CN114085219B - 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 PDFInfo
- Publication number
- CN114085219B CN114085219B CN202010861684.XA CN202010861684A CN114085219B CN 114085219 B CN114085219 B CN 114085219B CN 202010861684 A CN202010861684 A CN 202010861684A CN 114085219 B CN114085219 B CN 114085219B
- Authority
- CN
- China
- Prior art keywords
- benzyl
- solvent
- reaction
- pyridine
- structural formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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: n-benzyl piperidine dicarboximide is used as a raw material, a ring internal double bond is formed by partial oxidation, then an electron withdrawing group t-butoxycarbonyl is introduced into an NH group at the ortho position of the ring internal double bond, then asymmetric catalytic hydrogenation is carried out on the double bond by using a chiral catalyst, and finally the t-butoxycarbonyl is removed, thus obtaining the (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 up to 99.5%, low cost and industrial practical value.
Description
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
(1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane is an intermediate for synthesizing important raw material (S, S) -2, 8-diazabicyclo [4.3.0] nonane of moxifloxacin. Moxifloxacin is a fourth-generation quinolone drug and has a strong antibacterial effect on gram-positive bacteria, gram-negative bacteria (except pseudomonas aeruginosa), atypical pathogenic bacteria and anaerobic bacteria, so that 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.
Patent (WO 9415938) discloses the preparation of (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane by resolution of different chiral amines starting from 2, 3-dipicolinic acid, by the following route:
the method is used for resolving and obtaining the (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, and the 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 facilitating 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 above purpose, the present invention adopts the following technical scheme:
provided is a method for synthesizing (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, comprising the steps of:
n-benzyl piperidine dicarboximide with a structural formula I is used as a raw material, a ring double bond is formed by partial oxidation to obtain 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-dione with a structural formula II, an electron withdrawing group tert-butoxycarbonyl group is introduced 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 asymmetric catalytic hydrogenation is carried out on the ring double bond by using a chiral catalyst to obtain (4 aR,7 aS) -6-benzyl-octahydro-5, 7-dioxopyrrole [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester with a structural formula IV, and finally tert-butoxycarbonyl is removed to obtain (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [ 4.0.nonane with a structural formula V as shown in the following reaction formula:
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:
according to the scheme, the specific steps are as follows:
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 at room temperature for 3-6 hours to form a 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, removing excessive oxidant by post-treatment for the next reaction, wherein the reaction formula is as follows:
2) Dissolving 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-dione with a structural formula II obtained in the step 1) in a proper solvent, adding tert-butyl carbonate under the ice bath condition in the presence of a base catalyst, then reacting for 3-10 hours at normal temperature, introducing tert-butoxycarbonyl (Boc) on NH at the ortho position of a ring double bond obtained in the step 1), and performing post treatment to obtain 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylic acid tert-butyl ester with a structural formula III; wherein the molar ratio of the 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-dione with the structural formula II, the base catalyst and the tert-butyl carbonate is 1:0.1-1:1-2, the reaction formula is:
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 a structural formula III obtained in the step 2) in a proper solvent in the presence of an asymmetric catalyst to obtain (4 aR 7 aS) -6-benzyl-octahydro-5, 7-dioxo-pyrrolo [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester with a 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 with 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:
4) Reacting the (4 aR,7 aS) -6-benzyl-octahydro-5, 7-dioxo 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-butoxycarbonyl, 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:
according to the scheme, the solvent used in the step 1) is a polar solvent or a nonpolar solvent, wherein the polar solvent is acetonitrile, THF, DMF, acetone, dioxane or water, and the nonpolar solvent is benzene, toluene, 1, 2-dichloroethane, dichloromethane or chloroform; the volume weight ratio of the solvent to the N-benzyl piperidine dicarboximide with the structural formula I is 5-10:1mL/g.
According to the scheme, the oxidant in the step 1) is potassium permanganate, manganese dioxide, chromic acid, chromium trioxide, chromyl 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 in the post-treatment in the step 1) comprises the following steps: evaporating the solvent after the reaction 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 chloroform; the base catalyst used was 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 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 to the solvent is 1g:3-5mL.
