CN114085219A - Synthesis of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane - Google Patents

Synthesis of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane Download PDF

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CN114085219A
CN114085219A CN202010861684.XA CN202010861684A CN114085219A CN 114085219 A CN114085219 A CN 114085219A CN 202010861684 A CN202010861684 A CN 202010861684A CN 114085219 A CN114085219 A CN 114085219A
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申永存
甘梦琪
梁夏瑜
余鹏
付晨
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Wuhan University of Technology WUT
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Abstract

The invention discloses a method for synthesizing (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, which comprises the following specific steps: partial oxidation is carried out on N-benzyl piperidine dicarboximide which is used as raw material to form intra-ring double bond, then electron-withdrawing group tert-butyloxycarbonyl group is introduced into NH group at ortho position of intra-ring double bond, asymmetric catalytic hydrogenation is carried out on double bond by utilizing chiral catalyst, and finally tert-butyloxycarbonyl group is removed, thus obtaining (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane. The synthesis method has the advantages of simple operation, cheap and easily obtained raw materials, mild reaction conditions, high asymmetric conversion rate, high enantioselectivity of asymmetric reaction, ee value of 99.5 percent and low cost, and has industrial practical value.

Description

Synthesis of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for synthesizing (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane.
Background
The (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane is an intermediate of (S, S) -2, 8-diazabicyclo [4.3.0] nonane which is an important raw material for synthesizing moxifloxacin. Moxifloxacin is currently used in clinic, and is a fourth-generation quinolone drug, and has strong antibacterial effects on gram-positive bacteria, gram-negative bacteria (except pseudomonas aeruginosa), atypical pathogenic bacteria and anaerobic bacteria, so that the research on an effective synthesis method of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane is of great significance.
The patent (WO9415938) discloses that (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane is prepared by a method of resolving different chiral amines by using 2, 3-dipyridyl formic acid as a raw material, and the method route is as follows:
Figure BDA0002648345310000011
the method is used for obtaining (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane by resolution, and a recycling method of the other isomer (1R,6S) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane is not reported, so that the cost is high and the pollution is large. Therefore, people always search for a simple, safe, efficient and low-cost production method, thereby reducing the manufacturing cost of the medicine and being convenient for popularization and application.
Disclosure of Invention
The invention aims to provide a synthetic method of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, which has the advantages of simple operation, mild reaction conditions, high asymmetric conversion rate, high enantioselectivity of asymmetric reaction, low cost and industrial practical value.
In order to achieve the purpose, the invention adopts the technical scheme that:
provides a method for synthesizing (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, which comprises the following steps:
using N-benzyl piperidine dicarboximide with a structural formula I aS a raw material, partially oxidizing to form an intra-ring double bond to obtain 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-diketone with a structural formula II, introducing an electron-withdrawing group tert-butoxycarbonyl group on an NH group to obtain 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrole [3,4-b ] pyridine-1 (5H) carboxylic acid tert-butyl ester with a structural formula III, and then carrying out asymmetric catalytic hydrogenation on the intra-ring double bond by using a chiral catalyst to obtain (4aR,7aS) -6-benzyl-octahydro-5, 7-dioxo pyrrole [3 with a structural formula IV, 4-b ] pyridine-1-carboxylic acid tert-butyl ester, and finally removing tert-butyloxycarbonyl group to obtain (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with the structural formula as follows:
Figure BDA0002648345310000021
the chiral catalyst is any one of compounds A, B and C, and the structural formulas of the compounds A, B and C are as follows:
Figure BDA0002648345310000022
