CN112939848A - Preparation method of bupivacaine and intermediate (S) -2-piperidinecarboxylic acid thereof - Google Patents
Preparation method of bupivacaine and intermediate (S) -2-piperidinecarboxylic acid thereof Download PDFInfo
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Abstract
The invention discloses a bupivacaine and a preparation method of an intermediate (S) -2-piperidinecarboxylic acid thereof, wherein the intermediate (S) -2-piperidinecarboxylic acid is prepared by taking (R) -4-benzyl-2-oxazolidinone shown as a formula (I) as a chiral auxiliary agent through amidation, asymmetric alkylation, hydrolysis, cyclization and removal of auxiliary groups; the prepared (S) -2-piperidinecarboxylic acid is used as a raw material to prepare the local anesthetic drug (S) -bupivacaine. The method utilizes cheap and easily-obtained organic raw materials, and has the advantages of simple and convenient operation, mild reaction conditions, good stereoselectivity, high yield and the like.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a method for preparing bupivacaine and an intermediate (S) -2-piperidinecarboxylic acid thereof.
Background
Bupivacaine was first approved in swedish in 1999 and clinical trials have been completed in the us, europe, australia and new zealand and have been approved by the FDA in the united states. Bupivacaine is a long-acting local anesthetic, has dual effects of analgesia and anesthesia, is mainly used for surgical anesthesia and epidural block anesthesia, and can be used for various operations including lower limb operations of orthopedics, gynecology, urology and the like; can also be used for acute analgesia after operation or parturition, has low toxicity to heart, high safety and better clinical application range. Currently, the main methods for synthesizing bupivacaine are as follows: (1) synthesizing bupivacaine by a triphosgene method, taking 2-piperidinecarboxylic acid as a raw material, synthesizing the raw material through acyl chlorination, amidation, butylation and salification, and obtaining levobupivacaine through optical resolution; (2) the (S) -bupivacaine hydrochloride is obtained by using (S) -2-piperidinecarboxylic acid as a raw material, performing triphosgene chlorination, performing amidation with 2, 6-dimethylaniline, performing butyl bromination and salt formation. The synthesis method of bupivacaine reported in the literature has the defects of low yield, large environmental pollution, high cost and the like.
It is worth noting that (S) -2-piperidinecarboxylic acid is a key intermediate of local anesthetic bupivacaine, and the synthesis method mainly comprises the following steps:
in The literature (The Journal of organic chemistry, 2010, 75 (6): 2077-2080), chiral amide is used as a raw material, chiral N-iminopyridine salt is synthesized under The activation of trifluoromethanesulfonic anhydride, then phenyl is introduced under The action of Grignard reagent PhMgBr. LiBr, and (S) -2-piperidinecarboxylic acid is obtained through hydrogenation reduction, chiral auxiliary group removal, amino protection by trifluoroacetyl, phenyl oxidation and hydrolysis. The product of the synthetic route has good stereoselectivity, but the reaction steps are more complicated, and the synthetic route is not suitable for industrial production.
The literature (Organic Letters, 2000, 2 (2): 155-158) uses 3-hydroxypiperidine hydrochloride as raw material, and obtains N-Boc-piperidyl methyl ether through three-step reaction, and the N-Boc-piperidyl methyl ether is converted into unsaturated piperidine derivative under the catalysis of catalyst S-BuLi/TMEDA, and then is subjected to (S) -BINAP-RuCl2Under the action of the catalyst, asymmetric catalytic hydrogenation reaction is carried out to obtain (S) -N-Boc-piperidine formic acid, and the target product is obtained by deprotection. This route requires the use of expensive chiral ligands and is costly.
The literature (Tetrahedron letters, 2002, 43 (5): 779-782) uses allyl alcohol derivative as raw material, and obtains unsaturated piperidine derivative through asymmetric epoxidation, ring opening and RCM reaction, and then obtains the target product (S) -N-Boc-piperidinecarboxylic acid through catalytic hydrogenation and oxidation. The route has high stereoselectivity, but the catalyst is expensive and has high production cost, so the route is not suitable for industrial production.
In the literature (Tetrahedron: Asymmetry, 2005, 16 (23): 3858-. The process has complex steps, harsh reaction conditions and low reaction yield.
The literature (Tetrahedron: Asymmetry, 2014, 25 (16-17): 1246-4Oxidizing, Wittig olefination, debenzylating, cyclizing to obtain piperidone, and finally amide reducing, KMnO4Oxidizing to obtain the (S) -2-piperidinecarboxylic acid. The method has more steps, fussy operation and low yield, and is difficult to realize large-scale industrial production.
In conclusion, the literature reports that the synthetic method of (S) -2-piperidinecarboxylic acid has the defects of difficult obtainment of starting materials, need of using expensive noble metal catalysts, complicated steps, low yield, high production cost and the like. Therefore, the development of a novel method for synthesizing (S) -2-piperidinecarboxylic acid, which is simple and convenient to operate, mild in reaction conditions, good in stereoselectivity and high in yield, has important research value and good application prospect.
Disclosure of Invention
The invention provides a bupivacaine and a preparation method of an intermediate (S) -2-piperidinecarboxylic acid thereof, wherein the (S) -2-piperidinecarboxylic acid is prepared by taking (R) -4-benzyl-2-oxazolidinone as a chiral auxiliary agent and performing amidation, asymmetric alkylation, hydrolysis, cyclization and chiral auxiliary group removal, and the prepared (S) -2-piperidinecarboxylic acid is used as a raw material to further prepare the local anesthetic (S) -bupivacaine.
The technical scheme provided by the invention for solving the technical problem is as follows:
a preparation method of (S) -2-piperidinecarboxylic acid specifically comprises the following steps:
step A: under the catalysis of alkali, (R) -4-benzyl-2-oxazolidinone shown in the formula (I) and a compound (II) are subjected to condensation reaction to generate a compound (III);
and B: carrying out asymmetric alkylation on the compound (III) and 1, 4-dihalobutane under the action of alkali to prepare a compound (IV);
and C: hydrolyzing, cyclizing and removing chiral auxiliary group from the compound (IV) to obtain (S) -2-piperidinecarboxylic acid shown in the formula (V);
wherein, X is respectively and independently Cl, Br or I.
Said
Is composed of
The invention also provides a preparation method of bupivacaine, which comprises the following steps of firstly, preparing (S) -2-piperidinecarboxylic acid shown in a formula (V) according to the preparation method of (S) -2-piperidinecarboxylic acid; then, through step (D): reacting (S) -2-piperidinecarboxylic acid shown in a formula (V) with acid in a solvent D to form salt, and performing amidation reaction with 2, 6-dimethylaniline after the acyl chlorination reaction to obtain a compound (VI); finally, the step (E): the compound (VI) and 1-bromobutane are subjected to substitution reaction under the action of alkali to prepare (S) -bupivacaine (VII);
in the step A, the base is sodium hydride, potassium tert-butoxide, sodium tert-amylate, n-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium hexamethyldisilazide or lithium hexamethyldisilazide; n-butyllithium is preferred.
In the step A, the mass ratio of the (R) -4-benzyl-2-oxazolidinone, the compound (II) and the alkali is 1.0: 1.0-1.5, preferably 1.0: 1.0-1.2: 1.1-1.3, and more preferably 1.0: 1.1: 1.2.
The solvent A of the condensation reaction is tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether; the volume consumption of the solvent A for condensation reaction is 6-15 mL/g based on the mass of the compound (II).
The condensation reaction is carried out under the reaction condition of-85 to-70 ℃ for 15 to 30 minutes, and then the temperature is increased to 15 to 40 ℃ for 2 to 8 hours. The reaction is carried out at 15-40 ℃ for 2-8 hours, and preferably at 20-30 ℃ for 3-5 hours.
The step A: under the catalysis of alkali, carrying out condensation reaction on (R) -4-benzyl-2-oxazolidinone shown in a formula (I) and a compound (II) to generate a compound (III), which specifically comprises the following steps: dissolving (R) -4-benzyl-2-oxazolidinone shown in a formula (I) in a solvent A, adding alkali under the protection of nitrogen, cooling the mixed solution to-85 to-70 ℃, dissolving a compound (II) in the solvent A, then dropwise adding the compound (II) into the mixed solution, reacting for 15-30 minutes at-85 to-70 ℃, naturally raising the temperature to 15-40 ℃, reacting for 2-8 hours, and after the reaction is finished, performing post-treatment to obtain a compound (III).
The post-treatment method of the condensation reaction comprises the following steps: after the condensation reaction is finished, quenching the reaction by glacial acetic acid, adding water, extracting by an organic solvent, combining organic phases, washing by water, concentrating the organic phase, separating by column chromatography, collecting eluent containing the target compound by taking a mixed solution of petroleum ether and ethyl acetate as an eluent, and evaporating the organic solvent to obtain a compound (III); the organic solvent includes, but is not limited to, dichloromethane.
In the step B, the base is n-butyllithium, tert-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium hexamethyldisilazide or lithium hexamethyldisilazide; lithium hexamethyldisilazide is preferred.
The amount ratio of the compound (III), 1, 4-dihalobutane and alkali is 1.0: 1.0 to 1.5, preferably 1.0: 1.1 to 1.3, and more preferably 1.0: 1.2.
The solvent B for the one-pot reaction is tetrahydrofuran, 2-methyltetrahydrofuran or diethyl ether.
The volume consumption of the solvent B for the one-pot reaction is 5-10 mL/g based on the mass of the compound (III).
The reaction conditions of the one-pot reaction are that the reaction is carried out for 30-60 minutes at-85 to-70 ℃, and then the temperature is increased to 15-40 ℃ for reaction for 2-8 hours; the reaction is carried out at 15-40 ℃ for 1-6 hours, and preferably at 20-30 ℃ for 3-4 hours.
The step B: the compound (III) and 1, 4-dihalobutane are subjected to asymmetric alkylation under the action of alkali to prepare a compound (IV), which specifically comprises the following steps: dissolving a compound (III) in a solvent B, adding alkali under the protection of inert gas, cooling to-85 to-70 ℃, adding 1, 4-dihalobutane, continuing to react for 30-60 minutes at-85 to-70 ℃, then heating to 15-40, reacting for 1-6 hours, and after the reaction is finished, carrying out post-treatment to obtain a compound (IV).
The post-treatment comprises the following steps: after the reaction is finished, quenching the reaction liquid by glacial acetic acid, adding water, extracting a water phase by an organic solvent, combining organic phases, concentrating, carrying out column chromatography separation, collecting eluent containing a target compound by taking a mixed solution of petroleum ether and ethyl acetate as an eluent, and evaporating the organic solvent to obtain a compound (IV); the organic solvent includes, but is not limited to, ethyl acetate.
The step C: the compound (IV) is hydrolyzed, cyclized and chiral auxiliary group is removed to prepare the (S) -2-piperidinecarboxylic acid shown in the formula (V), which specifically comprises the following steps: dissolving the compound (IV) in a solvent C, adding hydrogen peroxide and lithium hydroxide, reacting at 20-40 ℃ for 2-3 h, and after the reaction is finished, performing post-treatment to obtain the (S) -2-piperidinecarboxylic acid shown in the formula (V).
The compound (IV): hydrogen peroxide: the mass ratio of the lithium hydroxide is 1.0: 2.0-5.0, preferably 1.0: 2.5-3.5: 3.5-4.5; further preferably 1.0: 3.0: 4.0.
The hydrogen peroxide is added in the form of 30% hydrogen peroxide.
The post-treatment in the step C comprises the following specific steps: after the reaction is finished, adding a saturated sodium sulfite aqueous solution, concentrating to remove the solvent C, adjusting the pH of an aqueous layer to 1.5-2.5 with hydrochloric acid, extracting an aqueous phase with an organic solvent, adjusting the pH of the aqueous phase to 6-7, precipitating a solid, filtering, and drying to obtain the (S) -2-piperidinecarboxylic acid represented by the formula (V).
The reaction condition of the acyl chlorination reaction is 40-80 ℃ for 1-5 h, preferably 50-60 ℃ for 1-5 h.
The reaction condition of the amidation reaction is 50-60 ℃ for 1-6 h.
