl protection is carried out at a reaction temperature of 0-40℃ in a reaction solvent a with o-vanillin, acetic anhydride and organic base a.

[0026] Further preferably, in the acetyl protection step, the organic base a is selected from pyridine, triethylamine and diisopropylamine; the reaction solvent a is selected from one or more of the same organic base as the organic base a, dichloromethane and toluene; the reaction temperature is 10-30℃; and the equivalent ratio of o-vanillin to acetic anhydride is 1:1-1.5.

[0027] As preferred, the bromination reaction is carried out at a reaction temperature of 10-40 °C in a reaction solvent b with compound b and bromine in the presence of catalyst b.

[0028] Further preferred, catalyst b is KBr; reaction solvent b is selected from one or more of water, acetic acid, chloroform; the reaction temperature of the bromination reaction is 25-30 °C; the equivalent ratio of compound b, bromine, catalyst b is 1:1.1-1.3:3.0-3.5.

[0029] As preferred, the deprotection and demethylation reaction is carried out at a reaction temperature of 50-100 °C in a reaction solvent c with compound c in the presence of Lewis acid catalyst c.

[0030] Further preferred, Lewis acid catalyst c is selected from one or more of polyphosphoric acid, sulfuric acid, methanesulfonic acid, ferric chloride, aluminum chloride, tin chloride, acetic anhydride, boron trifluoride etherate, trifluoroacetic acid, trifluoroacetic anhydride and PPE; reaction solvent c is selected from one or more of dichloroethane, toluene and chlorobenzene; the reaction temperature of the deprotection and demethylation reaction is 50-70 °C; the equivalent ratio of compound c and Lewis acid catalyst c is 1:2.5-4.0.

[0031] As preferred, the cyclization reaction is carried out at a reaction temperature of 100-160 °C in a reaction solvent d with compound d and dibromomethane in the presence of catalyst d.

[0032] Further preferred, catalyst d is selected from one or more of KF, potassium carbonate, CsF; reaction solvent d is selected from one or more of DMF, NMP, DMAC; the reaction temperature of the cyclization reaction is 120-140 °C; the equivalent ratio of compound d, dibromomethane, catalyst d is 1:1.0-1.5:3.0-7.0.

[0033] As preferred, the Pinnick oxidation reaction is carried out at a reaction temperature of 10-50 °C in a reaction solvent e with compound e and oxidant sodium chlorite, buffer salt potassium dihydrogen phosphate or sodium dihydrogen phosphate, hypochlorous acid scavenger e.

[0034] Further preferred, hypochlorous acid scavenger e is selected from one or more of DMSO, H2O2; reaction solvent e is selected from one or more of acetonitrile, water, t-butanol; the reaction temperature of the Pinnick oxidation reaction is 20-30 °C; the equivalent ratio of compound e, oxidant sodium chlorite, buffer salt potassium dihydrogen phosphate or sodium dihydrogen phosphate, hypochlorous acid scavenger e is 1:1.0-1.5:0.2-0.5:2.0-4.0.

[0035] Pinnick oxidation can selectively oxidize aldehyde to the corresponding carboxylic acid. The present application found that Pinnick oxidation also has good reaction effect for substrates with steric hindrance effect. When selecting a type of hypochlorous acid scavenger, the reactivity of the compound, side reactions and the effect on the target reaction should be considered. The present application found through experiments that compared with other hypochlorous acid scavengers, only DMSO or hydrogen peroxide as sodium hypochlorite scavenger has the best effect in the reaction system of the present application. In addition, the amount of NaH2PO4 and sodium chlorite will also affect the purity and yield of the product, among which sodium chlorite needs to be added in excess, because sodium chlorite will decompose under light or in the presence of impurities (such as Fe 2+ and Fe 3+ ); and the present application also found that sodium chlorite must be dissolved in water or buffer during the reaction process, otherwise the purity and yield of the product are not ideal.

[0036] In the second aspect, the bromo-piperonaline carboxylic acid prepared by the above preparation method is applied to the chemical synthesis of sanguinarine.