according to the scheme, the method comprises the following specific steps:
1) dissolving N-benzyl piperidine dicarboximide with a structural formula I in a solvent, adding an oxidant under ice bath, and then carrying out oxidation reaction for 3-6 hours at room temperature to form an intra-ring double bond to obtain 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-dione (II) with a structural formula II, wherein the molar ratio of the N-benzyl piperidine dicarboximide to the oxidant is 1: 1-5, post-treating to remove excessive oxidant for the next reaction, wherein the reaction formula is as follows:
Figure BDA0002648345310000031
2) dissolving the 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-dione with the structural formula II obtained in the step 1) in a proper solvent, adding tert-butyl carbonate under an ice bath condition in the presence of an alkali catalyst, then reacting at normal temperature for 3-10 hours, introducing tert-butoxycarbonyl (Boc) on NH at the ortho position of the intra-ring double bond obtained in the step 1), and carrying out aftertreatment to obtain tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate with the structural formula III; wherein the mol ratio of the 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-diketone with the structural formula II to the alkali catalyst to the tert-butyl carbonate is 1: 0.1-1: 1-2, the reaction formula is:
Figure BDA0002648345310000032
3) carrying out asymmetric hydrogenation on the 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylic acid tert-butyl ester with the structural formula III obtained in the step 2) in a proper solvent in the presence of an asymmetric catalyst to obtain (4aR 7aS) -6-benzyl-octahydro-5, 7-dioxo-pyrrolo [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester with the structural formula IV; wherein the molar ratio of the asymmetric catalyst to the tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate of the structural formula III is 0.001-0.5: 1, the asymmetric hydrogenation reaction temperature is 20-80 ℃, the reaction time is 8-24 hours, the reaction pressure is 20-80 kg, the asymmetric catalyst is any one of compounds A, B, C, and the reaction formula is as follows:
Figure BDA0002648345310000033
4) reacting (4aR,7aS) -6-benzyl-octahydro-5, 7-dioxygen pyrrole [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester with a structural formula IV obtained in the step 3) in a proper solvent for 3-6 hours under the catalysis of acid to remove tert-butyloxycarbonyl group, thus obtaining (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with a structural formula V, wherein the reaction formula is aS follows:
Figure BDA0002648345310000041
according to the scheme, the solvent used in the step 1) is a polar solvent or a non-polar solvent, wherein the polar solvent is acetonitrile, THF, DMF, acetone, dioxane or water, and the non-polar solvent is benzene, toluene, 1, 2-dichloroethane, dichloromethane or trichloromethane; the volume weight ratio of the solvent to the N-benzyl piperidine dicarboximide with the structural formula I is 5-10: 1 mL/g.
According to the scheme, the oxidant in the step 1) is potassium permanganate, manganese dioxide, chromic acid, chromium trioxide, chromic chloride acyl pyridine complex or DDQ, and the oxidant is added under the ice bath condition.
According to the scheme, the step of removing the excessive oxidant by post-treatment in the step 1) comprises the following steps: after the reaction is finished, evaporating the solvent to dryness to obtain a residue, dissolving the residue in a proper solvent, extracting and layering, and concentrating an organic layer until the organic layer is dried for the next reaction; wherein the solvent for dissolving the residue is toluene, acetonitrile, ethyl acetate, MTBE, isopropyl acetate or acetone, and the weight-volume ratio of the residue to the dissolved solvent is 1: 1-10.
According to the scheme, in the step 2), the solvent is one or two of benzene, toluene, 1, 2-dichloroethane, dichloromethane or trichloromethane; the base catalyst used is TEA, DIPEA, DBU, DBACO, pyridine or N, N-lutidine.
According to the scheme, in the step 3), the solvent is one or two of acetonitrile, THF, DMF, acetone, methanol, ethanol, isopropanol, dioxane, dichloromethane and water; the weight volume ratio of the tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate of the structural formula III to the solvent is 1 g: 3-5 mL.
According to the scheme, the step 3) is as follows: adding a chiral catalyst, vacuumizing according to the requirement of hydrogenation reaction, exchanging gas with nitrogen and hydrogen for multiple times, filling hydrogen to 20-80 kg, and stopping reaction until the system does not absorb hydrogen any more.
