CN110698388A - Method for industrially producing (S) -3- (4-bromophenyl) piperidine - Google Patents
Method for industrially producing (S) -3- (4-bromophenyl) piperidine Download PDFInfo
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- CN110698388A CN110698388A CN201911061485.4A CN201911061485A CN110698388A CN 110698388 A CN110698388 A CN 110698388A CN 201911061485 A CN201911061485 A CN 201911061485A CN 110698388 A CN110698388 A CN 110698388A
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- C07—ORGANIC CHEMISTRY
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The invention belongs to the field of chemical medicine synthesis, and provides a method for industrially producing (S) -3- (4-bromophenyl) piperidine. The method comprises the steps of taking (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine as a starting material, and removing a tert-butyloxycarbonyl protecting group to obtain (S) -3-hydroxypiperidine hydrochloride A; condensing the intermediate A and thionyl chloride to generate a five-membered ring sulfinate intermediate B; oxidizing the intermediate B to generate five-membered cyclic sulfonate C; then the compound C and aryl negative ions carry out nucleophilic substitution reaction, and the configuration is reversed at the same time, so that the target product (S) -3- (4-bromophenyl) piperidine is generated. The whole process does not use operations such as high-pressure hydrogenation, diazotization and the like, does not use a chiral resolution reagent, has lower overall cost and simple and convenient operation, can keep higher chiral purity, and is suitable for industrial mass production.
Description
Technical Field
The invention belongs to the field of chemical drug synthesis, and mainly relates to a technological method for synthesizing (S) -3- (4-bromophenyl) piperidine.
Background
Nilapanib (Niraparib) is an adenosine diphosphate ribose polymerase inhibitor developed by Tesaro corporation that acts by inhibiting DNA repair. Is mainly used for treating recurrent skin ovarian cancer, salpingemphraxis and primary peritoneal cancer. The PARP gene targeting drug is mainly used for patients with BRCA1/2 gene mutation, has clear target and accords with accurate cancer treatment. And the drug was approved by the FDA for marketing in 3 months of 2017. The production process for developing the bulk drug has good commercial prospect. The chemical name of the nilapanib is 2- [4- [ (3S) -3-piperidyl ] phenyl ] -2H-indole-7-formamide, and the chemical structural formula is as follows:
nilaparib structure
The current more economical route is the method disclosed in patent WO2014088983, prepared by coupling the N-protected key intermediate (S) -3- (4-bromophenyl) piperidine and the heterocyclic pyrazole, of the formula shown in scheme 1:
synthesis scheme 1
The patent WO2014088983 also discloses a preparation method of a key intermediate (S) -3- (4-bromophenyl) piperidine, as synthetic route 2:
synthesis scheme 2
The method has long synthesis route and more three wastes. The intermediate epoxy compound is unstable, and the preparation cost is high; in addition, the price of transaminase is high, and the problem of enzyme inactivation often appears in scale-up production, so that the scale-up to a hundred-kilogram scale is difficult.
In patent CN106854176A, Suzuki coupling, selective catalytic hydrogenation of Ru/C, selective bromination are adopted, and then (S) -3- (4-bromophenyl) piperidine is prepared by resolution. The preparation method is as shown in the synthesis scheme 3:
synthesis scheme 3
The method uses Suzuki coupling to prepare the biaryl cyclic compound, and the cost of the used starting raw material is higher; the position selectivity of the brominating is not described herein. Additionally, a high pressure hydrogenation using Rh catalysis is required.
The patent CN108203404A starts from raw material N-benzyl-3-piperidone, and generates an alcohol intermediate B through Grignard reaction with phenylmagnesium chloride; then dehydrating to generate an olefin intermediate mixture C, and simultaneously hydrogenating olefin and debenzylating the compound C to generate an intermediate D; the intermediate is subjected to thermodynamic resolution by a resolving agent such as L-tartaric acid to isolate the (S) -configuration product E. And (3) obtaining an intermediate G by carrying out N-protection and regioselective bromination on the compound E, and finally obtaining the target product (S) -3- (4-bromophenyl) piperidine by deacetylation protection. The preparation method comprises the following steps of synthetic route 4:
synthesis scheme 4
The synthetic route is long, and the used catalytic hydrogenation has high requirements on equipment; in addition, the yield of the resolution is low, and the intermediate with chiral purity of more than 99.0 percent can be obtained by repeated recrystallization. In the regioselectivity bromination process, the selectivity is poor, a qualified product can be obtained only by repeated recrystallization, and the overall route is difficult to be industrially amplified.
