A method for synthesizing berberine hydrochloride

Abstract

The application relates to the field of organic chemistry and specifically discloses a synthesis method of berberine hydrochloride. The synthesis method of the berberine hydrochloride comprises the following steps: S1, bromo-piperonyl ethylamine and o-veratraldehyde are subjected to reductive amination to synthesize an intermediate II; S2, the intermediate II is subjected to Suzuki coupling reaction with an organic boron compound under the catalysis of a palladium metal organic compound to synthesize an intermediate III; S3, the intermediate III is subjected to amino chlorination with an organic chloride to synthesize an intermediate IV; S4, the intermediate IV is subjected to intramolecular atom transfer radical addition and intramolecular Friedel-Crafts alkylation tandem reaction in a mixed solvent under the catalysis of a copper catalyst to synthesize an intermediate V; and S5, the intermediate V is subjected to oxidative aromatization reaction with iodine under the catalysis of a base to synthesize the berberine hydrochloride. The synthesis process is simpler, the reaction condition is easier to control, the yield is high, and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic chemistry, and particularly relates to a synthesis method of berberine hydrochloride. BACKGROUND

[0002] Berberine, also known as coptis, is a natural benzyl isoquinoline alkaloid. The chemical name is 5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-benzodioxolane[5,6-alpha]quinolizine hydrochloride dihydrate, the molecular formula is C 20 H 18 ClNO 4 • 2H2O, and the structural formula is as follows:

[0003] .

[0004] Currently, plant extraction and chemical synthesis are two main ways to obtain berberine. In 1969, Kametani et al. first completed the total synthesis of berberine iodide salt, but there are problems of low reaction yield and difficult raw materials. Later, many different methods for the total synthesis of berberine have been developed, mainly including palladium-catalyzed enol arylation, rhodium-catalyzed carbon hydrogen activation, nitrile-stabilized ammonium ylide, silver-catalyzed cyclization, cuprous iodide-catalyzed oxidation-reduction A3 reaction, Friedel-Crafts cyclization, trifluoroacetic anhydride-promoted decarboxylation elimination, etc. The core of these methods is around the synthesis of B and C rings in the structure of berberine, and the structures of B and C rings are as follows:

[0005] However, these methods are complex in operation, the reaction conditions are not easy to control, and there are challenges in selectivity, yield and environmental friendliness.

[0006] Nowadays, the synthesis of berberine in industry is still the synthesis process of Northeast Pharmaceutical General Factory, for example, Chinese patent application CN1312250A discloses a preparation method of coptis and its salt, which starts from two raw materials of piperonylamine and o-veratraldehyde, first performs reductive amination, then salt cyclization, and finally adjusts the pH to form berberine hydrochloride. However, this route has problems of using toxic cyanide, autoclave, difficult operation, etc. Chen Cheng et al. (Organic Chemistry, 2016, 36, 1426-1430) used sodium borohydride reduction instead of active nickel and hydrogen high-pressure reduction reaction to prepare N-2 ',3 '-dimethoxybenzyl piperonylamine, which is a key intermediate for preparing berberine hydrochloride. The reaction time is as long as 10 hours, after the reaction is completed, methanol needs to be removed by reduced pressure distillation, then N-2 ',3 '-dimethoxybenzyl piperonylamine oil is obtained by dissolving in ethyl ether, extraction, washing, drying, filtering and concentrating. However, the use of ethyl ether as a solvent in this method is dangerous and not suitable for industrial production.

[0007] Therefore, it is urgent to develop a new synthetic process of berberine hydrochloride, which is simpler, easier to control, less dangerous and has high yield. SUMMARY

[0008] The present application provides a synthetic method of berberine hydrochloride, which uses copper-catalyzed intramolecular atom transfer radical addition and intramolecular Friedel-Crafts alkylation in series to synthesize two key ring systems of berberine hydrochloride, and has simple preparation method and high yield.