According to the scheme, the solvent used in the step 4) is one or two of acetonitrile, THF, DMF, acetone, methanol, ethanol, isopropanol, dioxane, water, dichloromethane and ethyl acetate; the acid catalyst is trifluoroacetic acid, hydrochloric acid and hydrobromic acid; after the acid catalytic reaction is finished, concentrating to be dry, adding water and a proper organic solvent into residues or directly adding water, then adjusting the pH to be more than 8 by using ammonia water, extracting the water phase for multiple times by using the organic solvent, combining organic layers, drying and concentrating to obtain (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with the structural formula V; the organic solvent for extraction is toluene, dichloromethane, chloroform, dichloroethane, MTBE or EA.
The invention takes N-benzyl piperidine dicarboximide as a raw material, utilizes the electron-withdrawing action of two carbonyl groups in the raw material to enhance the activity of hydrogen on ortho-position carbon, and can obtain intra-ring double bonds, namely reaction sites of asymmetric catalytic hydrogenation by oxidizing agents under mild conditions. Due to the steric hindrance problem of the position of the double bond in the ring, the chiral induction capability and the catalytic activity of the chiral catalyst are greatly challenged. In the invention, the selected chiral iridium catalyst is only reported to be used for asymmetric addition of double bonds on a straight chain at present, and the chiral iridium catalyst is also used for asymmetric hydrogenation of intra-ring double bonds with steric hindrance for the first time to obtain a good effect. In the design of a reaction route, the Boc electron-withdrawing group is introduced by utilizing the imino group at the ortho position of the intra-ring double bond, so that the electron cloud density of the double bond is reduced, the reaction is further promoted, and the defect of low yield caused by steric effect is overcome. Finally, the target product with high corresponding selectivity can be obtained only by conventional de-Boc. Compared with the prior art, the invention can obtain more than 96% of asymmetric conversion rate, and the ee value can reach 99.5%, and has great advantages in yield and enantioselectivity.
The invention has the beneficial effects that:
1. the method obtains intra-ring double bonds through partial oxidation, introduces electron-withdrawing groups Boc to the ortho-positions of the double bonds, and obtains a single asymmetric target product through simple four-step reaction of asymmetric catalytic hydrogenation and electron-withdrawing group Boc removal of the intra-ring double bonds; the compound N-benzyl piperidine dicarboximide (I) is used as a raw material, on one hand, intra-ring double bonds can be obtained through partial oxidation under mild conditions to provide reaction sites for subsequent asymmetric catalytic hydrogenation reaction, on the other hand, NH at the ortho position of the intra-ring double bonds can be used for introducing electron-withdrawing group Boc, so that the intra-ring double bonds are activated, the yield and enantioselectivity of the asymmetric catalytic hydrogenation reaction are increased, the asymmetric catalytic hydrogenation conversion rate of the intra-ring double bonds is high and can reach more than 96%, the enantioselectivity of the asymmetric reaction is high, and the ee value can reach 99.5%.
2. The synthetic method has the advantages of mild reaction conditions, cheap and easily-obtained raw materials, simple operation, low process cost and industrial practical value.
Detailed Description
In order to better understand the present invention, the following examples are further provided to illustrate the present invention, but the present invention is not limited to the following examples.
The catalysts A, B and C used in the examples below have the following structures:
Figure BDA0002648345310000051
example 1:
synthesis of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane by the following steps:
1) preparation of 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-dione (II)
To a 250mL single neck flask was added N-benzylpiperidine dicarboximide (I) (FW 244,24.4g,0.1mol), acetone and water (1:1,100mL) and dissolved with stirring, potassium permanganate (FW 158,15.8g,0.1mol) was slowly added under ice bath cooling, after the addition was completed, the reaction was performed at room temperature for 5 hours, TLC followed the completion of the reaction, the solvent was removed by concentration under reduced pressure, DCM (50mL) and water (50) were added to the residue, the separated layers were extracted, the aqueous layer was extracted with DCM (10mL 3), the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to dryness for the next reaction. The nuclear magnetic data are as follows:
1H NMR(400M Hz,CDCl3)δ(ppm):1.59(m),1.96(m),2.65(m),4.74(s),7.06(d),7.07(d),7.14(dd)。
13C NMR(100.61M Hz,CDCl3)δ(ppm):22.1,22.6,42.1,42.4,60.4,74.2,123.3,126.8,127.0,128.6,141.7,148.8。
2) preparation of tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate (III)
Dissolving 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-dione (II) obtained in the step 1) in 100mL THF, adding TEA (9.6g,0.095), adding tert-butyl carbonate (FW ═ 174,16.44g,1.05eq) under cooling in an ice bath, heating to room temperature after the addition is finished, reacting for 8 hours, tracking the reaction of the raw materials by TLC, concentrating and recovering THF, adding DCM (50mL) and water (50mL) into the residue, extracting, standing and layering, extracting the organic layers with DCM (5mL × 3), combining the organic layers, drying, and concentrating to dryness to obtain 33.0g of light yellow solid (96.5% of two-step total yield). The nuclear magnetic data are as follows:
1H NMR(400M Hz,CDCl3)δ(ppm):1.40(s),1.59(m),1.96(m),2.96(m),4.74(s),7.06(d),7.07(dd),7.14(d)。
13C NMR(100.61M Hz,CDCl3)δ(ppm):19.3,44.9,22.6,28.5,42.1,79.9,125.5,126.8,127.0,128.6,135.8,141.7,148.9,160.4,174.2。
3) preparation of tert-butyl (4aR 7aS) -6-benzyl-octahydro-5, 7-dioxopyrrolo [3,4-b ] pyridine-1-carboxylate (IV)
To a small autoclave were added tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate (III) (FW ═ 342,3.42g,0.01mol), catalyst a (FW ═ 831,0.5 mol%), DCM (10mL), and the reaction was purged three times by hydrogenation, then the pressure of the hydrogen in the reactor was increased to 80 kg atm, the reaction was carried out at 30 ℃ for 24 hours, after the reaction did not absorb any more hydrogen, the reactor was vented by hydrogenation, the reaction mixture was concentrated to dryness under reduced pressure, MTBE (5mL) was added to the residue, and a pale yellow solid was precipitated by stirring, filtered, and dried to obtain 3.38g (FW ═ 344, yield 98.3%). The nuclear magnetic data are as follows:
1H NMR(400M Hz,CDCl3)δ(ppm):1.40(s),1.45-1.56(m),1.63-1.87(m),3.29-3.40(t),3.34(m),4.74(s),4.82(d),7.06(d),7.07(dd),7.14(d)。
13C NMR(100.61M Hz,CDCl3)δ(ppm):22.1,24.9,28.5,35.7,42.1,43.1,55.9,79.8,126.8,127.0,128.6,141.7,157.7,172.5,175.7。
HPLC analysis of the product, HPLC analysis conditions:
column: chiralcel AD-H, 250X 4.6mm
Mobile phase: n-hexane/isopropanol 99: 1 (volume ratio)
Flow rate: 1.0mL/min
Column temperature: 25 deg.C
Retention time: (S, S) -configuration 11min and (R, R) -configuration 12.5min
ee％＝93.3％
4) Preparation of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane
Tert-butyl (4aR,7aS) -6-benzyl-octahydro-5, 7-dioxopyrrolo [3,4-b ] pyridine-1-carboxylate (FW 344, 3g,0.0087mol) was weighed into a flask, dioxane (10mL) was added and dissolved with stirring, a dioxane solution (8mL) of concentrated hydrochloric acid (3mL) was slowly added dropwise, after the addition, the reaction was carried out at room temperature for 3 hours, TLC (TLC) followed until completion, the reaction was concentrated to dryness under reduced pressure, DCM (10mL) and water (10mL) were added to the residue and dissolved with stirring, the pH of the solution was adjusted to 8 or more with aqueous ammonia, extraction was allowed to stand for layer separation, the aqueous layer was extracted with DCM (5mL 3), the organic layers were combined and dried, and concentrated to obtain 1.97g (93%) of a pale yellow solid. The nuclear magnetic data are as follows:
1H NMR(400M Hz,CDCl3)δ(ppm):1.45-1.55(m),2.69-2.79(m),1.82-1.87(m),2.95(t),3.85(t),4.34(s),7.06(d),7.07(dd),7.14(dd)。
13C NMR(100.61M Hz,CDCl3)δ(ppm):24.9,38.5,42.1,45.1,58.6,126.8.127.0,128.6,141.7,172.5,175.7。
example 2:
synthesis of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane by the following steps:
1) preparation of 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-dione (II)
To a 250mL single neck flask was added N-benzylpiperidine dicarboximide (I) (FW 244,24.4g,0.1mol), toluene (100mL) was dissolved with stirring, and under cooling in an ice bath, manganese dioxide (FW 158,15.8g,0.1mol) was slowly added, after completion of addition, the reaction was carried out at room temperature for 5 hours, TLC tracing was completed, filtration was carried out, the solvent was removed by concentration under reduced pressure, DCM (50mL) and water (50mL) were added to the residue, the separated layers were extracted, the aqueous layer was extracted with DCM (10mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was used for the next reaction.
2) Preparation of tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate (III)
Dissolving 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-dione (II) obtained in the step 1) in 100mL THF, adding N, N-dimethylaminopyridine (11.6g,0.095mol), adding tert-butyl carbonate (FW ═ 174,16.44g,1.05eq) under cooling in an ice bath, heating to room temperature after the addition is finished, reacting for 8 hours, tracing the reaction of raw materials by TLC, concentrating and recovering THF, adding DCM (50mL) and water (50mL) to extract residues, standing for layering, extracting the organic layers with DCM (5mL × 3), combining the organic layers, drying, and concentrating to obtain 33.1g of light yellow solid (the total yield of the two steps is 96.8%).
3) Preparation of tert-butyl (4aR,7aS) -6-benzyl-octahydro-5, 7-dioxopyrrolo [3,4-b ] pyridine-1-carboxylate (IV)
Tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-B ] pyridine-1 (5H) carboxylate (III) (FW 342,3.42g,0.01mol), catalyst B (FW 859,0.5 mol%), DCM (10mL) were charged three times in accordance with hydrogenation reaction, the reaction vessel was charged with hydrogen pressure to 80 kg atm after replacement, reacted at 30 ℃ for 24 hours, after no further hydrogen absorption, the reaction vessel was vented in accordance with hydrogenation operation, the reaction mixture was concentrated to dryness under reduced pressure, MTBE (5mL) was added to the residue, and a pale yellow solid was precipitated by stirring, filtered, and dried to give 3.33g (FW 344, yield 97.4%). The product was analyzed by chiral HPLC and ee% ═ 97.3%.
4) Preparation of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane
Tert-butyl (4aR,7aS) -6-benzyl-octahydro-5, 7-dioxopyrrolo [3,4-b ] pyridine-1-carboxylate (FW 344, 3g,0.0087mol) was weighed into a flask, ethyl acetate (10mL) was added and dissolved with stirring, a methanol solution (8mL) of concentrated hydrochloric acid (3mL) was slowly added dropwise, after completion of the addition, the reaction was carried out at room temperature for 3 hours, the reaction was followed by TLC until complete, the reaction was concentrated to dryness under reduced pressure, DCM (10mL) and water (10mL) were added to the residue and dissolved with stirring, the pH of the solution was adjusted to 8 or more with aqueous ammonia, extraction was allowed to stand and separate layers, the aqueous layer was extracted with DCM (5mL 3), the organic layers were combined and dried, and concentrated to obtain 1.99g of a pale yellow solid (yield 93.9%).
Example 3:
synthesis of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane by the following steps:
1) preparation of 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-dione (II)
To a 250mL single-neck flask was added N-benzylpiperidine dicarboximide (I) (FW 244,24.4g,0.1mol), DCM (100mL) was dissolved with stirring, and under cooling in an ice bath, chromium trioxide (FW 100,10.0g,0.1mol) was slowly added, and after completion of the addition, the reaction was carried out at room temperature for 5 hours, TLC tracing was completed, filtration was carried out, water (50mL) was added to the filtrate, separation was extracted, the aqueous layer was extracted with DCM (10mL 3), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was used for the next reaction.