Chinese patent CN106432053A (2016) discloses a preparation method of (S) -3- (4-bromophenyl) piperidine, which comprises the steps of using (S) - (-) dinaphthenol phosphate as a catalyst, and enabling bromobenzene and 2-cyclopentenone to undergo alkylation reaction at the 4-position of phenyl to obtain chiral 4-cyclopentanonyl bromobenzene; then, obtaining a target structure through Beckmann rearrangement and amide reduction in sequence, wherein the reaction is as shown in a synthetic route 5:
synthesis scheme 5
The route is asymmetric alkylation induced by chiral catalysis, and the chiral catalyst is not commercialized in a large quantity; and the selectivity of the rearrangement process may be poor, and the cost of the used phenyl dichloro phosphate is high.
2019, patent CN109456253A discloses a method for synthesizing (S) -3- (4-bromophenyl) piperidine by chiral induction. The route takes trimethyl ortho-4-bromobenzoate and (S) - (-) -tert-butylimidodicarbonamide as starting materials, and sequentially carries out condensation, substitution, reduction, ring closing, chiral induction group removal and the like to obtain (S) -3- (4-bromophenyl) piperidine.
The preparation method is as shown in the synthetic scheme 6:
synthesis scheme 6
The second step of chiral induction of the method needs to be carried out under low temperature condition, and the selectivity is poor, and the diastereoselectivity is about 2: 1, which greatly reduces the yield. In addition, sodium hydride is required in the cyclization process, and the material is easy to ignite and should be avoided from production.
No reports have been made on the synthetic route of (S) -3- (4-bromophenyl) piperidine described above, other than the above representative methods. In view of the defects existing in the above route which are not beneficial to the economic cost control of the anticancer drug Nilaparib, the invention provides a process route which is economical and feasible and is easy for industrial mass production, further reduces the production cost, simplifies the operation steps, reduces the loss of raw materials and keeps higher chiral purity.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide an economically feasible method for preparing (S) -3- (4-bromophenyl) piperidine, which is easy to implement industrial mass production.
The method for industrially synthesizing (S) -3- (4-bromophenyl) piperidine provided by the invention comprises the following steps:
(1) removing a tert-butyloxycarbonyl protecting group from a starting material (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine to generate an intermediate A;
(2) the intermediate A and thionyl chloride are subjected to condensation reaction at low temperature in the presence of alkali to generate an intermediate B;
(3) the intermediate B is subjected to oxidation reaction under the catalysis of ruthenium, and a reaction product is purified through recrystallization to obtain a purified intermediate C;
(4) carrying out nucleophilic substitution reaction on the purified intermediate C and 4-bromophenyl negative ions, hydrolyzing to obtain a final product D, and recrystallizing the product D to obtain a pure (S) -3- (4-bromophenyl) piperidine product;
the intermediate A is 3-hydroxypiperidine hydrochloride; the intermediate B is a five-membered cyclic intermediate sulfinate; the intermediate C is sulfone.
The specific reaction process is as follows:
specifically, the reaction reagent for deprotection of the starting material (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine in the step (1) is an acidic reagent, and the acidic reagent is an ethyl acetate solution of hydrochloric acid, a dichloromethane solution of hydrochloric acid, a dioxane solution of hydrochloric acid or an isopropanol solution of hydrochloric acid; preferably an ethyl acetate solution of hydrochloric acid, a dichloromethane solution of hydrochloric acid or a dioxane solution of hydrochloric acid; further preferably an ethyl acetate solution of hydrochloric acid or a dichloromethane solution of hydrochloric acid; more preferably a solution of hydrochloric acid in ethyl acetate.
Specifically, in the step (1), the molar ratio of the starting material (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine to the acidic reagent is 1: 2-5, preferably 1: 2-3.
Specifically, the reaction temperature in step (1) is 0 to 40 ℃, preferably 20 to 30 ℃.
Specifically, the base in the step (2) is diisopropylethylamine, triethylamine, DBU or N-methylmorpholine, and is preferably triethylamine or diisopropylethylamine.
Specifically, the molar ratio of the base to the intermediate A in the step (2) is 4-4.5: 1.
specifically, the solvent used in the condensation reaction of step (2) is one or more of dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, hexane and heptane, preferably one or more of dichloromethane, ethyl acetate and acetonitrile.
Specifically, the reaction temperature in step (2) is-10 to 10 ℃, preferably 0 to 10 ℃.
Specifically, the molar ratio of the intermediate A to thionyl chloride in the step (2) is 1: 1.2-2.5, preferably 1: 1.5-2.0.
Specifically, the oxidizing agent used in the oxidation reaction in step (3) is peracetic acid, m-chloroperoxybenzoic acid, hydrogen peroxide or sodium periodate, and preferably sodium periodate or m-chloroperoxybenzoic acid.
Specifically, the oxidation reaction described in step (3) uses the intermediate B and the oxidizing agent in a molar ratio of 1: 1.5-3.5, preferably 1: 1.5-2.5.
Specifically, the temperature of the oxidation reaction in the step (3) is 0 to 50 ℃, preferably 10 to 30 ℃.
Specifically, the ruthenium catalyst for the oxidation reaction in step (3) is ruthenium trioxide, ruthenium trichloride trihydrate or tetrapropylammonium perruthenate, preferably ruthenium trichloride trihydrate.
Specifically, the solvent for nucleophilic substitution reaction in step (4) is tetrahydrofuran, 2-methyltetrahydrofuran, hexane, cyclohexane or n-heptane, preferably tetrahydrofuran or 2-methyltetrahydrofuran.
Specifically, the 4-bromophenyl anion of the nucleophilic substitution reaction in step (4) is 1, 4-dibromobenzene or 1-bromo-4-iodobenzene, preferably 1, 4-dibromobenzene.
Specifically, the solvent for recrystallization of the product D in the step (4) is hexane, cyclohexane, pentane or n-heptane, preferably n-heptane or cyclohexane.
Compared with the prior art, the invention has the following advantages:
(1) the raw material cost is low. The raw materials of the invention are conventional products which are already produced by the company with tonnage, and are directly utilized, so that the production cost is reduced.
(2) The operation steps are simple. The first step of deprotection and the second step of condensation do not separate an intermediate, and the crude product is directly put into the next step; both the third and last step can be purified by recrystallization.
(3) The chiral purity is high. The process starts from a cheap chiral source, and performs configuration inversion by nucleophilic substitution of SN2 in the middle, so that higher chiral purity can be maintained; conventional resolution processes, at least 50% of the starting material is lost.
Detailed Description
The present invention is further illustrated by the following specific examples, but the present invention is not limited to the following examples. All changes, combinations, and alterations that come within the scope of the description are intended to be embraced therein. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
First, an embodiment
Example 1
The first step is as follows: to a 2L three-necked flask with mechanical stirring, under nitrogen protection, was added (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine (100g, 496.9mmol) and methanol (1L). Then, dripping 35% hydrochloric acid aqueous solution (25mL) into the reaction bottle, and controlling the temperature to be 15-25 ℃; the mixed system was stirred at 15-25 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure at 35-40 ℃ to 200g, dichloromethane (1L) was added, and the mixture was stirred at 15-20 ℃ for 1 hour. Suction filtration and elution of the filter cake with dichloromethane (50mL) gave intermediate A (61.5g) in 92.8% GC purity and 90% yield.
The second step is that: under nitrogen protection, to a 3L three-necked flask with mechanical stirring was added intermediate a (60g, 0.44mol, 1.0eq.), dichloromethane (1.2L) was added and the system was cooled to 0-5 ℃. Imidazole (124.7g, 1.83mol, 4.2eq.) was then added portionwise, triethylamine (185.3g, 1.83mol, 4.2eq.) was added dropwise after that, and thionyl chloride (77.8g, 0.65mol, 1.5eq.) was slowly added dropwise to the reaction mixture, with the internal temperature T <5 ℃. The mixed system was stirred at 0-5 ℃ for 1 hour. Adding water (350g) dropwise into the system, controlling the temperature T <5 ℃ in the dropwise adding process, stirring the mixed system at-5-0 ℃ for 15 minutes, standing for 15 minutes, and separating liquid. The organic phase is then washed 3 times with 10% aqueous sodium chloride (350 g. times.3), dried over anhydrous sodium sulfate, filtered with suction and the filter cake is rinsed with dichloromethane (200 mL). The organic phase was concentrated at 35-40 ℃ to give intermediate B (51.3g) in 92.2% HPLC purity and 80% yield.