[0037] Compared with the prior art, the present application has the following beneficial effects:

[0038] (1) The present application uses 6-bromo-piperonaline intermediate instead of bromo-piperonaline intermediate, and does not need to react with the active reagent LDA at low temperature, so the operation safety is greatly improved, and it is suitable for industrial scale-up production.

[0039] (2) In the deprotection and demethylation step (from compound c to compound d) of the present application, the deprotection and demethylation reaction is carried out in one pot, avoiding the use of reagents such as boron tribromide; in the cyclization reaction, potassium fluoride is used instead of potassium carbonate or cesium carbonate, not only the raw material is easy to obtain, but also the yield is greatly improved, more than 90%; in the last step of aldehyde to acid oxidation, Pinnick oxidation is used, which uses economical and environmentally friendly oxidation reagents, the yield is more than 70%, at the same time, the use of expensive reagents such as silver nitrate and silver oxide in silver mirror reaction is avoided, without additional silver salt separation and recovery operation, and the use of potassium permanganate and other oxidizing agents is avoided, which not only has mild conditions, but also has no risk of heavy metal pollution.

[0040] (3) The synthesis route of the present application has the advantages of easy-to-obtain raw materials, short steps, mild reaction conditions, low production cost, environmental protection, high yield and high purity, which can meet the high quality requirements of pharmaceutical products. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 HPLC spectrum of compound b obtained in step 1-1 of example 1;

[0042] Figure 2 HPLC spectrum of compound c obtained in step 1-2 of example 1;

[0043] Figure 3 HPLC profile of compound d obtained in Example 1, step 1-3;

[0044] Figure 4 HPLC profile of compound e obtained in Example 2;

[0045] Figure 5 HPLC profile of compound II obtained in Example 3. DETAILED DESCRIPTION

[0046] The application will be further described in conjunction with the examples.

[0047] General example

[0048] A method for preparing bromo-piperine ring carboxylic acid using o-vanillin as a starting material, specifically comprising the following steps:

[0049] o-vanillin is acetylated to obtain compound b, which is subjected to bromination to obtain compound c, and then deprotection and demethylation to obtain compound d, which is subjected to cyclization to obtain e, and finally Pinnick oxidation to obtain bromo-piperine ring carboxylic acid compound II.

[0050]

[0051] Specifically:

[0052] The acetylation is carried out at a reaction temperature of 0-40°C (preferably 10-30°C) using o-vanillin, acetic anhydride and organic base a (preferably pyridine, triethylamine, diisopropylamine, etc.) in reaction solvent a (preferably the same organic base as a, dichloromethane, toluene, etc.). The equivalent ratio of o-vanillin to acetic anhydride is 1:1-1.5.

[0053] The bromination is carried out at a reaction temperature of 10-40°C (preferably 25-30°C) using compound b and bromine in the presence of catalyst b (preferably KBr) in reaction solvent b (preferably water, acetic acid, chloroform, etc.). The equivalent ratio of compound b to bromine to catalyst b is 1:1.1-1.3:3.0-3.5.

[0054] The deprotection and demethylation is carried out at a reaction temperature of 50-100°C (preferably 50-70°C) using compound c and Lewis acid catalyst c (preferably polyphosphoric acid, sulfuric acid, methanesulfonic acid, ferric chloride, aluminum chloride, tin chloride, acetic anhydride, boron trifluoride etherate, trifluoroacetic acid, trifluoroacetic anhydride and PPE, etc.) in reaction solvent c (preferably dichloroethane, toluene and chlorobenzene, etc.). The equivalent ratio of compound c to Lewis acid catalyst c is 1:2.5-4.0.

[0055] The cyclization reaction is carried out at a reaction temperature of 100-160°C (preferably 120-140°C) for compound d and dibromomethane, catalyst d (preferably KF, potassium carbonate, CsF, etc.) in reaction solvent d (preferably DMF, NMP, DMAC, etc.). Among them, the equivalent ratio of compound d, dibromomethane, catalyst d is 1:1.0-1.5:3.0-7.0.