According to the scheme, the step 3) is as follows: adding chiral catalyst, vacuumizing according to hydrogenation reaction requirement, ventilating with nitrogen and hydrogen for several times, charging hydrogen to 20-80 kg, and stopping reaction until the system does not absorb hydrogen.
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; concentrating to dryness after the acid catalytic reaction is finished, adding water and a proper organic solvent or directly adding water into residues, then adjusting the pH value to be more than 8 by using ammonia water, extracting an aqueous 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 a structural formula V; the organic solvent for extraction is toluene, dichloromethane, chloroform, dichloroethane, MTBE or EA.
The invention uses N-benzyl piperidine dicarboximide as raw material, uses electron-withdrawing function of two carbonyl groups in the raw material to enhance the activity of hydrogen on ortho carbon, and can obtain ring double bond, namely asymmetric catalytic hydrogenation reaction site through oxidation of oxidant under mild condition. The chiral inducibility and catalytic activity of chiral catalysts present significant challenges due to steric hindrance problems at the site of the ring double bond. In the invention, the selected chiral iridium catalyst is only reported to be used for asymmetric addition of double bonds on a straight chain, and the asymmetric hydrogenation of the double bonds in a ring with steric hindrance is also used for the first time, so that a good effect is obtained. In the design of a reaction route, boc electron-withdrawing groups are introduced by utilizing imino groups at the ortho positions of the double bonds in the ring, so that the electron cloud density of the double bonds is reduced, the reaction is further promoted, and the defect of low yield caused by steric hindrance effect is overcome. Finally, the target product with high corresponding selectivity can be obtained only through conventional Boc removal. Compared with the prior art, the invention can obtain more than 96% of asymmetric conversion rate, and the ee value can reach 99.5%, thereby having great advantages in yield and enantioselectivity.
The beneficial effects of the invention are as follows:
1. the invention obtains a single asymmetric target product through a simple four-step reaction of ring double bond, introduction of electron withdrawing group Boc at the ortho position of double bond and removal of electron withdrawing group Boc by asymmetric catalytic hydrogenation of ring double bond; the invention takes the compound N-benzyl piperidine dicarboximide (I) as a raw material, on one hand, the ring double bond can be obtained through partial oxidation under mild conditions, a reaction site of the subsequent asymmetric catalytic hydrogenation reaction is provided, on the other hand, the NH at the ortho position of the obtained ring double bond can be utilized to introduce an electron withdrawing group Boc, so that the ring double bond is activated, the yield and enantioselectivity of the asymmetric catalytic hydrogenation reaction are increased, the asymmetric catalytic hydrogenation conversion rate of the ring double bond 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 synthesis method has the advantages of mild reaction conditions, low-cost and easily-obtained raw materials, simple operation, low process cost and industrial practical value.
Detailed Description
For a better understanding of the present invention, the following examples are further illustrated, but are not limited to the following examples.
Catalysts a, B, C used in the examples below have the following structural formulae, respectively:
example 1:
synthesis of (1 s,6 r) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane by the following procedure:
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,0.1 mol), acetone and water (1:1, 100 mL) with stirring to dissolve, slowly potassium permanganate (fw=158, 15.8g,0.1 mol) was added under ice-bath cooling, after addition, room temperature was reacted for 5 hours, TLC followed by reaction, solvent was removed by concentration under reduced pressure, DCM (50 mL) and water (50) were added to the residue, the layers were extracted, the aqueous layer was extracted with DCM (10 ml×3), the organic layer was combined, dried over anhydrous sodium sulfate, and concentrated to dryness for the next reaction. The nuclear magnetic data are as follows:
1 H NMR(400M Hz,CDCl 3 )δ(ppm):1.59(m),1.96(m),2.65(m),4.74(s),7.06(d),7.07(d),7.14(dd)。
13 C NMR(100.61M Hz,CDCl 3 )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)