The third step: under the protection of nitrogen, acetonitrile (600g) and water (900g) were added to a mechanically stirred three-necked 5L flask and the temperature was reduced to-1-8 ℃. Then, sodium periodate (87.2g, 0.41mol, 1.2eq.) and ruthenium trichloride trihydrate (2.67g, 10.2mmol, 0.03eq.) were added to the system, and the system was stirred at-1-8 ℃ for 15 minutes. Intermediate B (50.0g, 0.34moL, 1.0eq.) was dissolved in acetonitrile (150g) and added dropwise to the flask with the internal temperature controlled at 0-10 ℃. The mixture was stirred at 0-10 ℃ for 15 minutes, and sodium periodate (21.8g, 0.10moL, 0.3eq.) was added. The mixed system is stirred for 3 hours at the temperature of 0-10 ℃. 7% sodium bicarbonate water solution (815g, 2eq.) is added into the reaction system to quench the reaction, and the process is controlled at 0-10 ℃. The mixed system was suction filtered through celite (50g), and the filter cake was rinsed with ethyl acetate (200 g). Extracting the filtrate with ethyl acetate (400g), drying the organic phase with anhydrous sodium sulfate (80g), and filtering; the filtrate was concentrated in vacuo at 50-55 deg.C to about (300 g). Cooling the concentrated solution to 15 +/-3 ℃, then stirring for 1.5 hours, and performing suction filtration to obtain a solid crude product. Adding methanol (300mL) into the crude product, heating to 40-45 ℃, stirring for 30min until the solid is clear, and then adding n-hexane (150 mL); cooling the solution to 15 ℃, stirring for 1 hour, carrying out suction filtration, and leaching a filter cake with a small amount of n-hexane. The filter cake was dried in vacuo at 40 ℃ for 4 h to give intermediate C (44.3g) as an off-white solid with an HPLC purity of 97.0% and 80% yield.
The fourth step: tetrahydrofuran (800mL)1, 4-dibromobenzene (57.8g, 245.1mmol, 1.0eq.) was added to a three-necked flask with mechanical stirring under nitrogen protection and the temperature was reduced to-78 ℃. Then, a 2.5M n-butyllithium n-hexane solution (107.9mL, 269.6mmol, 1.1eq.) was slowly added dropwise thereto, and the mixture was stirred for 30 minutes while maintaining at-78 ℃ and then heated to 0 ℃. And (3) dropwise adding the tetrahydrofuran solution (40.0g, 245.1mmol, 1.0eq., dissolved in 250mL of tetrahydrofuran) of the intermediate C into the reaction system, controlling the temperature at 0-10 ℃ in the process, and heating the system to room temperature and stirring for 1h after dropwise adding. The system was cooled to 0-10 ℃ and saturated ammonium chloride (100mL) was added to quench the reaction. The reaction was extracted twice with dichloromethane (500 mL. times.2). Combining organic phases, drying by anhydrous sodium sulfate, and performing suction filtration; concentrating the filtrate at 35-40 deg.C to about (100 g); n-heptane (300mL) was added to the system, which was then slowly cooled to 0-5 deg.C and stirred for 1h while maintaining the temperature. The pure (S) -3- (4-bromophenyl) piperidine (41.2g) was obtained by suction filtration, and had a HPLC purity of 98.0%, a chiral purity of 99.2% and a yield of 70%.
Example 2
The first step is as follows: to a mechanically stirred 2L three-necked flask was added (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine (100g, 496.9mmol) under nitrogen protection, ethyl acetate (1L) was added, and then a 5M ethyl acetate solution of hydrochloric acid (25mL) was added dropwise to the reaction flask, and the mixture was stirred at 15 to 25 ℃ for 2 hours. The system is concentrated to 200g at 35-40 ℃, petroleum ether (1L) is added, and the mixture is stirred for 1 hour at 15-20 ℃. Stirring was stopped, suction filtered and the filter cake rinsed with petroleum ether (50mL) to give intermediate A (58.7g) in 94.2% GC purity and 86% yield.