[0056] The Pinnick oxidation reaction is carried out at a reaction temperature of 10-50°C (preferably 20-30°C) for compound e and oxidant sodium chlorite, buffer salt potassium dihydrogen phosphate or sodium dihydrogen phosphate, hypochlorite scavenger e (preferably DMSO, H2O2, etc.) in reaction solvent e (preferably acetonitrile, water, tert-butyl alcohol, etc.). Among them, the equivalent ratio of compound e, oxidant sodium chlorite, buffer salt potassium dihydrogen phosphate or sodium dihydrogen phosphate, hypochlorite scavenger e is 1:1.0-1.5:0.2-0.5:2.0-4.0. Specific embodiments

[0058] Example 1: Preparation of 6-bromo-2,3-dihydroxybenzaldehyde

[0059]

[0060] 1-1 Acetyl protection: A reaction bottle is added with pyridine 265 mL, o-vanillin 500 g, acetic anhydride 340 g, and reacted at 25°C for 3 h. HPLC shows that there is no raw material left. Directly filter, add 400 mL of HCl solution to the mother liquor, filter, and combine the filter cakes. Dry to obtain 595 g of white solid, with HPLC purity of 99.63% ( Figure 1 ), and a yield of 93.2%.

[0061] 1-2 Bromination reaction: A reaction bottle is added with H2O 500 mL, KBr 98 g, stirred and dissolved, added with bromine 49.4 g, stirred for 10 min and dissolved, added with 50 g of b at room temperature, without obvious warming phenomenon, reacted at 25°C for 8 h, directly filtered and dried to obtain 68.2 g of orange solid powder c, with HPLC purity of 97.60% ( Figure 2 ), and a yield of 97.0%.

[0062] 1-3 Deprotection and demethylation: A reaction bottle is added with 50 g of c, dichloroethane 300 mL, stirred and dissolved, added with 61 g of AlCl3 in batches, control the temperature T<35°C, stirred at room temperature for 1 h, the system is dark green, heated to 70°C and reacted for 30 h. Directly post-treat, add 200 mL of water to the reaction system, control T<35°C, vacuum concentration to remove dichloroethane, add 500 mL of ethyl acetate, filter, separate layers, water layer is extracted with ethyl acetate twice, combine the organic layers, activated carbon is refluxed and decolorized, filtered and concentrated to dryness, vacuum dried to obtain 38.4 g of yellow-green solid d, with HPLC purity of 95.12%Figure 3 ), yield 96.6%.

[0063] The following are examples of preparing 6-bromo-2,3-dihydroxybenzaldehyde using different reagents and process parameters:

[0064] Example 1-1a / 1-1b

[0065]

[0066]

[0067] Example 1-2a / 1-2b

[0068]

[0069] Example 1-3a / 1-3b

[0070] Serial number Compound c Lewis acid catalyst c Reaction solvent c Temperature Product HPLC purity, yield 1-3a 50g Trifluoroacetic acid 62.6 g Toluene 250 mL 60℃ 38.2g 98.65％，96.1％ 1-3b 50g Iron trichloride 110 g Chlorobenzene 350 mL 65℃ 39.2g 91.13％，98.6％

[0071] Example 2: Preparation of 6-bromopiperonal

[0072]

[0073] Cyclization reaction: 60 g of compound d, DMF 350 mL, stirring solution, adding KF 80.4 g, dibromomethane 62.6 g, heating to 130 °C for 6 h, HPLC tracking until no raw material is left. Direct post-treatment, drop 1 L water into the reaction system, filter and dry to get 59.8 g of black solid compound e, as shown in Figure 4 HPLC purity 96.89%, yield 94.4%.