The 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-dione (II) obtained in step 1) was dissolved in 100mL of THF, TEA (9.6 g, 0.095) was added, tert-butyl carbonate (fw=174, 16.44g,1.05 eq) was added with ice-bath cooling, after addition was warmed to room temperature for 8 hours, TLC followed by complete reaction of starting material, THF was recovered by concentration, the residue was extracted with DCM (50 mL) and water (50 mL), the organic layer was extracted with DCM (5 mL x 3) and the organic layer was combined, dried and concentrated to dryness to give 33.0g of pale yellow solid (96.5% total yield in two steps). The nuclear magnetic data are as follows:
1 H NMR(400M Hz,CDCl 3 )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)。
13 C NMR(100.61M Hz,CDCl 3 )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 (4 aR 7 aS) -6-benzyl-octahydro-5, 7-dioxopyrrolo [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester (IV)
To a small autoclave was 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,0.01 mol), catalyst a (fw=831, 0.5 mol%) DCM (10 mL), the hydrogenation reaction was ventilated three times, the autoclave was charged with hydrogen pressure to 80 kg atmospheric pressure after the exchange, the reaction was allowed to react at 30 ℃ for 24 hours, after no more hydrogen absorption, the autoclave was vented by hydrogenation, the reaction solution was concentrated to dryness under reduced pressure, MTBE (5 mL) was added to the residue, and a pale yellow solid was precipitated by stirring, filtered, and dried to give 3.38g (fw=344, yield 98.3%). The nuclear magnetic data are as follows:
1 H NMR(400M Hz,CDCl 3 )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)。
13 C NMR(100.61M Hz,CDCl 3 )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。
product HPLC analysis, 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: 11min for the (S, S) -configuration and 12.5min for the (R, R) -configuration
ee％＝93.3％
4) Preparation of (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane
Tert-butyl (4 ar,7 as) -6-benzyl-octahydro-5, 7-dioxopyrrole [3,4-b ] pyridine-1-carboxylate (fw=344, 3g,0.0087 mol) was weighed into a flask, dioxane (10 mL) was added and dissolved with stirring, a dioxane solution (8 mL) of concentrated hydrochloric acid (3 mL) was slowly added dropwise, after addition, the reaction was carried out at room temperature for 3 hours, TLC followed by reaction to completion, vacuum concentration to dryness, DCM (10 mL) and water (10 mL) were added to the residue, stirred and dissolved, pH of the solution was adjusted to 8 or more with ammonia, extraction was stopped for delamination, the aqueous layer was extracted with DCM (5 ml×3), organic layer was combined and dried, and concentrated to give 1.97g (yield 93%) of pale yellow solid. The nuclear magnetic data are as follows:
1 H NMR(400M Hz,CDCl 3 )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)。
13 C NMR(100.61M Hz,CDCl 3 )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 (1 s,6 r) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane by the following procedure:
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,0.1 mol), toluene (100 mL) was dissolved with stirring, and under ice-bath cooling, manganese dioxide (fw=158, 15.8g,0.1 mol) was slowly added, and after addition, the reaction was carried out at room temperature for 5 hours, TLC followed by filtration, the solvent was removed by concentration under reduced pressure, the residue was added DCM (50 mL) and water (50 mL), the layers were extracted, the aqueous layer was extracted with DCM (10 ml×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)
The 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-dione (II) obtained in step 1) was dissolved in 100mL of THF, N-dimethylaminopyridine (11.6 g,0.095 mol) was added, tert-butyl carbonate (fw=174, 16.44g,1.05 eq) was added with ice-bath cooling, after addition was warmed to room temperature for 8 hours, TLC followed by complete reaction of the starting material, THF was recovered by concentration, the residue was extracted with DCM (50 mL) and water (50 mL), and allowed to stand for delamination, the organic layer was extracted with DCM (5 mL of 3), the organic layer was combined, dried, concentrated to dryness to give a pale yellow solid of 33.1g (96.8% in total yield in two steps).
3) Preparation of (4 aR,7 aS) -6-benzyl-octahydro-5, 7-dioxopyrrolo [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester (IV)
To a small autoclave was 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,0.01 mol), catalyst B (fw=859, 0.5 mol%) DCM (10 mL), the hydrogenation reaction was ventilated three times, the autoclave was charged with hydrogen pressure to 80 kg atmospheric pressure after the exchange, the reaction was allowed to proceed for 24 hours at 30 ℃, the reaction was vented by hydrogenation operation after the reaction was no longer hydrogen absorbed, the reaction solution was concentrated to dryness under reduced pressure, MTBE (5 mL) 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, ee% = 97.3%.