The second step is that: under nitrogen protection, to a 3L three-necked flask with mechanical stirring was added intermediate a (55.0g, 0.40mol, 1.0eq.), dichloromethane (1.1L) was added and the system was cooled to 0-5 ℃. Imidazole (122.5g, 1.80mol, 4.5eq), diisopropylethylamine (232.6g, 1.80mol, 4.5eq.) were then added in that order. After the addition, thionyl chloride (71.3g, 0.60mol, 1.5eq.) was slowly added dropwise to the system, with the internal temperature controlled at 0-5 ℃. The mixed system was stirred at 0-5 ℃ for 1 hour. After the reaction, water (300g) is added into the system in a dropwise manner, the internal temperature is controlled to be 0-10 ℃ in the dropwise adding process, and the quenched system is separated. The organic phase was washed with 10% aqueous sodium chloride (300g), dried over anhydrous sodium sulfate, filtered and the cake organic phase concentrated at 35-40 ℃ to give intermediate B (46.5g) in 93.5% HPLC purity and 79% yield.
The third step: under the protection of nitrogen, acetonitrile (600g) and water (950g) are added into a 5L three-necked flask with mechanical stirring, and the temperature is reduced to-5-5 ℃. Then, sodium periodate (130.8g, 0.61mol, 2.0eq.) and ruthenium trichloride trihydrate (2.39g, 9.17mmol, 0.03eq.) were added to the system, and the system was stirred at 0-10 ℃ for 15 minutes. Dissolving the intermediate B (45.0g, 0.31mol, 1.0eq) in acetonitrile (150g), dropwise adding into a reaction bottle, controlling the internal temperature to be 0-10 ℃ during the dropwise adding process, and stirring the mixed system at 0-10 ℃ for 2 h. The reaction was quenched by adding 7% aqueous sodium bicarbonate (734g, 2eq.) dropwise to the system while maintaining the temperature at 0-10 ℃, and the quenched reaction solution was filtered through celite (50 g). The filtrate was extracted with ethyl acetate (800g), and then the organic phase was washed with water (200g), dried over anhydrous sodium sulfate, and filtered with suction. Vacuum concentrating the filtrate at 50-55 deg.C to 250mL, naturally cooling to 10-15 deg.C, and vacuum filtering to obtain crude product. The volume ratio of the crude product to ethyl acetate n-heptane is 1: 2(300mL), cooling to 10-15 ℃, stirring for 1 hour, filtering, and leaching the filter cake with the cooled solvent (20mL) in the same proportion. The filter cake was dried in vacuo at 40 ℃ for 4 h to give intermediate C (38.9g) as an off-white solid with HPLC purity 98.2% and 78% yield.
The fourth step: tetrahydrofuran (800mL), 1, 4-dibromobenzene (50.6g, 214.5mmol, 1.0eq.) were added to a three-necked flask with mechanical stirring under nitrogen protection and the temperature was reduced to 15 ℃. Then 2M solution of isopropyl magnesium bromide in tetrahydrofuran (118mL, 236mmol, 1.1eq.) was slowly added dropwise, and the mixture was stirred for 30 minutes while maintaining at 15-25 ℃. Dissolving the intermediate C (35.0g, 214.5mmol, 1.0eq.) in tetrahydrofuran (200mL) and dropwise adding into the reaction system, controlling the temperature at 15-20 ℃ during the process, and stirring the mixed system for 2 hours at 15-25 ℃. After completion of the reaction, a 13% aqueous solution of ammonium chloride (500mL) was added dropwise at 0-5 ℃ and extracted twice with dichloromethane (350 mL. times.2). Combining organic phases, drying by anhydrous sodium sulfate, and performing suction filtration; the filtrate was concentrated to about 80g at 40 ℃; the crude product was recrystallized from petroleum ether (300mL) to give pure (S) -3- (4-bromophenyl) piperidine (32.4g) in 98.5% HPLC purity, 99.8% chiral purity and 63% yield.