The reaction condition of the substitution reaction is 50-100 ℃ for 2-6 h.
The alkali in the substitution reaction is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate or sodium carbonate; potassium carbonate is preferred.
The following steps: compound (VI): 1-bromobutane: the ratio of the amount of the alkali is 1.0: 1.0 to 1.2: 1.0 to 1.5, preferably 1.0: 1.05 to 1.15: 1.1 to 1.3, and more preferably 1.0: 1.1: 1.2.
And the solvent E in the step E is tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, acetone, acetonitrile or dimethyl sulfoxide.
And the volume dosage of the solvent E in the step E is 3-5 mL/g based on the mass of the compound (VI).
The post-processing method of the step E comprises the following steps: after the reaction is finished, pouring the reaction liquid into ice water, stirring to generate white solid, and performing suction filtration to obtain (S) -bupivacaine.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method of the (S) -2-piperidinecarboxylic acid can obtain the (S) -2-piperidinecarboxylic acid which is the key chiral intermediate of the (S) -bupivacaine only by three steps, greatly improves the synthesis efficiency, and has the advantages of cheap and easily-obtained raw materials, short route, high yield, good stereoselectivity and the like.
The preparation method of (S) -bupivacaine provided by the invention is efficient, simple and convenient, good in atomic economy, low in production cost and good in market application prospect.
Detailed Description
The technical scheme of the invention is further specifically explained by the specific embodiment; however, the present invention is not limited to these examples.
Example 1 Synthesis of Compound (III)
Dissolving (R) -4-benzyl-2-oxazolidinone I (1.62g, 16mmol) in tetrahydrofuran (20mL), adding n-hexane solution of n-butyllithium (7.7mL, 19.2mmol, 2.5mol/L) at-78 ℃ under the protection of nitrogen, stirring at-78 ℃ for 30 minutes, adding tetrahydrofuran solution (25mL) of compound II (3.92g, 17.6mmol), continuing the reaction at the temperature for 30 minutes, and naturally raising the temperature to room temperature for reaction for 3 hours. After the reaction is finished, 2mL of glacial acetic acid is dripped to quench the reaction, 30mL of water is added to stir, dichloromethane is used for extraction (2X 100mL), an organic phase is collected, the organic phase is dried and concentrated, a crude product is purified by silica gel column chromatography, an eluent is petroleum ether and ethyl acetate (the volume ratio is 5: 1-3: 1), 5.3g of a light yellow oily liquid compound III is obtained after concentration, and the yield is 91%.
1H NMR(500MHz，Chloroform-d)δ7.92-7.74(m，4H)，7.36-7.19(m，5H)，5.13-5.00(m，2H)，4.70-4.66(m，1H)，4.42-4.21(m，2H)，3.25(dd，J＝13.6，3.2Hz，1H)，2.88(dd，J＝13.5，9.2Hz，1H)ppm.13C NMR(125MHz，Chloroform-d)δ167.73，166.62，153.53，134.71，134.26，132.11，129.45，129.06，127.48，123.64，67.25，55.10，41.72，37.50ppm。
Example 2 Synthesis of Compound (III)
Dissolving (R) -4-benzyl-2-oxazolidinone I (1g, 10mmol) in tetrahydrofuran (10mL), adding sodium hydride (480mg, 12mmol, content 60%) at-5 ℃ under nitrogen protection, stirring at 0 ℃ for 1h, adding a tetrahydrofuran solution (15mL) of compound II (2.45g, 11mmol), and naturally heating to room temperature for reaction for 5 h. After the reaction is finished, 1mL of glacial acetic acid is added dropwise to quench the reaction, 20mL of water is added, the mixture is stirred, dichloromethane is used for extraction (2X 80mL), an organic phase is collected, the organic phase is dried and concentrated, a crude product is purified by silica gel column chromatography, and an eluent is petroleum ether: ethyl acetate (volume ratio 5: 1-3: 1) was concentrated to give 3.13g of a pale yellow oily liquid compound III, 86% yield.