[0009] To achieve the above object, the technical scheme adopted by the present application is as follows:

[0010] The present application provides a synthetic method of berberine hydrochloride, which includes the following steps:

[0011] S1, bromo-piperonylamine and o-veratraldehyde undergo reductive amination reaction to synthesize intermediate II;

[0012] S2, intermediate II undergoes Suzuki coupling reaction with organic boron compound under the catalysis of palladium metal organic matter to synthesize intermediate III;

[0013] S3, intermediate III undergoes amino-chlorination reaction with organic chloride to synthesize intermediate IV;

[0014] S4, intermediate IV undergoes intramolecular atom transfer radical addition and intramolecular Friedel-Crafts alkylation in series under the catalysis of copper catalyst in mixed solvent to synthesize intermediate V;

[0015] S5, intermediate V undergoes oxidative aromatization reaction with iodine under the catalysis of base to synthesize berberine hydrochloride.

[0016] Preferably, the temperature in the synthesis reaction of intermediate II in step S1 is 0-30℃.

[0017] Preferably, the palladium metal organic matter in step S2 includes at least one of tetrakis(triphenylphosphine)palladium, bis(diphenylphosphino)ferrocene dichloropalladium, bis(triphenylphosphine)palladium dichloride and palladium acetate.

[0018] Further preferably, the palladium metal organic matter is tetrakis(triphenylphosphine)palladium.

[0019] Preferably, the organic boron compound in step S2 includes vinylboronic acid pinacol ester and / or vinylboronic acid.

[0020] Further preferably, the organic boron compound is vinylboronic acid pinacol ester.

[0021] Preferably, the organic chloride in step S3 includes N-chlorosuccinimide and / or tert-butyl hypochlorite.

[0022] Further preferably, the organic chloride is N-chlorosuccinimide.

[0023] Preferably, the copper catalyst in step S4 comprises cuprous chloride and / or copper chloride.

[0024] Further preferably, the copper catalyst in step S4 consists of cuprous chloride and copper chloride, and the molar ratio of the cuprous chloride to the copper chloride is 1:2-4.

[0025] Most preferably, the molar ratio of the cuprous chloride to the copper chloride is 1:2.

[0026] Preferably, the mixed solvent in step S4 comprises at least one of tetrahydrofuran, water and acetic acid.

[0027] Further preferably, the volume ratio of the tetrahydrofuran, water and acetic acid in step S4 is 1:2:2.

[0028] Most preferably, the volume ratio of the tetrahydrofuran, water and acetic acid in step S4 is 1:1.5-4:1.5-4.

[0029] Preferably, the base in step S5 comprises at least one of potassium acetate, sodium acetate, potassium carbonate, sodium carbonate and potassium phosphate.

[0030] Preferably, the reaction condition of the intramolecular atom transfer radical addition and intramolecular Friedel-Crafts alkylation tandem reaction in step S4 is 4h-8h in time and 20℃-50℃ in temperature.

[0031] Preferably, an organic solvent is also needed in step S5, and the organic solvent comprises at least one of ethanol, methanol and isopropanol.

[0032] Compared with the prior art, the present application has the following beneficial effects:

[0033] The present application provides a new synthetic route of berberine hydrochloride, which uses copper-catalyzed intramolecular atom transfer radical addition and intramolecular Friedel-Crafts alkylation tandem to synthesize the B and C ring systems of berberine hydrochloride, and the operation process is simpler, the reaction condition is easier to control, the yield is high, and the route is suitable for industrial production. DETAILED DESCRIPTION

[0034] The present application will be described in detail below through specific examples, so that the technical scheme of the present application is easier to understand and master, but the present application is not limited thereto, and the described examples are only a part of the examples of the present application, but not all the examples.

[0035] The endpoints of the ranges and any values disclosed herein are not limited to the precise values recited as the exact dimensions are not considered critical for the purposes of the application. The ranges disclosed herein are understood to include all values and subranges therebetween unless otherwise indicated. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0036] All other embodiments obtained by those of ordinary skill in the art based on the embodiments disclosed in the present application without creative effort shall fall within the scope of the present application. The experimental methods described in the following examples are conventional methods unless otherwise specified, and the reagents and materials can be obtained commercially unless otherwise specified.

[0037] The present application uses bromo-piperonyl ethylamine and o-veratraldehyde as raw materials to synically berberine hydrochloride through 5 steps, and the specific synthesis method and the structural formula of the specific compound I, intermediate II, intermediate III, intermediate IV, intermediate V and compound VI (i.e. berberine hydrochloride) are as follows:

[0038] .

[0039] In the process of synthesizing intermediate V, first, intermediate IV is subjected to intramolecular atom transfer radical addition to the double bond under copper catalysis to form intermediate IVa, and then intermediate IVa is subjected to intramolecular Friedel-Crafts alkylation under copper catalysis to form intermediate V.

[0040] The structural formula of intermediate IVa in the present application is as follows: .

[0041] Example 1

[0042] 1.1 Synthesis of intermediate II

[0043] Compound I (bromopiperonyl ethylamine) (100 g, 411 mmol) was dissolved in 200 mL of ethanol and cooled to 0 °C to obtain an ethanol solution of bromopiperonyl ethylamine. O-veratraldehyde (69.6 g, 419 mmol) was dissolved in 100 mL of ethanol to obtain an ethanol solution of o-veratraldehyde. The ethanol solution of o-veratraldehyde was added dropwise into the ethanol solution of bromopiperonyl ethylamine while maintaining the internal temperature at 5 °C. The reaction mixture was then warmed to 25 °C and stirred for 3 h. HPLC monitoring of the disappearance of the bromopiperonyl ethylamine starting material indicated that the Schiff base preparation was complete. The reaction mixture was cooled to 0 °C and then added dropwise to a solution of sodium borohydride (11.7 g, 308 mmol) in 100 mL of tetrahydrofuran while maintaining the internal temperature at 10 °C. After the dropwise addition was complete, the reaction mixture was warmed to 25 °C and stirred for 8 h. HPLC monitoring of the disappearance of the Schiff base intermediate indicated that the reaction was complete. The reaction mixture was cooled to 0 °C and quenched with the addition of an aqueous ammonium chloride solution while maintaining the internal temperature below 25 °C. After the reaction was complete, most of the ethanol and tetrahydrofuran were removed by concentration, and the aqueous phase was extracted three times with DCM (150 mL x 3). The combined organic phases were dried with the addition of anhydrous sodium sulfate, filtered, and concentrated to obtain 153.6 g of a yellow solid crude product with a purity of 98% and a yield of 95%.

[0044] Related test data: LCMS (ESI) m / z calcd for: C 18 H 20 BrNO4: 393. Found: 394 (M+1) + NMR (400 MHz, CDCl3) δ 7.11-6.62 (m, 5H), 5.92 (s, 2H), 3.86 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 2.84 (s, 4H).

[0045] 1.2 Synthesis of Intermediate III

[0046] Intermediate II (153.6 g, 390 mmol) and tetrakis triphenylphosphine palladium (1.3 g, 1.15 mmol) were dissolved in DME 780 mL, replaced with nitrogen three times, then stirred at room temperature for 20 min under nitrogen protection to obtain a mixed solution. K2CO3(53.9 g, 390 mmol), water 156 mL, and vinyl boronic acid pinacol ester (60 g, 390 mmol) were added to the mixed solution, replaced with nitrogen three times again, and then the reaction mixture was protected with nitrogen. After the reaction mixture was heated to reflux for 10 h, the reaction raw material was monitored to disappear by HPLC, then cooled to room temperature, extracted with dichloromethane (200 mL x 3) three times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated. 300 mL of n-heptane was added to the slurry, and a yellowish solid 119.9 g was obtained by filtration, with a purity of 99.2% and a yield of 90%.