Example 3
The first step is as follows: to a mechanically stirred 2L three-necked flask was added (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine (100g, 496.9mmol) under nitrogen protection, ethyl acetate (1L) was added, and then a 4M dioxane solution (125mL) of hydrochloric acid was added dropwise to the reaction flask, and the mixture was stirred at room temperature for 2 hours. The reaction system was concentrated to 200g at 35-40 deg.C, n-heptane (1L) was added and the suspension was stirred for 1 hour at 15-20 deg.C. Stirring was stopped, suction filtered and the filter cake rinsed with n-heptane (50mL) to give intermediate A (60.1g) in 93.5% GC purity and 88% yield.
The second step is that: under nitrogen protection, to a 3L three-necked flask with mechanical stirring was added intermediate a (55.0g, 0.40mol, 1.0eq), dichloromethane (1.1L) was added and the system was cooled to 0-5 ℃. Imidazole (122.5g, 1.80mol, 4.5eq.) and N-methylmorpholine (181.8g, 1.80mol, 4.5eq.) were then added in sequence; after the addition, thionyl chloride (85.59g, 0.72mol, 1.8eq.) was slowly added dropwise, controlling the internal temperature at 0-5 ℃. The mixed system was stirred at 0-5 ℃ for 1 hour. After the reaction, water (300g) is added into the system dropwise to quench the reaction, and the temperature is controlled to be 0-5 ℃ in the dropwise adding process. The organic phase after separation was washed with an aqueous solution of sodium chloride (300mL), dried over anhydrous sodium sulfate, and filtered with suction. The filtrate was concentrated at 35-40 deg.C to give intermediate B (46.5g) in 95.2% HPLC purity and 79% yield.
The third step: dichloromethane (350mL), intermediate B (45.0g, 0.31mol, 1.0eq) was added to a mechanically stirred 2L three-necked flask under nitrogen, and dissolved by stirring at 20-25 ℃ for 10 minutes. Then, the temperature is reduced to 0 ℃, m-chloroperoxybenzoic acid (150.7g, 0.61mol, 2.0eq, content 70%) is added in batches and slowly, after the addition is finished, the reaction is carried out for 30 minutes at 0-5 ℃, and then the reaction is transferred to 20-25 ℃ for 2 hours. After the reaction, saturated aqueous sodium bicarbonate (300g) is added dropwise to quench the reaction, the pH is adjusted to 8-9, and the process is controlled at 0-5 ℃. Separating, and extracting the water phase with dichloromethane (450 mL); the organic phases were combined, and saturated aqueous sodium bisulfite (300mL) was added to the organic phase, followed by stirring for 15 min. After the liquid separation, the organic phase was washed with water (400mL) and saturated brine (400mL) in this order, stirred for 5 minutes, and separated. And drying the organic phase after liquid separation by using anhydrous sodium sulfate, and performing suction filtration. The filtrate was concentrated to 50mL, methyl tert-butyl ether (250mL) was added and heated to 40 ℃ to dissolve it, and then cooled to 0-5 ℃ over 1h, gradually precipitating a large amount of solid. Suction filtration and vacuum drying of the filter cake at 35-40 ℃ for 4 h gave off-white solid intermediate C (35.4g) with HPLC purity 98.5% and yield 71%.
The fourth step: under the protection of nitrogen, 2-methyltetrahydrofuran (700mL) and 1, 4-dibromobenzene (50.6g, 214.5mmol, 1.0eq.) were added to a mechanically stirred three-necked flask and cooled to-78 ℃. Then 2.5M n-hexane solution of n-hexyllithium (94.4mL, 235.9mmol, 1.1eq.) was slowly added dropwise, the mixed system was stirred for 30 minutes at-78 ℃ and the system was heated to 15-20 ℃. Dissolving the intermediate C (35.0g, 245.1mmol, 1.0eq.) in tetrahydrofuran (200ml), and dropwise adding the solution into the reaction system, wherein the temperature is controlled to be 15-25 ℃ in the process, and reacting for 5h after the dropwise adding is finished. Heating the system obtained after the reaction to 0-10 ℃, and adding saturated ammonium chloride to quench the reaction (150 mL); the quenched system was extracted with dichloromethane (400 mL. times.2). Combining organic phases, drying by anhydrous sodium sulfate and filtering; the filtrate cyclohexane (250g) was recrystallized to give pure (S) -3- (4-bromophenyl) piperidine (37.1g) in HPLC purity 99.2%, chiral purity 99.5%, yield 72%.
Second, comparative example
Comparative example 1
Starting from raw material N-benzyl-3-piperidone, carrying out Grignard reaction with phenylmagnesium chloride to generate an alcohol intermediate B; then dehydrating to generate an olefin intermediate mixture C, and simultaneously hydrogenating olefin and debenzylating the compound C to generate an intermediate D; the intermediate is subjected to thermodynamic resolution by a resolving agent such as L-tartaric acid to isolate the (S) -configuration product E. And (3) obtaining an intermediate G by carrying out N-protection and regioselective bromination on the compound E, and finally obtaining the target product (S) -3- (4-bromophenyl) piperidine by deacetylation protection.
Comparative example 2
The first step is as follows: to a mechanically stirred 2L three-necked flask was added (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine (100g, 496.9mmol) under nitrogen protection, ethyl acetate (1L) was added, and then a 5M solution of hydrochloric acid in methylene chloride (25mL) was added dropwise to the reaction flask, and the mixture was stirred at 15 to 20 ℃ for 2 hours. The system is concentrated to 200g at 35-40 ℃, petroleum ether (1L) is added, and the mixture is stirred for 1 hour at 15-20 ℃. Stirring was stopped, suction filtered and the filter cake rinsed with petroleum ether (50mL) to give intermediate A (49.2g) in 72% yield.
The second step is that: under nitrogen protection, add intermediate a (55.0g, 0.40mol, 1.0eq.) to a 3L three-necked flask with mechanical stirring, add toluene (1.1L), and cool the system to 0-5 ℃. Imidazole (122.5g, 1.80mol, 4.5eq), diisopropylethylamine (232.6g, 1.80mol, 4.5eq.) were then added in that order. After the addition, thionyl chloride (71.3g, 0.60mol, 1.5eq.) was slowly added dropwise to the system, with the internal temperature controlled at 0-5 ℃. The mixed system was stirred at 0-5 ℃ for 1 hour. After the reaction, water (300g) is added into the system in a dropwise manner, the internal temperature is controlled to be 0-10 ℃ in the dropwise adding process, and the quenched system is separated. The organic phase was washed with 10% aqueous sodium chloride (300g), dried over anhydrous sodium sulfate, filtered and the organic filter cake phase concentrated at 35-40 ℃ to give intermediate B (40.6g) in 69% yield.
The third step: under the protection of nitrogen, acetonitrile (600g) and water (950g) are added into a 5L three-necked flask with mechanical stirring, and the temperature is reduced to-5-5 ℃. Then 30% peracetic acid (120mL) and ruthenium trichloride (0.5) were added to the system, and the mixture was stirred at 0-10 ℃ for 15 minutes. Dissolving the intermediate B (45.0g, 0.31mol, 1.0eq) in acetonitrile (150g), dropwise adding into a reaction bottle, controlling the internal temperature to be 0-10 ℃ during the dropwise adding process, and stirring the mixed system at 0-10 ℃ for 2 h. The reaction was quenched by adding 7% aqueous sodium bicarbonate (734g, 2eq.) dropwise to the system while maintaining the temperature at 0-10 ℃, and the quenched reaction solution was filtered through celite (50 g). The filtrate was extracted with ethyl acetate (800g), and then the organic phase was washed with water (200g), dried over anhydrous sodium sulfate, and filtered with suction. Vacuum concentrating the filtrate at 50-55 deg.C to 250mL, naturally cooling to 10-15 deg.C, and vacuum filtering to obtain crude product. The volume ratio of the crude product to ethyl acetate n-heptane is 1: 2(300mL), cooling to 10-15 ℃, stirring for 1 hour, filtering, and leaching the filter cake with the cooled solvent (20mL) in the same proportion. The filter cake was dried in vacuo at 40 ℃ for 4 h to give intermediate C (32.4g) as an off-white solid in 65% yield.