2) Preparation of tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate (III)
Dissolving 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-dione (II) obtained in the step 1) in 100mL of toluene, adding N, N-dimethylaminopyridine (11.6g,0.095mol), adding tert-butyl carbonate (FW ═ 174,16.44g,1.05eq) under cooling in an ice bath, heating to room temperature after the addition is finished, reacting for 8 hours, tracking the reaction of raw materials by TLC, adding water (50mL) into the reaction solution, extracting, standing for layering, extracting organic layers by using toluene (10mL 3), combining the organic layers, drying, and concentrating to obtain light yellow solid 33.3g (total yield in two steps 97.4%).
3) Preparation of tert-butyl (4aR,7aS) -6-benzyl-octahydro-5, 7-dioxopyrrolo [3,4-b ] pyridine-1-carboxylate (IV)
Tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate (III) (FW 342,3.42g,0.01mol), catalyst C (FW 891,0.5 mol%), DCM (10mL) were charged three times by hydrogenation, the reaction vessel was charged with a hydrogen pressure of 80 kg atm after the replacement, reacted at 30 ℃ for 24 hours, after no further hydrogen absorption, the reaction vessel was vented by hydrogenation, the reaction mixture was concentrated to dryness under reduced pressure, MTBE (5mL) was added to the residue, and a pale yellow solid was precipitated by stirring, filtered, and dried to obtain 3.30g (FW 344, yield 96.5%). The product was analyzed by chiral HPLC and ee% ═ 99.3%.
4) Preparation of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane
Tert-butyl (4aR,7aS) -6-benzyl-octahydro-5, 7-dioxopyrrole [3,4-b ] pyridine-1-carboxylate (FW 344, 3g,0.0087mol) was weighed and added to a flask, dichloromethane (10mL) was added and dissolved with stirring, a dichloromethane solution (8mL) of trifluoroacetic acid (3mL) was slowly added dropwise thereto, after completion of the addition, the reaction was carried out at room temperature for 3 hours, TLC followed the completion of the reaction, water (10mL) was added to the reaction mixture, dissolved with stirring, the pH of the solution was adjusted to 8 or more with aqueous ammonia, the mixture was extracted and allowed to stand, the aqueous layer was extracted with DCM (5mL 3), the organic layers were combined and dried, and concentrated to obtain a pale yellow solid 1.95g (yield 92.9%).
Example 4:
synthesis of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane by the following steps:
1) preparation of 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-dione (II)
To a 250mL single vial was added N-benzylpiperidine dicarboximide (I) (FW 244,24.4g,0.1mol), DCM (100mL) was dissolved with stirring, dichlorochromyl pyridine complex (FW 234, 23.4g, 0.1mol) was slowly added under cooling in an ice bath, the reaction was completed at room temperature for 5 hours, TLC tracing the completion of the reaction, filtration was completed, water (50mL) was added to the filtrate, the separated layers were extracted, the aqueous layer was extracted with DCM (10mL × 3), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was used for the next reaction.
2) Preparation of tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate (III)
Dissolving 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-dione (II) obtained in the step 1) in 100mL of toluene, adding N, N-dimethylaminopyridine (11.6g,0.095mol), adding tert-butyl carbonate (FW ═ 174,16.44g,1.05eq) under cooling in an ice bath, heating to room temperature after the addition is finished, reacting for 5 hours, tracking the reaction of raw materials by TLC, adding water (50mL) into the reaction solution, extracting, standing for layering, extracting organic layers by using toluene (10mL 3), combining the organic layers, drying, and concentrating to obtain light yellow solid 33.1g (total yield in two steps 96.8%).