Example 3 Synthesis of Compound (III)
Dissolving (R) -4-benzyl-2-oxazolidinone I (1g, 10mmol) in tetrahydrofuran (10mL), adding potassium tert-butoxide (1.35g, 12mmol) at 0 ℃ under the protection of nitrogen, stirring at the temperature for 1h, adding a tetrahydrofuran solution (15mL) of compound II (2.45g, 11mmol), and naturally raising the temperature to room temperature for 5 h. After the reaction is finished, 20mL of water is added for quenching reaction, dichloromethane is used for extraction (2X 80mL), an organic phase is collected, the organic phase is dried and concentrated, a crude product is purified by silica gel column chromatography, an eluent is petroleum ether and ethyl acetate (the volume ratio is 5: 1-3: 1), and a light yellow oily liquid compound III3g is obtained after concentration, wherein the yield is 82%.
EXAMPLE 4 Synthesis of Compound (IV)
Compound III (1.82g, 5mmol) was dissolved in tetrahydrofuran (10mL), a solution of n-butyllithium in n-hexane (2.4mL, 6mmol, 2.5mol/L) was added at-78 deg.C under nitrogen, a solution of 1, 4-dibromobutane (1.2g, 5.5mmol) in tetrahydrofuran (5mL) was added after stirring at-78 deg.C for 30 minutes, and the reaction was continued at this temperature for 4 hours. After the reaction is finished, 10mL of water is added dropwise to quench the reaction, dichloromethane is used for extraction (3X 50mL), an organic phase is collected, the organic phase is dried and concentrated, a crude product is purified by silica gel column chromatography, and an eluent is petroleum ether: ethyl acetate (volume ratio 3: 1-1: 1) was concentrated to give 2.0g of compound IV as a yellow oil in 80% yield.
1H NMR(400MHz，D2O)δ1.22-1.28(m，2H)，1.81-1.95(m，4H)，3.00(dd，J＝13.6，3.2Hz，1H)，2.68(dd，J＝13.5，9.2Hz，1H)，3.52(t，J＝7.2Hz，2H)，4.16-4.24(m，1H)，4.41-4.48(m，1H)，4.70-4.81(m，2H)，7.21-7.28(m，5H)，7.81-7.91(m，4H)ppm。
The purity was 98% by HPLC area normalization method [ chromatographic conditions: chromatographic column Kromasil C18Column (4.6 mm. times.250 mm, 5 μm), mobile phase acetonitrile-water (volume ratio 30: 70), detection wavelength: 254nm, column temperature: 25 ℃, flow rate: 1.0 mL/min-1]。
Optical purity 98% [ chromatographic conditions: chiral column CHIRALPAK AD-H (250 mm. times.4.6 mm, 5 μm); mobile phase: n-hexane-isopropanol (volume ratio: 85: 15); detection wavelength: 254 nm; column temperature: 25 ℃; flow rate: 0.8 mL/min-1]。
Example 5 Synthesis of (S) -2-Piperidinecarboxylic acid represented by the formula (V)
The crude compound IV (2.7g) obtained in example 4 was dissolved in a mixed solution of tetrahydrofuran (12mL) and water (1.2mL), and 30% hydrogen peroxide solution (1.8g, 15mmol) and lithium hydroxide (0.5g, 20mmol) were added, respectively, and stirred at room temperature overnight, TLC showed completion of the reaction of the starting materials, saturated aqueous sodium sulfite solution was added, the tetrahydrofuran was concentrated to remove tetrahydrofuran, the pH of the aqueous layer was adjusted to 2 with 1mol/L hydrochloric acid, the aqueous phase was extracted with ethyl acetate (2 × 20mL), and then adjusted to 6-7 with saturated aqueous sodium bicarbonate solution, and a solid was precipitated, filtered, and dried to obtain (S) -2-piperidinecarboxylic acid V483 mg as a white solid in 75% yield.