[0074] The following are examples of preparing 6-bromopiperonal using different reagents and process parameters:

[0075]

[0076] Example 3: Preparation of bromopiperonic acid ring

[0077]

[0078] Oxidation: In a reaction flask, 50 g of compound e, acetonitrile 150 mL, H2O 150 mL, DMSO 34.1 g, NaH2PO4 7.8 g were added in sequence, mechanically stirred, placed in an ice water bath, and NaClO2 aqueous solution (80% sodium chlorite 32.2 g in 500 ml water) was added dropwise, controlling T < 25 °C, after dropping, 20 °C reaction for 5 h, HPLC tracking until no raw material was left. Direct post-treatment, 50 mL of 10% dilute hydrochloric acid was added, stirred for 1 h, 400 mL of ethyl acetate was added, filtered, separated, the water layer was extracted with ethyl acetate, the combined organic phase was washed with saturated brine, decolorized with activated carbon, and concentrated to give a dark yellow solid 39.6 g, as shown in Figure 5

[0079] The following are examples of preparing bromo-piperonal carboxylic acid using different reagents and process parameters:

[0080]

[0081] Preparation of 6-bromopiperonal in Comparative Example 1

[0082] Comparative Example 1-1: Synthetic method and data recorded in the reference (BMS WO1998038991A1)

[0083] 6-bromo-2,3-dihydroxybenzaldehyde was cyclized with dibromomethane in KF, CsF, DMF solvent; or in NaOH, phase transfer catalyst, water. The specific steps are as follows:

[0084] 6-bromo-2,3-dihydroxybenzaldehyde (1.82 g, 8.39 mmol) was dissolved in DMF (20 ml), and dibromomethane (1.57 g, 9.00 mmol) and KF (2.44 g, 42.00 mmol) were added. The reaction mixture was heated to 100 °C for 2 h, and TLC was used to monitor the completion of the reaction. After cooling to room temperature, dichloromethane and water were used for extraction, and the organic layer was washed with water, dried, and concentrated to give 6-bromopiperonal (2.62 mmol, yield 31%).

[0085] In the cyclization reaction of Example 2 of the present application, the optimal reaction conditions were determined, and the yield was increased to 90%, which was much higher than the literature yield of 31% (Comparative Example 1).

[0086] Comparative Example 1-2:

[0087] In a reaction flask, c (1 g, 3.66 mmol), 48% aqueous hydrogen bromide solution (10 mL, 10V) were added in sequence, and reacted at 100 °C for 4 h. HPLC analysis showed only 18% product, and there were a large number of impurity peaks, and 8% debromination impurities were produced.

[0088] Comparative Example 1-3:​

[0089] In a reaction flask, c (0.1 g, 0.366 mmol), DMF (1 mL, 10V), LiCl (0.046 g, 1.1 mmol) were added successively, and the mixture was reacted at 110°C for 4h. HPLC analysis showed that only 35% of the product was obtained, and 10% of debromination impurities were generated.

[0090] Comparative Examples 1-4:

[0091] In a reaction flask, c (0.1 g, 0.366 mmol), methanesulfonic acid (1 mL, 10V), methionine (0.03 g, 0.183 mmol) were added successively, and the mixture was reacted at 30°C for 4h. HPLC analysis showed that only 8% of the product was obtained, and the reaction was impure.

[0092] The deprotection and demethylation reactions under different conditions are shown in the following table:

[0093]

[0094]

[0095] Comparative Examples 1-2 to 1-4 are the same as Example 1, and compound d (6-bromopiperonal) is prepared from compound c by one-pot method. As can be seen from the above table, the main difference between Comparative Examples 1-2 to 1-4 and Example 1 is that different demethylation reagents are used, and the results show that the purity of 6-bromopiperonal prepared in Comparative Examples 1-2 to 1-4 is low, because the Lewis acid such as aluminum chloride complexes the protected aldehyde group, and the reaction conditions are mild, which can reduce the generation of debromination impurities.

[0096] In summary, in the deprotection and demethylation steps of Example 1 of the present application, a specific Lewis acid is used for one-pot deprotection and demethylation reaction, avoiding the use of boron tribromide and other reagents, and the reaction conditions are mild, which can reduce the generation of debromination impurities, and improve the purity and yield of the product.