4) Preparation of (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane
Tert-butyl (4 ar,7 as) -6-benzyl-octahydro-5, 7-dioxopyrrole [3,4-b ] pyridine-1-carboxylate (fw=344, 3g,0.0087 mol) was weighed into a flask, ethyl acetate (10 mL) was added to stir and dissolve, concentrated hydrochloric acid (3 mL) in methanol (8 mL) was slowly added dropwise, after addition, the reaction was completed at room temperature for 3 hours, TLC followed by reaction to completion, concentrated to dryness under reduced pressure, DCM (10 mL) and water (10 mL) were added to the residue, stirred and dissolved, the pH of the solution was adjusted to 8 or more with aqueous ammonia, the layer was allowed to stand for extraction, the aqueous layer was extracted with DCM (5 ml×3), the organic layer was combined and dried, and concentrated to give 1.99g (yield 93.9%) of pale yellow solid.
Example 3:
synthesis of (1 s,6 r) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane by the following procedure:
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,0.1 mol), DCM (100 mL) was dissolved with stirring, chromium trioxide (fw=100, 10.0g,0.1 mol) was slowly added with ice-bath cooling, reaction was completed by TLC at room temperature for 5 hours, filtration was completed, water in filtrate (50 mL) was filtered, the extract was separated, the aqueous layer was extracted with DCM (10 ml×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 the 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-dione (II) obtained in step 1) in 100mL of toluene, adding N, N-dimethylaminopyridine (11.6 g,0.095 mol), cooling with ice bath, adding tert-butyl carbonate (FW=174, 16.44g,1.05 eq), heating to room temperature after the addition for 8 hours, tracking the reaction of the raw materials by TLC, adding water (50 mL) to the reaction solution for extraction, standing for delamination, extracting the organic layer with toluene (10 mL. Times.3), combining the organic layers, drying, concentrating to dryness to obtain light yellow solid (total yield of two steps is 97.4%).
3) Preparation of (4 aR,7 aS) -6-benzyl-octahydro-5, 7-dioxopyrrolo [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester (IV)
To a small autoclave was 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,0.01 mol), catalyst C (fw=891, 0.5 mol%) DCM (10 mL), the hydrogenation reaction was ventilated three times, the autoclave was charged with hydrogen pressure to 80 kg atmospheric pressure after the exchange, the reaction was allowed to proceed for 24 hours at 30 ℃, the reaction was vented by hydrogenation operation after the reaction was no longer hydrogen absorbed, the reaction solution was concentrated to dryness under reduced pressure, MTBE (5 mL) was added to the residue, and a pale yellow solid was precipitated by stirring, filtered, and dried to give 3.30g (fw=344, yield 96.5%). The product was analyzed by chiral HPLC, ee% = 99.3%.
4) Preparation of (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane
Tert-butyl (4 ar,7 as) -6-benzyl-octahydro-5, 7-dioxopyrrole [3,4-b ] pyridine-1-carboxylate (fw=344, 3g,0.0087 mol) was weighed into a flask, dichloromethane (10 mL) was added and stirred to dissolve, trifluoroacetic acid (3 mL) in dichloromethane (8 mL) was slowly added dropwise, after addition, the reaction was completed at room temperature for 3 hours, TLC followed by reaction to completion, water (10 mL) was added to the reaction solution, stirred to dissolve, pH of the solution was adjusted to above 8 with ammonia, static stratification was extracted, the aqueous layer was extracted with DCM (5 ml×3), the organic layer was combined and dried, and concentrated to 1.95g (yield 92.9%) of pale yellow solid.
Example 4:
synthesis of (1 s,6 r) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane by the following procedure:
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,0.1 mol), DCM (100 mL) was dissolved with stirring, and under ice-bath cooling, the dichloropyridine complex (fw=234, 23.4g,0.1 mol) was slowly added, and after the addition, the reaction was carried out at room temperature for 5 hours, TLC followed the reaction, filtration, water (50 mL) in the filtrate, extraction of the layers, extraction of the aqueous layer with DCM (10 ml×3), and the combined organic layers, 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 the 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-dione (II) obtained in step 1) in 100mL of toluene, adding N, N-dimethylaminopyridine (11.6 g,0.095 mol), cooling with ice bath, adding tert-butyl carbonate (FW=174, 16.44g,1.05 eq), heating to room temperature after the addition for reaction for 5 hours, TLC tracking the reaction of the raw materials, adding water (50 mL) to the reaction solution for extraction, standing for delamination, extracting the organic layer with toluene (10 mL. Times.3), combining the organic layers, drying, concentrating to dryness to obtain light yellow solid (96.8% of total yield in two steps).