[0047] Related test data: LCMS (ESI) m / z calcd for: C 20 H 23 NO4: 341. Found: 342. NMR (400 MHz, CDCl3) δ 7.42 (dd, 1H) 7.33-6.28 (m, 5H), 6.06 (s, 2H), 5.66 (dd, 1H), 5.74 (dd, 1H), 3.84 (s, 2H), 3.81 (s, 3H), 3.73 (s, 3H), 2.65 (s, 4H).

[0048] 1.3 Synthesis of Intermediate IV

[0049] Intermediate III (119.9 g, 351 mmol) was dissolved in DCM 1 L, cooled to 0°C, and NCS (total mass of three batches 47.8 g, 358 mmol) was added in three batches. Stirring was performed at 0°C for 2.5 h until the raw material was monitored to disappear by HPLC, and the reaction was stopped to obtain a reaction solution. The reaction solution was poured into 300 mL of saturated brine to quench, and the organic phase was separated. The aqueous phase was extracted with DCM (200 mL x 3) three times, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated. A yellow solid crude product 129 g was obtained, with a purity of 97.8% and a yield of 98%.

[0050] Related test data: LCMS (ESI) m / z calcd for: C 20 H 22 ClNO4: 375. Found: 376 (M+1) +NMR (400 MHz, CDCl3) δ 7.49(dd, 1 H) 7.33 -6.36 (m, 5H),6.17 (s,2H),5.82(dd, 1 H), 5.63(dd, 1 H), 3.99(S,2H), 3.85(S,3H), 3.91(S,3H), 2.55 (S,4H)。

[0051] 1.4 Synthesis of Intermediate V

[0052] Intermediate IV (129 g, 344 mmol) was dissolved in mixed solvent 1.3 L (volume ratio-tetrahydrofuran: water: acetic acid = 1 : 2: 2), replaced with nitrogen three times, and cuprous chloride (340 mg, 3.44 mmol), copper chloride (925 mg, 6.88 mmol) were added under nitrogen protection. Replaced with nitrogen three times again, warmed to 50 ℃ and stirred for 5 h, HPLC monitored the disappearance of raw materials, and the reaction was stopped. Lowered to room temperature, concentrated tetrahydrofuran and acetic acid, added concentrated ammonia water 85 mL and stirred for 1 h. Then extracted with dichloromethane (200 mL x 3) three times. The organic phase was combined, dried with anhydrous sodium sulfate, filtered, and concentrated. Added methanol 400 mL for recrystallization. Obtained light yellow crystals 96.8 g, purity 98.8 %, yield 83 %.

[0053] Related test data: LCMS (ESI) m / z calcd for : C 20 H 21 NO4:339. Found: 340 (M+1) + NMR (400 MHz, CDCl3) δ 6.87 (d, 1H), 6.79 (d, 1H), 6.73 (s, 1H), 6.59 (s,1H), 5.92 (s, 2H), 4.26 (d, 1H), 3.85 (s, 6H), 3.53 (d, 2H), 3.25-3.14 (m,2H), 3.14-3.05 (m, 1H), 2.81 (dd, 1H), 2.70-2.54 (m, 2H).

[0054] 1.5 Synthesis of Berberine Hydrochloride

[0055] Intermediate V (96.8 g, 285 mmol) was dissolved in ethanol 1.2 L, potassium acetate (62.9 g, 641 mmol) was added, the temperature was raised to 45 °C, iodine (total mass of five batches 144 g, 570 mmol) was added in five batches, the temperature was maintained for 1.5 h of stirring, HPLC monitoring of the disappearance of the starting material. The reaction was quenched by adding 10% aqueous sodium thiosulfate solution 300 mL, the ethanol was concentrated. 30% aqueous sodium hydroxide solution 100 mL was added, stirred for 10 min. The aqueous phase was extracted three times with DCM (250 mL x 3), the combined organic phase was extracted once with 1 M hydrochloric acid 600 mL, twice with water (200 mL x 2). The combined aqueous phase was concentrated to obtain berberine hydrochloride yellow solid 101.5 g, yield 96%, purity 99.2%.