3) Preparation of tert-butyl (4aR,7aS) -6-benzyl-octahydro-5, 7-dioxopyrrolo [3,4-b ] pyridine-1-carboxylate (IV)
Tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate (III) (FW 342,3.42g,0.01mol), catalyst C (0.5 mol%), DCM (10mL) were charged three times in accordance with the hydrogenation reaction, after which the reaction vessel was charged with hydrogen gas under a pressure of 80 kg at atmospheric pressure and reacted at 30 ℃ for 24 hours, after no further hydrogen absorption, the reaction vessel was vented in accordance with the hydrogenation operation, the reaction mixture was concentrated to dryness under reduced pressure, MTBE (5mL) was added to the residue, and a pale yellow solid was precipitated by stirring, filtered and dried to give 3.33g (FW 344, yield 96.8%). The product was analyzed by chiral HPLC and ee% ═ 99.5%.
4) Preparation of (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane
Tert-butyl (4aR,7aS) -6-benzyl-octahydro-5, 7-dioxopyrrole [3,4-b ] pyridine-1-carboxylate (FW 344, 3g,0.0087mol) was weighed and added to a flask, dioxane (10mL) was added and dissolved with stirring, a dioxane solution (8mL) of concentrated hydrochloric acid (3mL) was slowly added dropwise, after the addition, the reaction was carried out at room temperature for 3 hours, TLC (TLC) followed until completion, the reaction was concentrated to dryness under reduced pressure, DCM (10mL) and water (10mL) were added to the residue and dissolved with stirring, the pH of the solution was adjusted to 8 or more with aqueous ammonia, extraction was allowed to stand for separation, the aqueous layer was extracted with DCM (5mL 3), the organic layers were combined and dried, and concentrated to obtain 1.98g (yield 93.4%) of a pale yellow solid.
The upper and lower limit values and interval values of the raw materials of the invention can realize the invention, and the enumerated raw materials can realize the invention, so the examples are not necessarily listed.
It is noted that all references mentioned in this application are incorporated herein by reference as if each reference were individually incorporated by reference. It should be understood that the above-described embodiments of the present invention and the technical principles applied thereto are described, and those skilled in the art can make various modifications and alterations to the present invention without departing from the spirit and scope of the present invention, which also fall within the scope of the present invention.

Claims (9)

1. A method for synthesizing (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane is characterized by comprising the following steps:
using N-benzyl piperidine dicarboximide with a structural formula I aS a raw material, partially oxidizing to form an intra-ring double bond to obtain 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-diketone with a structural formula II, introducing an electron-withdrawing group tert-butoxycarbonyl group on an NH group to obtain 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrole [3,4-b ] pyridine-1 (5H) carboxylic acid tert-butyl ester with a structural formula III, and then carrying out asymmetric catalytic hydrogenation on the intra-ring double bond by using a chiral catalyst to obtain (4aR,7aS) -6-benzyl-octahydro-5, 7-dioxo pyrrole [3 with a structural formula IV, 4-b ] pyridine-1-carboxylic acid tert-butyl ester, and finally removing tert-butyloxycarbonyl group to obtain (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with the structural formula as follows:
Figure FDA0002648345300000011
the chiral catalyst is any one of compounds A, B and C, and the structural formulas of the compounds A, B and C are as follows:
Figure FDA0002648345300000012
2. the preparation method according to claim 1, comprising the following steps:
1) dissolving N-benzyl piperidine dicarboximide with a structural formula I in a solvent, adding an oxidant under ice bath, and then carrying out oxidation reaction for 3-6 hours at room temperature to form an intra-ring double bond to obtain 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-dione (II) with a structural formula II, wherein the molar ratio of the N-benzyl piperidine dicarboximide to the oxidant is 1: 1-5, post-treating to remove excessive oxidant for the next reaction, wherein the reaction formula is as follows:
Figure FDA0002648345300000021
2) dissolving the 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-dione with the structural formula II obtained in the step 1) in a proper solvent, adding tert-butyl carbonate under an ice bath condition in the presence of an alkali catalyst, then reacting at normal temperature for 3-10 hours, introducing tert-butoxycarbonyl on NH at the ortho position of the intra-ring double bond obtained in the step 1), and carrying out aftertreatment to obtain tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate with the structural formula III; wherein the mol ratio of the 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-diketone with the structural formula II to the alkali catalyst to the tert-butyl carbonate is 1: 0.1-1: 1-2, the reaction formula is:
Figure FDA0002648345300000022
3) carrying out asymmetric hydrogenation on the 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylic acid tert-butyl ester with the structural formula III obtained in the step 2) in a proper solvent in the presence of an asymmetric catalyst to obtain (4aR 7aS) -6-benzyl-octahydro-5, 7-dioxo-pyrrolo [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester with the structural formula IV; wherein the molar ratio of the asymmetric catalyst to the tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate of the structural formula III is 0.001-0.5: 1, the asymmetric hydrogenation reaction temperature is 20-80 ℃, the reaction time is 8-24 hours, the reaction pressure is 20-80 kg, the asymmetric catalyst is any one of compounds A, B, C, and the reaction formula is as follows:
Figure FDA0002648345300000023
4) reacting (4aR,7aS) -6-benzyl-octahydro-5, 7-dioxygen pyrrole [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester with a structural formula IV obtained in the step 3) in a proper solvent for 3-6 hours under the catalysis of acid to remove tert-butyloxycarbonyl group, thus obtaining (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with a structural formula V, wherein the reaction formula is aS follows:
Figure FDA0002648345300000031
3. the synthesis method according to claim 2, wherein the solvent used in step 1) is a polar solvent or a non-polar solvent, wherein the polar solvent is acetonitrile, THF, DMF, acetone, dioxane or water, and the non-polar solvent is benzene, toluene, 1, 2-dichloroethane, dichloromethane or trichloromethane; the volume weight ratio of the solvent to the N-benzyl piperidine dicarboximide with the structural formula I is 5-10: 1 mL/g.
4. The synthesis method according to claim 2, wherein the oxidant in step 1) is potassium permanganate, manganese dioxide, chromic acid, chromium trioxide, chromyl chloride pyridine complex or DDQ.
5. The synthesis method according to claim 2, wherein the step of post-treating to remove excess oxidant in the step 1) comprises: after the reaction is finished, evaporating the solvent to dryness to obtain a residue, dissolving the residue in a proper solvent, extracting and layering, and concentrating an organic layer until the organic layer is dried for the next reaction; wherein the solvent for dissolving the residue is toluene, acetonitrile, ethyl acetate, MTBE, isopropyl acetate or acetone, and the weight-volume ratio of the residue to the dissolved solvent is 1: 1-10.
6. The synthesis method according to claim 2, wherein in the step 2), the solvent is one or two of benzene, toluene, 1, 2-dichloroethane, dichloromethane or trichloromethane; the base catalyst used is TEA, DIPEA, DBU, DBACO, pyridine or N, N-lutidine.
7. The synthesis method according to claim 2, wherein in the step 3), the solvent is one or two of acetonitrile, THF, DMF, acetone, methanol, ethanol, isopropanol, dioxane, dichloromethane and water; the weight volume ratio of the tert-butyl 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylate of the structural formula III to the solvent is 1 g: 3-5 mL.
8. The synthesis method according to claim 2, wherein the step 3) is: adding a chiral catalyst, vacuumizing according to the requirement of hydrogenation reaction, exchanging gas with nitrogen and hydrogen for multiple times, filling hydrogen to 20-80 kg, and stopping reaction until the system does not absorb hydrogen any more.
9. The synthesis method of claim 2, wherein the solvent used in step 4) is one or two of acetonitrile, THF, DMF, acetone, methanol, ethanol, isopropanol, dioxane, water, dichloromethane and ethyl acetate; the acid catalyst is trifluoroacetic acid, hydrochloric acid and hydrobromic acid; after the acid catalytic reaction is finished, concentrating to be dry, adding water and a proper organic solvent into residues or directly adding water, then adjusting the pH to be more than 8 by using ammonia water, extracting the water phase for multiple times by using the organic solvent, combining organic layers, drying and concentrating to obtain (1S,6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane with the structural formula V; the organic solvent for extraction is toluene, dichloromethane, chloroform, dichloroethane, MTBE or EA.
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