3) Preparation of (4 aR,7 aS) -6-benzyl-octahydro-5, 7-dioxopyrrolo [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester (IV)
To a small autoclave was 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,0.01 mol), catalyst C (0.5 mol%), DCM (10 mL), the hydrogenation was ventilated three times, after the exchange, the autoclave was pressurized to 80 kg atmospheric pressure, reacted at 30℃for 24 hours, after the reaction was no longer hydrogen-absorbing, the autoclave was vented by hydrogenation, the reaction mixture was concentrated to dryness under reduced pressure, MTBE (5 mL) was added to the residue, and a pale yellow solid was stirred and precipitated, filtered, and dried to obtain 3.33g (FW=344, yield 96.8%). The product was analyzed by chiral HPLC, ee% = 99.5%.
4) Preparation of (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane
Tert-butyl (4 ar,7 as) -6-benzyl-octahydro-5, 7-dioxopyrrole [3,4-b ] pyridine-1-carboxylate (fw=344, 3g,0.0087 mol) was weighed into a flask, dioxane (10 mL) was added and dissolved with stirring, concentrated hydrochloric acid (3 mL) dioxane solution (8 mL) was slowly added dropwise, after addition, the reaction was completed at room temperature for 3 hours, TLC followed by reaction to completion, vacuum concentration to dryness, DCM (10 mL) and water (10 mL) were added to the residue, stirred and dissolved, pH of the solution was adjusted to 8 or more with ammonia, extraction was stopped for delamination, the aqueous layer was extracted with DCM (5 ml×3), organic layer was combined and dried, and concentrated to obtain pale yellow solid (yield 93.4%).
The present invention can be realized by the upper and lower limit values and the interval values of the respective raw materials, and the present invention can be realized by the respective raw materials, and examples are not limited to this.
It should be noted that all documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. It will be appreciated that in view of the foregoing, it will be evident to those skilled in the art that various modifications and changes may be made to this invention without departing from the broader spirit and scope of the invention as set forth in the appended claims.
Claims (9)
1. A method for synthesizing (1 s,6 r) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane, comprising the steps of:
n-benzyl piperidine dicarboximide with a structural formula I is used as a raw material, a ring double bond is formed by partial oxidation to obtain 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-dione with a structural formula II, an electron withdrawing group tert-butoxycarbonyl group is introduced 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 asymmetric catalytic hydrogenation is carried out on the ring double bond by using a chiral catalyst to obtain (4 aR,7 aS) -6-benzyl-octahydro-5, 7-dioxopyrrole [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester with a structural formula IV, and finally tert-butoxycarbonyl is removed to obtain (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [ 4.0.nonane with a structural formula V as shown in the following reaction formula:
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:
2. the preparation method according to claim 1, characterized by the specific steps of:
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 at room temperature for 3-6 hours to form a 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, removing excessive oxidant by post-treatment for the next reaction, wherein the reaction formula is as follows:
2) Dissolving 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrolo [3,4-b ] pyridine-5, 7-dione with a structural formula II obtained in the step 1) in a proper solvent, adding tert-butyl carbonate under the ice bath condition in the presence of a base catalyst, then reacting for 3-10 hours at normal temperature, introducing tert-butoxycarbonyl on NH at the ortho position of a ring double bond obtained in the step 1), and performing post treatment to obtain 6-benzyl-3, 4,6, 7-tetrahydro-5, 7-dioxo-2H-pyrrolo [3,4-b ] pyridine-1 (5H) carboxylic acid tert-butyl ester with a structural formula III; wherein the molar ratio of the 6-benzyl-1, 2,3, 4-tetrahydro-6H-pyrrole [3,4-b ] pyridine-5, 7-dione with the structural formula II, the base catalyst and the tert-butyl carbonate is 1:0.1-1:1-2, the reaction formula is:
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 a structural formula III obtained in the step 2) in a proper solvent in the presence of an asymmetric catalyst to obtain (4 aR 7 aS) -6-benzyl-octahydro-5, 7-dioxo-pyrrolo [3,4-b ] pyridine-1-carboxylic acid tert-butyl ester with a 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 with 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:
4) Reacting the (4 aR,7 aS) -6-benzyl-octahydro-5, 7-dioxo 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-butoxycarbonyl, 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:
3. the method according to claim 2, wherein the solvent used in step 1) is a polar solvent or a nonpolar solvent, wherein the polar solvent is acetonitrile, THF, DMF, acetone, dioxane or water, and the nonpolar solvent is benzene, toluene, 1, 2-dichloroethane, dichloromethane or chloroform; the volume weight ratio of the solvent to the N-benzyl piperidine dicarboximide with the structural formula I is 5-10:1mL/g.