[0056] Related test data: LCMS (ESI) m / z calcd for [C 20 H 18 NO4] + :336. found 336。NMR(400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.95 (s, 1H), 8.21 (d, 1H), 8.00 (d, 1H),7.80(s, 1H), 7.09 (s, 1H), 6.17 (s, 2H), 4.94 (t, 2H), 4.09 (s, 3H), 4.07 (s,3H), 3.21 (t, 2H)。

[0057] Example 2

[0058] The synthesis steps of intermediate V are as follows:

[0059] Intermediate IV (129 g, 344 mmol) was dissolved in a mixed solvent 1.3 L (volume ratio - tetrahydrofuran: water: acetic acid = 1:2:2), replaced with nitrogen three times, added cuprous chloride (340 mg, 3.44 mmol), copper chloride (1.39 g, 10.32 mmol) under nitrogen protection. Replace with nitrogen three times again, raise the temperature to 50 °C and stir for 5 h, HPLC monitoring of the disappearance of the starting material, stop the reaction. Lower the temperature to room temperature, concentrate tetrahydrofuran and acetic acid, add concentrated ammonia water 85 mL and stir for 1 h. Then extract three times with dichloromethane (200 mL x 3). The combined organic phase was dried by adding anhydrous sodium sulfate, filtered and concentrated. Recrystallized with methanol 400 mL. Obtained light yellow crystals 96.1 g, purity 98.4%, yield 82.4%.

[0060] Example 3

[0061] The synthesis steps of intermediate V are as follows:

[0062] The intermediate IV (129 g, 344 mmol) was dissolved in a mixed solvent 1.3 L (volume ratio-tetrahydrofuran: water: acetic acid = 1:2:2), replaced with nitrogen three times, and then cuprous chloride (340 mg, 3.44 mmol) and copper chloride (1.85 g, 13.76 mmol) were added under the protection of nitrogen. The nitrogen was replaced three times again, and the temperature was increased to 50°C for stirring for 5 h. The disappearance of the raw material was monitored by HPLC, and the reaction was stopped. After being cooled to room temperature, tetrahydrofuran and acetic acid were concentrated, 85 mL of concentrated ammonia was added, and stirred for 1 h. Then dichloromethane (200 mL x 3) was added and extracted three times. The organic phase was combined, dried with anhydrous sodium sulfate, filtered, and concentrated. 400 mL of methanol was added for recrystallization. 97.6 g of light yellow crystals were obtained, with a purity of 98.5%, and a yield of 83.7%.

[0063] Comparative Example 1

[0064] The synthesis steps of intermediate V are as follows:

[0065] The intermediate IV (129 g, 344 mmol) was dissolved in a mixed solvent 1.3 L (volume ratio-tetrahydrofuran: water: acetic acid = 1:2:2), replaced with nitrogen three times, and then cuprous chloride (340 mg, 3.44 mmol) and copper chloride (1.85 g, 13.76 mmol) were added under the protection of nitrogen. The nitrogen was replaced three times again, and the temperature was increased to 50°C for stirring for 5 h. The disappearance of the raw material was monitored by HPLC, and the reaction was stopped. After being cooled to room temperature, tetrahydrofuran and acetic acid were concentrated, 85 mL of concentrated ammonia was added, and stirred for 1 h. Then dichloromethane (200 mL x 3) was added and extracted three times. The organic phase was combined, dried with anhydrous sodium sulfate, filtered, and concentrated. 400 mL of methanol was added for recrystallization. 97.6 g of light yellow crystals were obtained, with a purity of 98.5%, and a yield of 83.7%.