[0097] Comparative Example 2: Oxidation of 6-bromopiperonal to prepare bromopiperolyl carboxylic acid

[0098] Comparative Example 2-1: Synthetic method and data recorded in reference (BMS WO1998038991A1)

[0099] 6-bromopiperonal potassium permanganate oxidation: Potassium permanganate (1.03 g, 6.55 mmol) was dissolved in 25 ml water, 6-bromopiperonal (0.60 g, 2.62 mmol) was dissolved in acetone (25 ml) and slowly added to the potassium permanganate aqueous solution, stirred at room temperature for 24 h, TLC monitored the reaction was complete. The reaction was quenched with 5% sodium sulfide (100 ml). Added 10 ml of concentrated hydrochloric acid, extracted with ethyl acetate, the organic layer was dried and concentrated to give bromopiperonic acid (1.39 mmol, yield 53%).

[0100] Comparative Example 2-2: Reference literature synthesis method and data (Bernardo, JMC 2008)

[0101] 6-bromopiperonal in acetonitrile solution, 0.1 M silver nitrate solution and 10% NaOH solution were added, and the reaction was carried out at room temperature for 16 h, and filtered through Celite 545. The acetonitrile solvent was removed by vacuum concentration, and the organic layer was washed with 1 M HC1, dried and concentrated to give bromopiperonic acid (yield 98%).

[0102] Comparative Example 2-3: Experimental results of synthesizing bromopiperonic acid from 6-bromopiperonal under different oxidation conditions

[0103] Hydrogen peroxide: In the reaction bottle, compound e (0.5 g, 2.18 mmol), hydrogen peroxide (5 mL, 10V), K2CO3(1.81 g, 13.08 mmol) were added in turn, and stirred at 30°C with a magnetic stirrer. HPLC showed no product formation, but ring-opening by-products were formed.

[0104] Oxone: In the reaction bottle, compound e (0.5 g, 2.18 mmol), oxone (2.68 g, 4.36 mmol), water (5 mL, 10V) were added in turn, and stirred at 30°C with a magnetic stirrer. HPLC showed no product formation, but ring-opening by-products were formed.

[0105] Comparative Example 2-4: Pinnick oxidation, Pinnick oxidation was carried out using different oxidation reagents or process parameters from Example 3, Example 3a and Example 3b, respectively. The process differences and experimental results are shown in the following table:

[0106]

[0107]

[0108] The Pinnick oxidation reaction can selectively oxidize aldehydes to the corresponding carboxylic acids. It is found in the present application that the Pinnick oxidation also has good reaction effect for substrates with steric hindrance effect. When selecting the type of hypochlorous acid scavenger, the reactivity of the compound, the side reaction and the influence on the target reaction should be considered. As can be seen from the data comparison in the above table, compared with the use of DMSO or hydrogen peroxide as the hypochlorous acid scavenger in Examples 3 / 3a and 3b, when the commonly used hypochlorous acid scavengers 2-methyl-2-butene, resorcinol and sulfamic acid are used in Comparative Examples 2-4(a)~(c) respectively, it is found that neither the product purity nor the yield effect is ideal, so it can be known that only DMSO or hydrogen peroxide as the sodium hypochlorite scavenger is suitable for the reaction system of the present application. Further, as can be known from Comparative Example 2-4(d), if the amount of NaH2PO4 is not appropriate, it will also lead to the decrease of the product purity and yield; in addition, as can be known from Comparative Example 2-4(e), it is also found that sodium chlorite must be added in excess, otherwise it will also affect the purity and yield of the product, and the reason may be that sodium chlorite will decompose under light or in the presence of impurities (such as Fe 2+ and Fe 3+ ), and it is usually slightly excessive; finally, as can be known from Comparative Example 2-4(f), it is also found in the present application that the sodium chlorite must be dissolved in water or buffer during the reaction process, otherwise the product purity and yield are not ideal. In summary, the present application selects the most suitable hypochlorous acid scavenger and reaction conditions in combination with the characteristics of the substrate, ensures the conversion rate, and avoids the generation of side products such as debromination impurities, and the oxidation yield is >70%.

[0109] In summary, in the oxidation step from aldehyde to acid in Example 3 of the present application, Pinnick oxidation is used, and an economic and environmentally friendly oxidizing agent is used, which not only reduces the cost, but also greatly improves the yield. Avoiding the use of traditional silver oxide or potassium permanganate oxidation, there is no need for additional silver salt separation and recovery operation, and avoiding the use of oxidizing agents such as potassium permanganate, not only the conditions are mild, but also there is no risk of heavy metal pollution.

[0110] The raw materials and equipment used in the present application are conventional raw materials and equipment in the art unless otherwise specified; the methods used in the present application are conventional methods in the art unless otherwise specified.

[0111] The above is only a preferred embodiment of the present application, and does not limit the present application in any way, and any simple modification, change and equivalent transformation of the above embodiment according to the technical essence of the present application still belongs to the protection scope of the technical solution of the present application.

Claims

1. A method for preparing a bromopiperidine carboxylic acid, characterized in that: 1) Compound b was obtained by acetyl protection of o-vanillin as the starting material; 2) Compound b and bromine are brominated in reaction solvent b at 10-40℃ under KBr catalysis in an equivalent ratio of 1:1.1-1.3:3.0-3.5 to give compound c; reaction solvent b is one or more of water, acetic acid and chloroform. 3) Compound c is reacted with trifluoroacetic acid or aluminum trichloride in reaction solvent c at an equivalence ratio of 1:2.5-4 to undergo deprotection and demethylation reactions, yielding compound d; the reaction solvent c for trifluoroacetic acid is toluene, and the reaction solvent c for aluminum trichloride is dichloroethane. 4) Compound d, dibromomethane, and catalyst d are cyclized in reaction solvent d at 100-160℃ in an equivalence ratio of 1:1-1.5:3-7 to obtain compound e; reaction solvent d is one or more of methylpyrrolidone (NMP) and dimethylacetamide (DMAC); 5) Compound e, oxidant sodium chlorite, buffer salt potassium dihydrogen phosphate or sodium dihydrogen phosphate, and hypochlorous acid scavenger e are reacted in reaction solvent e at 10-50℃ using an equivalent ratio of 1:1-1.5:0.2-0.5:2-4 to undergo Pinnick oxidation reaction. Hypochlorous acid scavenger e is one or more of dimethyl sulfoxide (DMSO) and H2O2; The reaction solvent e is one or more of acetonitrile, water, and tert-butanol; The overall synthesis route is as follows:

2. The preparation method according to claim 1, characterized in that: The acetyl protection is carried out by reacting o-vanillin with acetic anhydride and organic base a in reaction solvent a at a reaction temperature of 0-40°C.

3. The preparation method according to claim 2, characterized in that: The organic base a is selected from pyridine, triethylamine, and diisopropylamine; The reaction solvent a is selected from one or more of the following: organic base a, dichloromethane, and toluene.

4. The preparation method according to claim 2, characterized in that: The reaction temperature for acetyl protection is 10-30℃; The equivalent ratio of o-vanillin to acetic anhydride is 1:1-1.

5.

5. The preparation method according to claim 1, characterized in that: The reaction temperature for the bromination reaction is 25-30℃.

6. The preparation method according to claim 1, characterized in that: The reaction temperature for the deprotection and demethylation reactions is 50-70℃.

7. The preparation method according to claim 1, characterized in that: The catalyst d is selected from one or more of KF, potassium carbonate and CsF.

8. The preparation method according to claim 1, characterized in that: The cyclization reaction is carried out at a temperature of 120-140℃.

9. The preparation method according to claim 1, characterized in that: The reaction temperature for the Pinnick oxidation reaction is 20-30℃.

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