4. The method according to claim 2, wherein the oxidizing agent in step 1) is potassium permanganate, manganese dioxide, chromic acid, chromium trioxide, chromyl pyridine complex or DDQ.
5. The method according to claim 2, wherein the step of removing the excess oxidant by post-treatment in step 1) comprises: evaporating the solvent after the reaction 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 method according to claim 2, wherein in the step 2), the solvent is one or two of benzene, toluene, 1, 2-dichloroethane, dichloromethane and chloroform; the base catalyst used was TEA, DIPEA, DBU, DBACO, pyridine or N, N-lutidine.
7. The 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, water; the weight volume ratio of 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 to the solvent is 1g:3-5mL.
8. The synthesis method according to claim 2, wherein the step 3) is: adding chiral catalyst, vacuumizing according to hydrogenation reaction requirement, ventilating with nitrogen and hydrogen for several times, charging hydrogen to 20-80 kg, and stopping reaction until the system does not absorb hydrogen.
9. The method according to claim 2, wherein the solvent used in the step 4) is one or two of acetonitrile, THF, DMF, acetone, methanol, ethanol, isopropanol, dioxane, water, dichloromethane, ethyl acetate; the acid catalyst is trifluoroacetic acid, hydrochloric acid and hydrobromic acid; concentrating to dryness after the acid catalytic reaction is finished, adding water and a proper organic solvent or directly adding water into residues, then adjusting the pH value to be more than 8 by using ammonia water, extracting an aqueous 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 a structural formula V; the organic solvent for extraction is toluene, dichloromethane, chloroform, dichloroethane, MTBE or EA.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010861684.XA CN114085219B (en) | 2020-08-25 | 2020-08-25 | Synthesis of (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010861684.XA CN114085219B (en) | 2020-08-25 | 2020-08-25 | Synthesis of (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114085219A CN114085219A (en) | 2022-02-25 |
| CN114085219B true CN114085219B (en) | 2023-08-01 |
Family
ID=80294859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010861684.XA Active CN114085219B (en) | 2020-08-25 | 2020-08-25 | Synthesis of (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114085219B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102408427A (en) * | 2011-10-22 | 2012-04-11 | 浙江普洛康裕制药有限公司 | Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane |
| CN102746294A (en) * | 2011-10-12 | 2012-10-24 | 郭峰 | Preparation method of (S,S)-2,8-diazabicyclo[4.3.0] |
| CN103788090A (en) * | 2014-01-26 | 2014-05-14 | 绍兴文理学院 | Racemization method of (1R, 6S)-8-benzyl-7, 9-dioxo-2, 8- diazabicyclo (4, 3, 0) nonane |
| CN110317201A (en) * | 2019-07-31 | 2019-10-11 | 武汉理工大学 | The method of asymmetric synthesis of (S, S) -2,8- diazabicyclo [4,3,0] nonane |
| CN111100125A (en) * | 2019-12-31 | 2020-05-05 | 厦门本素药业有限公司 | Preparation method of moxifloxacin intermediate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112707901B (en) * | 2020-12-07 | 2022-03-22 | 泰安汉威集团有限公司 | Preparation method of compound A |
-
2020
- 2020-08-25 CN CN202010861684.XA patent/CN114085219B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746294A (en) * | 2011-10-12 | 2012-10-24 | 郭峰 | Preparation method of (S,S)-2,8-diazabicyclo[4.3.0] |