[0066] Comparative Example 2

[0067] The synthesis steps of intermediate V are as follows:

[0068] Intermediate IV (129 g, 344 mmol) was dissolved in mixed solvent 1.3 L (volume ratio - tetrahydrofuran: water: acetic acid = 1:2:2), replaced with nitrogen three times, and cuprous chloride (340 mg, 3.44 mmol), cupric chloride (462 mg, 3.44 mmol) was added under the protection of nitrogen. Replaced with nitrogen three times again, and stirred at 50 ℃ for 5 h, and the disappearance of the raw material was monitored by HPLC, and the reaction was stopped. Reduced to room temperature, concentrated tetrahydrofuran and acetic acid, and added concentrated ammonia water 85 mL and stirred for 1 h. Then extracted three times with dichloromethane (200 mL x 3). Combined the organic phase, added anhydrous sodium sulfate for drying, filtered, and concentrated. Added methanol 400 mL for recrystallization. Obtained light yellow crystals 71.2 g, purity 95.9 %, yield 61 %.

[0069] Comparative Example 3

[0070] The synthesis steps of intermediate V are as follows:

[0071] Intermediate IV (129 g, 344 mmol) was dissolved in mixed solvent 1.3 L (volume ratio - tetrahydrofuran: water: acetic acid = 1:2:2), replaced with nitrogen three times, and cuprous chloride (340 mg, 3.44 mmol), cupric chloride (462 mg, 3.44 mmol) was added under the protection of nitrogen. Replaced with nitrogen three times again, and stirred at 50 ℃ for 5 h, and the disappearance of the raw material was monitored by HPLC, and the reaction was stopped. Reduced to room temperature, concentrated tetrahydrofuran and acetic acid, and added concentrated ammonia water 85 mL and stirred for 1 h. Then extracted three times with dichloromethane (200 mL x 3). Combined the organic phase, added anhydrous sodium sulfate for drying, filtered, and concentrated. Added methanol 400 mL for recrystallization. Obtained light yellow crystals 71.2 g, purity 95.9 %, yield 61 %.

[0072] Finally, it should be noted that the above content is only used to illustrate the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. A method for synthesizing berberine hydrochloride, characterized in that: Includes the following steps: S1, bromopiperidine, undergoes a reductive amination reaction with o-veratrol to synthesize intermediate II; S2 and intermediate II undergo a Suzuki coupling reaction with an organoboron compound under the catalysis of palladium organometallic compounds to synthesize intermediate III; S3, intermediate III undergoes an aminochlorination reaction with an organochloride to synthesize intermediate IV; S4 and intermediate IV undergo intramolecular atom transfer radical addition and intramolecular Friedel-Crafts alkylation tandem reactions in a mixed solvent under the catalysis of a copper catalyst to synthesize intermediate V; S5 and intermediate V undergo oxidative aromatization with iodine under the catalysis of a base to synthesize berberine hydrochloride; The palladium organometallic compound mentioned in step S2 is selected from at least one of tetratriphenylphosphine palladium, bis(diphenylphosphine)ferrocene palladium dichloride, bistriphenylphosphine palladium dichloride, and palladium acetate; The organoboron compound mentioned in step S2 is selected from pinacol vinylboronate and / or vinylboric acid; The organochloride mentioned in step S3 is selected from N-chlorosuccinimide and / or tert-butyl hypochlorite; The copper catalyst described in step S4 is composed of cuprous chloride and cupric chloride, wherein the molar ratio of cuprous chloride to cupric chloride is 1:2-4. The mixed solvent mentioned in step S4 is: tetrahydrofuran, water, and acetic acid; The volume ratio of the tetrahydrofuran, water, and acetic acid is 1:1.5-4:1.5-4.

2. The synthesis method according to claim 1, characterized in that: The alkali mentioned in step S5 is selected from at least one of potassium acetate, sodium acetate, potassium carbonate, sodium carbonate, and potassium phosphate.

3. The synthesis method according to claim 1, characterized in that: The reaction conditions for the intramolecular atom transfer radical addition and intramolecular Friedel-Crafts alkylation tandem reaction described in step S4 are: time 4h-8h, temperature 20℃-50℃.