the purity was 98% by HPLC area normalization method [ chromatographic conditions: chromatographic column Kromasil C18Column (4.6mm × 250mm, 5 μm), mobile phase: acetonitrile-water (volume ratio 70: 30), detection wavelength: 220nm, column temperature: 25 ℃, flow rate: 1.0 mL/min-1]。
Optical purity 98% [ chromatographic conditions: chiral column CHIRALPAK AD-H (250 mm. times.4.6 mm, 5 μm); mobile phase: n-hexane-isopropanol(volume ratio: 75: 25); detection wavelength: 220 nm; column temperature: 25 ℃; flow rate: 1.0 mL/min-1]。
Example 6 Synthesis of Compound (VI)
(S) -2-Piperidinecarboxylic acid (3.25g, 25mmol) and toluene (100mL) were mixed, and dry hydrogen chloride gas was introduced at room temperature until the solution was strongly acidic, to give a white solid. The reaction was then heated to 55 deg.C, N-dimethylformamide (1mL) was added dropwise, thionyl chloride (2.7mL, 37mmol) was added slowly dropwise, and stirring was continued at this temperature for 3 h. Cooling the reaction solution to room temperature, and introducing N2Residual thionyl chloride and hydrogen chloride gas were removed, the reaction solution was heated to 55 ℃, 2, 6-dimethylaniline (16mL, 125mmol) in toluene (6mL) was slowly added dropwise, and the reaction was continued for 3 hours after the dropwise addition was completed. Filtering, dissolving the filter cake in water (70mL), adjusting the pH to 4.0-5.0 by using 20% sodium hydroxide solution by mass fraction, extracting with toluene, separating out an aqueous phase, adjusting the pH of the aqueous phase to 11-12 by using 20% sodium hydroxide solution by mass fraction, extracting with ethyl acetate (3X 50mL), combining organic phases, drying, filtering, and concentrating under reduced pressure to obtain 5.2g (22.2mmol) of a white solid compound VI with the yield of 88%.
Melting point: 128-129 ℃ of the temperature,1H NMR(500MHz，CDCl3)δ8.26(s，1H)，7.08(d，J＝2.2Hz，3H)，3.41(m，1H)，3.19-3.07(m，1H)，2.84-2.71(m，1H)，2.23(s，6H)，2.07(m，1H)，1.91-1.78(m，2H)，1.73-1.58(m，2H)，1.57-1.43(m，2H)ppm.13C NMR(125MHz，CDCl3)δ172.3，135.0，133.6，128.0，126.9，60.6，45.7，30.3，25.9，23.9，18.4ppm。
the purity was 98% by HPLC area normalization method [ chromatographic conditions: chromatographic column Kromasil C18Column (4.6mm × 250mm, 5 μm), mobile phase: acetonitrile-water (volume ratio 40: 60), detection wavelength: 254nm, column temperature: 25 ℃, flow rate: 1.0 mL/min-1]。
Optical purity 98% [ chromatographic conditions: in a sex column CHIRALPAK AD-H (250 mm. times.4.6 mm, 5 μm); mobile phase: n-hexane-isopropanol (volume ratio: 80: 20); detection wavelength: 254 nm; column temperature: 25 ℃; flow rate: 1.0 mL/min-1]。
Example 7 Synthesis of (S) -bupivacaine (1-N-butyl-N- (2, 6-dimethylphenyl) -2-piperidinecarboxamide) Compound represented by the formula (VII)
Dissolving compound VI (3g, 12.9mmol) in N, N-dimethylformamide (10mL), adding 1-bromobutane (1.93g, 14.2mmol), potassium carbonate (2.14g, 15.5mmol), and reacting at 80 deg.C for 3 h; after completion of the reaction, the reaction mixture was poured into ice water and stirred to give a white solid, which was filtered under suction to give (S) -bupivacaine (3.53g) in yield: 95 percent.
the purity was 98% by HPLC area normalization method [ chromatographic conditions: chromatographic column Kromasil C18Column (4.6mm × 250mm, 5 μm), mobile phase: acetonitrile-water (volume ratio 60: 40), detection wavelength: 254nm, column temperature: 25 ℃, flow rate: 1.0 mL/min-1]。
Optical purity 98% [ chromatographic conditions: chiral column CHIRALPAK AD-H (250 mm. times.4.6 mm, 5 μm); mobile phase: n-hexane-isobutanol (volume ratio: 90: 10); detection wavelength: 254 nm; column temperature: 25 ℃; flow rate: 0.8 mL/min-1]。
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