The fourth step: hexane (350mL), 1-bromo-4-iodobenzene (67.6g, 236mmol) was added to a three-necked flask with mechanical stirring under nitrogen and the temperature was reduced to 15 ℃. Then 2M solution of isopropyl magnesium bromide in tetrahydrofuran (118mL, 236mmol, 1.1eq.) was slowly added dropwise, and the mixture was stirred for 30 minutes while maintaining at 15-25 ℃. Dissolving the intermediate C (35.0g, 214.5mmol, 1.0eq.) in tetrahydrofuran (200mL) and dropwise adding into the reaction system, controlling the temperature at 15-20 ℃ during the process, and stirring the mixed system for 2 hours at 15-25 ℃. After completion of the reaction, a 13% aqueous solution of ammonium chloride (500mL) was added dropwise at 0-5 ℃ and extracted twice with dichloromethane (350 mL. times.2). Combining organic phases, drying by anhydrous sodium sulfate, and performing suction filtration; the filtrate was concentrated to about 80g at 40 ℃; the crude product was recrystallized from petroleum ether (300mL) to give pure (S) -3- (4-bromophenyl) piperidine (21.7g) in 62% yield.
Thirdly, analyzing results:
comparing examples 1-3 with comparative example 1, the reaction route in comparative example 1 is more complicated than that in examples 1-3, the catalytic hydrogenation has high requirements on reaction equipment, the resolution yield is lower, and multiple recrystallization is needed to obtain the intermediate with chiral purity of more than 99.0%. In the process of regioselectivity bromination, the selectivity is poor, a qualified product can be obtained only by repeated recrystallization, and the technical route is difficult to be industrially amplified.
Comparing examples 1-3 with comparative example 2, the total yield of (S) -3- (4-bromophenyl) piperidine obtained in comparative example 2 in four steps is 20%, which is lower than the yield of (S) -3- (4-bromophenyl) piperidine obtained in examples 1-3, indicating that the preferred reagents can contribute to the technical problem of high yield solved by the present application, suitable for industrial mass production.
Claims (10)
1. A method for industrially producing (S) -3- (4-bromophenyl) piperidine, characterized by comprising the following steps:
(1) removing a tert-butyloxycarbonyl protecting group from a starting material (S) -1-tert-butyloxycarbonyl-3-hydroxypiperidine to generate an intermediate A;
(2) the intermediate A and thionyl chloride are subjected to condensation reaction at low temperature in the presence of alkali to generate an intermediate B;
(3) the intermediate B is subjected to oxidation reaction under the catalysis of ruthenium, and a reaction product is purified through recrystallization to obtain a purified intermediate C;
(4) carrying out nucleophilic substitution reaction on the purified intermediate C and 4-bromophenyl negative ions, hydrolyzing to obtain a product D, and recrystallizing the product D to obtain a pure (S) -3- (4-bromophenyl) piperidine product;
the intermediate A is 3-hydroxypiperidine hydrochloride; the intermediate B is a five-membered cyclic intermediate sulfinate; the intermediate C is sulfone.
2. The process according to claim 1, characterized by the fact that it is carried out by the following reaction scheme:
3. the method according to any one of claims 1 to 2, wherein the reagent for deprotecting the starting material (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine in step (1) is an acidic reagent which is a solution of hydrochloric acid in ethyl acetate, hydrochloric acid in dichloromethane, hydrochloric acid in dioxane or hydrochloric acid in isopropanol.
4. The process according to claim 3, wherein the molar ratio of the starting material (S) -1-tert-butoxycarbonyl-3-hydroxypiperidine and the acidic reagent in step (1) is 1: 2-5.
5. The method according to claim 1, wherein the base in step (2) is diisopropylethylamine, triethylamine, DBU or N-methylmorpholine.
6. The method according to claim 1, wherein the solvent used in the condensation reaction of step (2) is one or more of dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, hexane and heptane.
7. The process according to claim 1, wherein the reaction temperature in step (2) is-10 to 10 ℃.
8. The method as claimed in claim 1, wherein the oxidation reaction in step (3) uses an oxidant selected from peracetic acid, m-chloroperoxybenzoic acid, hydrogen peroxide and sodium periodate; the ruthenium catalyst is ruthenium trioxide, ruthenium trichloride hydrate or tetrapropylammonium perruthenate.
9. The method according to claim 1, wherein the solvent used in the recrystallization purification in step (3) comprises a good solvent and a poor solvent, and the good solvent is ethyl acetate, dichloromethane, methyl tert-butyl ether or methanol; the poor solvent is petroleum ether, n-heptane or toluene.
10. The process according to claim 1, wherein the solvent used for the recrystallization reaction in the step (4) is tetrahydrofuran, 2-methyltetrahydrofuran, hexane, cyclohexane or n-heptane.
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