| CN102408427A (en) * | 2011-10-22 | 2012-04-11 | 浙江普洛康裕制药有限公司 | Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane |
| CN103788090A (en) * | 2014-01-26 | 2014-05-14 | 绍兴文理学院 | Racemization method of (1R, 6S)-8-benzyl-7, 9-dioxo-2, 8- diazabicyclo (4, 3, 0) nonane |
| CN110317201A (en) * | 2019-07-31 | 2019-10-11 | 武汉理工大学 | The method of asymmetric synthesis of (S, S) -2,8- diazabicyclo [4,3,0] nonane |
| CN111100125A (en) * | 2019-12-31 | 2020-05-05 | 厦门本素药业有限公司 | Preparation method of moxifloxacin intermediate |
Non-Patent Citations (2)
| Title |
|---|
| Enantioselective Synthesis of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogenation: A Facile Approach to the Preparation of Chiral Allylic and Homoallylic Compounds;Taigang Zhou 等;《Journal of the American Chemical Society》;第134卷;13592-13595 * |
| Highly Enantioselective Iridium-Catalyzed Hydrogenation of a, b -Unsaturated Esters;Jia-Qi Li 等;《Chem. Eur. J.》;第18卷;10609-10616 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114085219A (en) | 2022-02-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113880750B (en) | Synthesis method of chiral 3-substituted-3-aryl oxindole compound | |
| CN111978236B (en) | Preparation method of N-substituted-3-morpholinyl-4-phenylseleno maleimide compound | |
| CN107602577A (en) | Chiral bridge ring skeleton hydroxyindole spiro piperidines and its synthetic method | |
| CN104262225B (en) | 3-aminopyrrolidine compounds, and synthetic method and uses thereof | |
| CN109942593B (en) | Total synthesis method of racemic tetrandrine | |
| CN112916042A (en) | Chiral quaternary ammonium salt phase transfer catalyst based on tetramethyl spiroindane skeleton and preparation method thereof | |
| CN112028809A (en) | Preparation method of 3-amino-4-phenylseleno maleimide compound | |
| CN114085219B (en) | Synthesis of (1S, 6R) -8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane | |
| CN103183673B (en) | The synthetic method of (S, S)-2,8-diazabicyclo [4,3,0] nonane | |
| CN108863890B (en) | 4-pyrroline-2-ketone derivative and preparation method thereof | |
| CN111978237B (en) | Preparation method of 3-morpholinyl-4-arylseleno maleimide compound | |
| WO2012131629A1 (en) | A process for preparation of intermediate of moxifloxacin | |
| Zhu et al. | Asymmetric synthesis. 29. Preparation of 1, 8-diazaspiro [5.5] undecane derivatives | |
| CN108191863A (en) | A kind of B-carboline of carboxylic acid derivatization and preparation method thereof | |
| CN108623583B (en) | Preparation method of iridium-catalyzed moxifloxacin side chain intermediate | |
| CN114874139B (en) | Synthesis method of 1-benzyl or allyl 3, 4-dihydroisoquinoline | |
| SHIMIZU et al. | Asymmetric synthesis and absolute configuration of (-)-trypargine | |
| CN110317201A (en) | The method of asymmetric synthesis of (S, S) -2,8- diazabicyclo [4,3,0] nonane | |
| CN111560017B (en) | Dipeptide mimetic based on azabicyclo [ X, Y, 0] alkanone framework and preparation method thereof | |
| CN108690017B (en) | Preparation method of rhodium-catalyzed moxifloxacin side chain intermediate | |
| CN109265403B (en) | Synthesis method of benzimidazole and derivatives thereof | |
| CN108129404B (en) | Synthesis method of chiral piperazinone derivative | |
| Zhang et al. | Synthetic Studies on Camptothecins. Part 1: An Improved Asymmetric Total Synthesis of (20S)‐Camptothecin | |
| KR102673606B1 (en) | Method for producing L-erythrobiopterin type compounds | |
| Urban et al. | Synthesis of an optically active octahydro-2H-pyrido [1, 2-a] pyrazine based CNS agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |