CN112939849B - (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and preparation method and application thereof - Google Patents
(S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D211/30—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 with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—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 with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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- 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
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Abstract
The invention discloses a (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and a preparation method and application thereof, wherein a new compound, namely compounds II to V, is used as a key intermediate to develop a new route for synthesizing (S, S) -2, 8-diazabicyclo [4.3.0] nonane, and the route takes dialkoxy acetate as an initial raw material and sequentially carries out claisen condensation, substitution reaction, intramolecular dehydration cyclization, catalytic hydrogenation reduction, chiral resolution, dissociation, hydrolysis, intramolecular dehydration cyclization and catalytic hydrogenation to obtain the (S, S) -2, 8-diazabicyclo [4.3.0] nonane. The preparation method disclosed by the invention is simple in preparation process, high in total reaction yield, good in product quality, green and environment-friendly in process route, and has good industrial application prospect.
Description
Technical Field
The invention relates to the technical field of preparation of medical intermediates, in particular to a (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate and a preparation method and application thereof.
Background
The moxifloxacin as a fourth-generation quinolone drug has the advantages of high efficiency, wide antibacterial spectrum, excellent pharmacokinetic property and low toxicity, is widely applied to treatment of respiratory tract infection such as acquired pneumonia, acute attack of chronic bronchitis and the like, and achieves great success. (S, S) -2, 8-diazabicyclo [4.3.0]Nonane is a key chiral intermediate for the synthesis of moxifloxacin. (S, S) -2, 8-diazabicyclo [4.3.0]The CAS number of nonane is 151213-40-0, and the molecular formula is C7H14N2Colorless to pale yellow liquid, structural formula as follows:
at present, the preparation routes of (S, S) -2, 8-diazabicyclo [4.3.0] nonane suitable for industrial production reported by domestic and foreign documents are mainly as follows:
route one:
using 2, 3-pyridine dicarboxylic acid as initial raw material, dehydrating and cyclizing with benzylamine in acetic anhydride, then catalytically hydrogenating and reducing pyridine, and then reacting with NaBH4/BF3The system reduces carbonyl, and then (S, S) -2, 8-diazabicyclo [4.3.0] is obtained through tartaric acid resolution and hydrogenation debenzylation]Nonane. The synthetic literature of the route is also reported to be the most widely used route at present. When reducing carbonyl, a large amount of NaBH which is a relatively expensive reducing agent is used4Therefore, the cost is high, the post-treatment is complicated, and a large amount of solid waste is generated and is not environment-friendly.
And a second route:
patent CN103282361A is an asymmetric synthesis method, which comprises the steps of taking a 3-pyrrolidone compound as a raw material, carrying out substitution reaction with 1-chloro-3-iodopropane, removing ester groups of the obtained compound under an acidic condition, then carrying out reduction amination with (R) -1-phenylethylamine, then carrying out intramolecular condensation cyclization, and finally carrying out catalytic hydrogenation to remove protective groups to obtain (S, S) -2, 8-diazabicyclo [4.3.0] nonane. The synthesis of the route is complicated, the raw materials are expensive, and the production cost is high.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides an (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate, a preparation method thereof and an application thereof in preparing (S, S) -2, 8-diazabicyclo [4.3.0] nonane, and when the (S, S) -2, 8-diazabicyclo [4.3.0] nonane is prepared from the intermediates, the adopted raw materials are cheap and easy to obtain, a carbonyl reduction step is not needed, and the whole process route is easier to industrialize.
In order to solve the problems, the technical scheme of the invention is as follows:
an (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate which is compound II, compound III, compound IV or compound V;
the structural formulas of the compound II, the compound III, the compound IV and the compound V are as follows:
wherein R is1Is C1-4An alkyl group. Further, R1Methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, most preferably methyl.
When R is1When the methyl group is adopted, the compound II, the compound III and the compound IV are respectively marked as a compound II-1, a compound III-1 and a compound IV-1, and the structural formula is as follows:
the compound II, the compound III, the compound IV or the compound V are all new compounds, and the invention uses the compoundsThe new compound is a key intermediate, and a new synthetic (S, S) -2, 8-diazabicyclo [4.3.0] is developed]A new route to nonanes. Compared with the prior art route I, the method does not need to carry out a carbonyl reduction step, and avoids using expensive NaBH4/BF3A reducing agent; compared with the second route, the adopted raw materials are cheap and easy to obtain, the cost is lower, and the method has better industrialization prospect.
The invention also provides a synthetic method of the (S, S) -2, 8-diazabicyclo [4.3.0] nonane intermediate, which comprises the following steps:
(1) carrying out substitution reaction on the compound I and halogenated propylamine under an alkaline condition, and then carrying out intramolecular dehydration and cyclization to obtain a compound II;
(2) carrying out catalytic hydrogenation reduction on the compound II to obtain a compound III;
(3) carrying out chiral resolution and alkalinization dissociation on the compound III to obtain a compound IV;
(4) hydrolyzing the compound IV under the action of acid, and then performing intramolecular dehydration cyclization to obtain a compound V;
the structural formula of compound I is as follows:
R1when R is as defined above1When the substituent is methyl, the compound I is represented as a compound I-1.
Each step is described below.
In the step (1), the reaction formula is as follows:
in the step (1), the base is one or more of sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate and the like, and potassium carbonate is preferred.
In the step (1), the halogenated propylamine is chloropropylamine, bromopropylamine or iodopropylamine, and is preferably chloropropylamine.
In the step (1), the solvent for the substitution reaction is one or more selected from n-hexane, toluene, tetrahydrofuran, chlorobenzene, dichloromethane and acetone, and tetrahydrofuran is preferred; the reaction temperature is 30-100 ℃, and preferably 40-80 ℃; the reaction time is 2-6 hours.
During this step, a certain amount of a drying agent (e.g., calcium chloride) may also be added to facilitate the dehydration process.
In the step (2), the reaction formula is as follows:
in the step (2), the catalyst for catalytic hydrogenation is selected from palladium carbon, ruthenium black, Raney nickel or palladium carbon hydroxide, preferably palladium carbon; the dosage of the catalyst is 2-20% of the mass of the substrate, preferably 5% -10%; the solvent is one or more selected from toluene, xylene, n-hexane, tetrahydrofuran and methanol, preferably methanol; the reaction temperature is 60-130 ℃, and preferably 65-105 ℃; the reaction time is 2-10 hours, preferably 3-8 hours; the reaction pressure is 5-10 MPa, preferably 8-10 MPa.
In the step (3), the reaction formula is as follows:
in the step (3), the chiral resolving agent used for chiral resolving is L-tartaric acid, D-dibenzoyltartaric acid or L-camphorsulfonic acid, preferably L-tartaric acid; the molar ratio of the chiral resolution reagent to the compound III is (1-3): 1, preferably (1.1-2.5): 1, more preferably 2: 1.
in the step (3), the alkaline reagent used for the alkalization dissociation can be one or more of potassium carbonate, sodium hydroxide and potassium hydroxide, and is preferably sodium hydroxide; the dosage of the alkaline reagent is to adjust the pH of the reaction system to 7.0-12.0, preferably 8.0-11.0.
In the step (4), the reaction formula is as follows:
in the step (4), the acid is selected from one or more of acetic acid, hydrochloric acid, nitric acid and p-toluenesulfonic acid, and hydrochloric acid is preferred.
In the step (4), after the hydrolysis of the compound IV is finished, alkalization and extraction are firstly carried out, then a drying agent is added into an extracted organic phase for intramolecular dehydration cyclization reaction, a solvent used for extraction is one or more of ethyl acetate, dichloromethane and n-hexane, preferably ethyl acetate, and the drying agent can be a conventional drying agent, such as calcium chloride, calcium sulfate, silica gel and the like, preferably calcium chloride; the cyclization reaction temperature is 20-77 ℃, and the reaction time is 2-6 hours.
In the alkalization step in the step (4), the alkaline reagent can be one or more of potassium carbonate, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide; the dosage of the alkaline reagent is used for adjusting the pH value of the reaction system to 7.0-12.0, preferably 8.0-10.0.
The invention also provides application of the intermediates, namely a method for preparing (S, S) -2, 8-diazabicyclo [4.3.0] nonane by using the intermediates, which comprises the following steps:
(A) performing a claisen condensation reaction on a compound VII and acetonitrile under the action of strong alkali to obtain a compound I;
compound VII has the structure:
r is C1-4Alkyl, preferably methyl;
R1as defined above;
(B) compound I compound V was obtained according to the procedure described above;
(C) and (3) carrying out catalytic hydrogenation on the compound V to obtain a compound VI, wherein the compound VI is the (S, S) -2, 8-diazabicyclo [4.3.0] nonane.
In the step (A), the reaction formula is as follows:
in the step (A), the strong base is selected from sodium methoxide, sodium ethoxide or NaH, and is preferably sodium methoxide; the claisen condensation reaction is carried out in a solvent, wherein the solvent is selected from one or more of toluene, n-hexane, chlorobenzene, tetrahydrofuran, methanol, dichloromethane and acetone, and is preferably toluene; the temperature of the claisen condensation reaction is 30-100 ℃; the reaction time is 2-6 hours.
In the step (A), the post-treatment process is as follows: firstly, adjusting the pH value to 2.0-6.0, and then extracting to obtain a compound I; preferably, the pH is adjusted to 3.0-5.0 and then extracted to give compound I.
In the step (C), the reaction formula is as follows:
in the step (C), the catalyst for catalytic hydrogenation is ruthenium black, palladium hydroxide carbon, palladium carbon or Raney nickel; the dosage of the catalyst is 2-20% of the mass of the substrate, preferably 5% -10%; the solvent for catalytic hydrogenation is toluene, xylene, n-hexane, tetrahydrofuran or methanol, preferably methanol; the reaction temperature is 60-130 ℃, and preferably 65-85 ℃; the reaction time is 2-10 hours, preferably 3-8 hours; the reaction pressure is 5-10 MPa, preferably 8-10 MPa.
Compared with the prior art, the invention has the beneficial effects that:
the raw materials adopted by the invention are cheap and easy to obtain, the reaction conditions are relatively mild, a new route is developed to construct the double N-heterocycle, and NaBH of imide is bypassed4/BF3The system is reduced, all reduction reactions use a conventional catalytic hydrogenation mode, the price of the product is greatly reduced while the process is green, and the method is favorable for industrialization.
Detailed Description
The following is merely a specific application example of the present invention, and the protection scope of the present invention is not limited in any way. All the technical solutions formed by equivalent transformation or equivalent replacement fall within the protection scope of the present invention.
The purities mentioned in the following examples are HPLC purities unless otherwise specified.
Example 1: preparation of Compound I-1
82.20g of acetonitrile and 81.03g of sodium methoxide are weighed into a 1500mL three-neck flask, 600g of toluene is added, the temperature is raised to 90 ℃ under the protection of inert gas, stirring reaction is carried out, 134.13g of dimethoxyacetic acid methyl ester is added after 1 hour of reaction, the reaction is carried out for 5 hours at 90 ℃, and the reaction is stopped. Cooling to room temperature, adding 200mL of distilled water, adjusting the pH value to 3.0-5.0 by using hydrochloric acid, extracting for three times by using ethyl acetate as an extracting agent, combining organic phases, and performing reduced pressure distillation (at 40 ℃ and under-0.08 MPa) to recover the ethyl acetate. After completion of the recovery, vacuum drying was carried out for 4 hours to obtain Compound I-1133.01g as a pale yellow liquid with a purity of 96.85%.
The nuclear magnetic data are as follows:1H NMR(500MHz，CDCl3):δ3.27(s,6H),3.62(s,2H),4.31(s,1H)。
example 2: preparation of Compound I-1
74.73g of acetonitrile and 73.66g of sodium methoxide are weighed into a 1500mL three-neck flask, 550g of tetrahydrofuran is added, the temperature is raised to reflux under the protection of inert gas, stirring reaction is carried out, reaction is carried out for 1 hour, 134.13g of dimethoxyacetic acid methyl ester is added, reaction is carried out for 6 hours at 66 ℃, and the reaction is stopped. Cooling to room temperature, recovering the solvent, adding 200mL of distilled water, adjusting the pH value to 3.0-5.0 by using hydrochloric acid, extracting with ethyl acetate for three times, combining organic phases, distilling under reduced pressure (40 ℃ and-0.08 MPa) to recover the ethyl acetate, and after recovery, drying in vacuum for 4 hours to obtain a light yellow liquid compound I-196.16 g with the purity of 95.88%.
Example 3: preparation of Compound I-1
51.54 g of acetonitrile and 50.60g of sodium methoxide are weighed into a 1000mL three-necked flask, 350g of chlorobenzene is added, the temperature is raised to 30 ℃ under the protection of inert gas, stirring reaction is carried out, reaction is carried out for 4 hours, 83.80g of dimethoxyacetic acid methyl ester is added, reaction is carried out for 2 hours at 30 ℃, and the reaction is stopped. Cooling to room temperature, adding 150mL of distilled water, adjusting the pH value to 3.0-5.0 by using hydrochloric acid, extracting with ethyl acetate for three times, combining organic phases, distilling under reduced pressure (40 ℃ and-0.08 MPa) to recover ethyl acetate, and after recovery, drying in vacuum for 4 hours to obtain a light yellow liquid compound I-178.66 g with the purity of 94.59%.
Example 4: preparation of Compound II-1
The above compound I-1133.01g (prepared by the method of example 1), 192.68g of sodium carbonate, 104.40g of chloropropylamine, and 200g of anhydrous calcium chloride were charged in a 4000mL three-necked flask, 1200g of tetrahydrofuran was added thereto, the mixture was heated to 60 ℃ and stirred to react for 5 hours, and then the reaction was stopped. Cooling to room temperature, filtering, distilling out tetrahydrofuran under reduced pressure, adding 400mL of water, extracting for three times by using ethyl acetate as a catalyst, combining the extracted organic phases, distilling under reduced pressure (40 ℃ and-0.08 MPa) to recover ethyl acetate, and drying in vacuum for 4 hours after recovery to obtain a light yellow compound II-1160.65g with the purity of 95.72%.
The nuclear magnetic data are as follows:1H-NMR(500MHz,CDCl3):δ4.31(s,1H),3.27(s,6H),2.90(m,2H),2.00(bs,2H),1.8(m,2H)。
example 5: preparation of Compound II-1
The above-mentioned compound I-1100.00 g (prepared by the method of example 1), 144.51g of sodium carbonate, 78.40g of chloropropylamine and 150g of anhydrous calcium chloride were placed in a 4000mL three-necked flask, 900g of methylene chloride was added thereto, the temperature was raised to 30 ℃ and the reaction was stirred for 2 hours, and the reaction was stopped. Cooling to room temperature, filtering, distilling under reduced pressure to remove dichloromethane, adding 300mL of water, extracting with ethyl acetate for three times, combining organic phases, distilling under reduced pressure (40 ℃ and-0.08 MPa) to recover ethyl acetate, and after recovery, drying in vacuum for 4 hours to obtain light yellow compound II-1113.36 g with the purity of 91.83%.
Example 6: preparation of Compound II-1
The above-mentioned compound I-1115.21 g (prepared by the method of example 1), 166.90g of sodium carbonate, 133.40g of bromopropylamine, and 174g of anhydrous calcium chloride were put into a 2000mL three-necked flask, 1050g of toluene was added thereto, the temperature was raised to 100 ℃ to carry out a reaction with stirring, and the reaction was stopped after 6 hours. Cooling to room temperature, filtering, distilling under reduced pressure to remove tetrahydrofuran, adding 350mL of water, extracting with ethyl acetate for three times, combining organic phases, distilling under reduced pressure (40 ℃ and-0.08 MPa) to recover ethyl acetate, and after recovery, drying in vacuum for 4 hours to obtain light yellow compound II-1126.04 g with the purity of 88.13%.
Example 7: preparation of Compound III-1
The liquid II-1160.65g (prepared by the method of example 4) and 8.03g of 5% Pd/C were weighed into a 2L autoclave, 800g of methanol was added, hydrogen was introduced, and the reaction was stirred at 70 ℃ under 8MPa for 6 hours, and then stopped. Cooled to room temperature, filtered, and distilled under reduced pressure (40 ℃ C., -0.08MPa) to remove methanol, to give pale yellow compound III-1159.56 g, having a purity of 92.33%.
The nuclear magnetic data are as follows:1H-NMR(500MHz,CDCl3):δ4.31(s,1H),3.28(s,6H),3.09-3.04(m,1H),2.93-2.86(m,2H),2.68-2.58(m,2H),1.87-1.81(m,1H),1.71-1.62(m,2H),1.59-1.52(m,2H)。
example 8: preparation of Compound III-1
The liquid II-1100.00 g (prepared by the method of example 4) and 5.04g Raney nickel were weighed into a 2L autoclave, 480.00g toluene was added, hydrogen was introduced, and the reaction was stirred at 60 ℃ under 8MPa for 10 hours, and then the reaction was stopped. Cooling to room temperature, filtering, and distilling under reduced pressure (80 deg.C, 0.08MPa) to remove toluene to obtain pale yellow compound III-193.64 g with purity of 91.00%.
Example 9: preparation of Compound III-1
The liquid II-1135.66 g (prepared by the method of example 4) and 7.18g of 5% Pd/C were weighed into a 2L autoclave, 750g of THF was added, hydrogen gas was introduced, and the reaction was stirred at 60 ℃ under 5MPa for 2 hours, and then stopped. Cooling to room temperature, filtering, and distilling under reduced pressure (40 deg.C, 0.08MPa) to remove methanol to obtain light yellow compound III-1125.50 with purity of 91.86%.
Example 10: preparation of Compound III-1
The liquid II-1115.00 g (prepared by the method of example 4) and 5.87g of 5% Pd/C were weighed into a 2L autoclave, 600g of xylene was added, hydrogen was introduced, and the reaction was stirred and reacted at 130 ℃ under 10MPa for 10 hours, and then the reaction was stopped. Cooling to room temperature, filtering, and distilling under reduced pressure (40 deg.C, 0.08MPa) to remove methanol to obtain pale yellow compound III-1118.35 g with purity of 88.45%.
Example 11: preparation of Compound IV-1
Weighing the liquid III-1159.56 g (prepared according to the method of example 7) into a 4000mL three-necked flask, adding 1600g of 95% ethanol water, stirring for dissolving, heating to reflux, dissolving 280.00g L-tartaric acid in 200g of 95% ethanol water, slowly dropwise adding into a reaction bottle, stirring for 1 hour to separate out crystals, cooling, filtering, and vacuum-drying a filter cake for 4 hours to obtain 131.07g of light yellow solid. 131.07g of the obtained solid was dissolved in 5% aqueous sodium hydroxide, the solution was stirred for 2 hours while adjusting the pH to 11.0, extracted three times with ethyl acetate, the organic phases were combined, and the ethyl acetate was recovered by vacuum distillation (40 ℃ C., -0.08MPa), and after recovery, vacuum-dried for 4 hours to obtain pale yellow compound IV-160.12 g, which had a purity of 99.72% and an ee value of 99.18%.
The nuclear magnetic data are as follows:1H-NMR(500MHz,CDCl3):δ4.31(s,1H),3.28(s,6H),3.09-3.04(m,1H),2.93-2.86(m,2H),2.68-2.58(m,2H),1.87-1.81(m,1H),1.71-1.62(m,2H),1.59-1.52(m,2H)。
example 12: preparation of Compound IV-1
Weighing the liquid III-1110.00 g (prepared according to the method of example 7) into a 4000mL three-necked flask, adding 1375g of 95% ethanol water, stirring and dissolving, heating to reflux, slowly dripping 385.00g D-dibenzoyltartaric acid 206.25g of 95% ethanol water into a reaction bottle, stirring for 0.5 hour to separate out crystals, cooling, filtering, and drying a filter cake in vacuum for 4 hours to obtain 131.73g of light yellow solid. 131.73g of the obtained solid was dissolved in a 5% aqueous solution of sodium hydroxide, the solution was stirred for 2 hours while adjusting the pH to 12.0, extracted three times with ethyl acetate, the organic phases were combined, and the ethyl acetate was recovered by vacuum distillation (40 ℃ C., -0.08MPa), and after completion of recovery, vacuum-dried for 4 hours to obtain pale yellow compound IV-138.62 g, having a purity of 98.72% and an ee value of 98.43%.
Example 13: preparation of Compound IV-1
Weighing the liquid III-1133.20 g (prepared according to the method of example 7) into a 4000mL three-necked flask, adding 1335g of 95% ethanol water, stirring for dissolving, heating to reflux, adding 367.31g L-camphorsulfonic acid into 210g of 95% ethanol water, slowly dropwise adding into a reaction bottle, stirring for 1 hour to separate out crystals, cooling, filtering, and vacuum-drying a filter cake for 4 hours to obtain 119.77g of light yellow solid. 119.77g of the obtained solid is dissolved in 5 percent sodium hydroxide aqueous solution, the pH value is adjusted to be 7.0, the mixture is stirred for 2 hours, ethyl acetate is extracted for three times, organic phases are combined, reduced pressure distillation (40 ℃ and minus 0.08MPa) is carried out to recover ethyl acetate, and after the recovery, vacuum drying is carried out for 4 hours to obtain light yellow compound IV-142.93 g, the purity is 99.03 percent, and the ee value is 99.00 percent.
Example 14: preparation of Compound IV-1
Weighing the liquid III-1120.00 g (prepared according to the method of example 7) into a 4000mL three-necked flask, adding 1200g of 90% ethanol water, stirring for dissolving, heating to reflux, dissolving 210.57g L-tartaric acid into 150g of 90% ethanol water, slowly dropwise adding into a reaction bottle, stirring for 2 hours to separate out crystals, cooling, filtering, and vacuum-drying a filter cake for 4 hours to obtain 84.42g of light yellow solid. 84.42g of the obtained solid was dissolved in a 5% aqueous solution of sodium hydroxide, the pH was adjusted to 7.5, the mixture was stirred for 2 hours, ethyl acetate was extracted three times, the organic phases were combined, ethyl acetate was recovered by reduced pressure distillation (40 ℃ C., -0.08MPa), and after completion of recovery, vacuum drying was carried out for 4 hours to obtain pale yellow compound IV-137.62 g, the purity was 99.83%, and the ee value was 99.68%.
Example 15: preparation of Compound V
Compound IV-160.12 g (prepared by the method of example 11) and 8.00g hydrochloric acid were weighed in a 1L three-necked flask, 600g of water was added thereto, and the reaction was stirred at 60 ℃ for 6 hours to terminate the reaction. Adjusting pH to 9.0 by using 10% NaOH solution, extracting with ethyl acetate for three times, combining organic phases, adding 30g of anhydrous calcium chloride, stirring and reacting at 40 ℃, stopping the reaction after reacting for 3 hours, filtering, recovering the ethyl acetate by reduced pressure distillation (40 ℃, minus 0.08MPa), and obtaining a light yellow liquid compound V32.98g with the purity of 96.72 percent after the recovery.
The nuclear magnetic data are as follows:1H-NMR(500MHz,CDCl3):δ7.28(s,1H),4.08-4.05(m,1H),3.55-3.52(m,1H),3.36-3.32(m,1H),3.16-3.09(m,1H),2.72-2.66(m,1H),2.46-2.40(m,1H),1.83-1.77(m,1H),1.67-1.53(m,3H)。
example 16: preparation of Compound V
Compound IV-150.00 g (prepared by the method of example 11) and 6.65g of acetic acid were weighed into a 500mL three-necked flask, 330g of water was added thereto, and the reaction was stirred at 60 ℃ for 7 hours to stop the reaction. Adjusting pH to 7.0 by using 10% NaOH solution, extracting with ethyl acetate for three times, combining organic phases, adding 33g of anhydrous calcium chloride, stirring and reacting at 30 ℃ for 2 hours, stopping the reaction, filtering, recovering the ethyl acetate by reduced pressure distillation (40 ℃ and-0.08 MPa), and obtaining a light yellow liquid compound V25.32 g with the purity of 95.46% after the recovery.
Example 17: preparation of Compound V
Compound IV-155.25 g (prepared by the method of example 11) and 9.19g hydrochloric acid were weighed in a 1L three-necked flask, and 500g of water was added thereto, and the reaction was stirred at 60 ℃ for 7 hours to terminate the reaction. Adjusting pH to 12.0 by using 10% potassium carbonate solution, extracting with ethyl acetate for three times, combining organic phases, adding 28g of anhydrous calcium chloride, stirring and reacting at 35 ℃ for 6 hours, stopping the reaction, filtering, recovering the ethyl acetate by reduced pressure distillation (40 ℃ and-0.08 MPa), and obtaining a light yellow liquid compound V28.55 g with the purity of 96.42% after the recovery.
Example 18: preparation of Compound V
Compound IV-125.00 g (prepared by the method of example 11) and 7.00g of p-toluenesulfonic acid were weighed in a 500mL three-necked flask, 250g of water was added thereto, and the reaction was stirred at 80 ℃ for 7 hours to stop the reaction. Adjusting the pH value to 7.0 by using 10% NaOH solution, extracting with ethyl acetate for three times, combining organic phases, adding 12g of anhydrous calcium chloride, stirring and reacting at 77 ℃ for 4 hours, stopping the reaction, filtering, recovering the ethyl acetate by reduced pressure distillation (40 ℃ and-0.08 MPa), and obtaining a light yellow liquid compound V11.92g with the purity of 90.57 percent after the recovery is finished.
Example 19: preparation of (S, S) -2, 8-diazabicyclo [4.3.0] nonane
Compound v32.98g (prepared according to the method of example 15) and 1.65g of 5% Pd/C were weighed into a 1L autoclave, 350g of methanol was added, hydrogen was introduced, and the reaction was stirred and reacted at 9MPa and 70 ℃ for 6 hours, and the reaction was stopped. Cooling to room temperature, filtering, and rectifying under reduced pressure to obtain light yellow liquid (S, S) -2, 8-diazabicyclo [4.3.0]Nonane 29.63g, purity 99.55%, ee 99.18%, nuclear magnetic data as follows:1H NMR(500MHz,CDCl3):δ3.08-3.07(m,1H),3.06-2.81(m,4H),2.70-2.67(m,1H),2.52-2.51(m,1H),2.00-1.99(m,1H),1.95-1.87(br,2H),1.63-1.60(m,2H),1.35-1.32(m,2H)。
example 20: preparation of (S, S) -2, 8-diazabicyclo [4.3.0] nonane
Compound v30.18g (prepared by the method of example 15) and 6.00g raney nickel were weighed into a 1L autoclave, 320g of methanol was added, hydrogen gas was introduced, and a reaction was stirred at 60 ℃ under 5MPa to stop the reaction for 10 hours. Cooling to room temperature, filtering, and rectifying under reduced pressure to obtain light yellow liquid (S, S) -2, 8-diazabicyclo [4.3.0] nonane 26.71g with purity of 99.43% and ee value of 89.55%.
Example 21: preparation of (S, S) -2, 8-diazabicyclo [4.3.0] nonane
Compound v25.00g (prepared according to example 15) and 0.50g of 5% Pd/C were weighed into a 1L autoclave, 230g of xylene was added, hydrogen was introduced, the reaction was stirred at 130 ℃ under 10MPa, and the reaction was stopped after 2 hours. Cooling to room temperature, filtering, and rectifying under reduced pressure to obtain light yellow liquid (S, S) -2, 8-diazabicyclo [4.3.0] nonane 22.79g with purity of 98.98% and ee value of 89.55%.
Claims (17)
1. An intermediate, wherein the intermediate is compound II, compound III, compound IV or compound V;
the structural formulas of the compound II, the compound III, the compound IV and the compound V are as follows:
wherein R is1Is C1-4 An alkyl group.
2. The intermediate of claim 1, wherein R is1Is methyl.
3. A process for the preparation of compound V, comprising the steps of:
(1) carrying out substitution reaction on the compound I and halogenated propylamine under an alkaline condition, and then carrying out intramolecular dehydration and cyclization to obtain a compound II;
(2) carrying out catalytic hydrogenation reduction on the compound II to obtain a compound III;
(3) carrying out chiral resolution and alkalinization dissociation on the compound III to obtain a compound IV;
(4) hydrolyzing the compound IV under the action of acid, and then performing intramolecular dehydration cyclization to obtain a compound V;
the structural formulas of compound I, compound II, compound III, compound IV, and compound V are as follows:
R1is C1-4 An alkyl group.
4. A process for the preparation of compound V according to claim 3, wherein R is1Is methyl.
5. The method of claim 3, wherein in step (1), the halopropylamine is chloropropylamine, bromopropylamine, or iodopropylamine.
6. The process of claim 5, wherein in step (1), said halopropylamine is chloropropylamine.
7. The method for preparing the compound V according to claim 3, wherein in the step (1), the solvent for the substitution reaction is one or more selected from n-hexane, toluene, tetrahydrofuran, chlorobenzene, dichloromethane and acetone; the reaction temperature is 30-100 ℃; the reaction time is 2-6 hours.
8. The process for preparing compound V according to claim 7, wherein the solvent for the substitution reaction in step (1) is tetrahydrofuran.
9. The method for preparing the compound V according to claim 3, wherein in the step (2), the catalyst for catalytic hydrogenation is selected from palladium on carbon, ruthenium black, Raney nickel or palladium on carbon hydroxide; the solvent is one or more selected from toluene, xylene, n-hexane, tetrahydrofuran and methanol; the reaction temperature is 60-130 ℃; the reaction time is 2-10 hours; the reaction pressure is 5-10 MPa.
10. The process for preparing compound V according to claim 3, wherein in step (3), the chiral resolving agent used for chiral resolution is L-tartaric acid, D-dibenzoyltartaric acid or L-camphorsulfonic acid; the molar ratio of the chiral resolution reagent to the compound III is (1-3): 1.
11. the process for the preparation of compound V according to claim 10, characterized in that the molar ratio of chiral resolving agent to compound III is 2: 1.
12. the method according to claim 3, wherein in the step (4), the acid is one or more selected from the group consisting of acetic acid, hydrochloric acid, nitric acid and p-toluenesulfonic acid.
13. The method for preparing the compound V according to claim 12, wherein in the step (4), after the hydrolysis of the compound IV, the compound IV is alkalized and extracted, and then a drying agent is added into the extracted organic phase to perform intramolecular dehydration cyclization reaction, wherein the extraction solvent is one or more of ethyl acetate, dichloromethane and n-hexane; the cyclization reaction temperature is 20-77 ℃, and the reaction time is 2-6 hours.
14. The process according to claim 13, wherein the extraction solvent is ethyl acetate.
15. A method for preparing (S, S) -2, 8-diazabicyclo [4.3.0] nonane, comprising the steps of:
(A) performing a claisen condensation reaction on a compound VII and acetonitrile under the action of strong alkali to obtain a compound I;
the structures of the compound VII and the compound I are as follows:
r is C1-4 An alkyl group;
R1is C1-4 An alkyl group;
(B) obtaining compound V according to the process of any one of claims 3 to 14;
(C) and (3) carrying out catalytic hydrogenation on the compound V to obtain a compound VI, wherein the compound VI is the (S, S) -2, 8-diazabicyclo [4.3.0] nonane.
16. The process for preparing (S, S) -2, 8-diazabicyclo [4.3.0] nonane according to claim 15, wherein in step (a), the strong base is selected from sodium methoxide, sodium ethoxide or NaH; the claisen condensation reaction is carried out in a solvent, wherein the solvent is selected from one or more of toluene, n-hexane, chlorobenzene, tetrahydrofuran, methanol, dichloromethane and acetone; the temperature of the claisen condensation reaction is 30-100 ℃; the reaction time is 2-6 hours.
17. The method for preparing (S, S) -2, 8-diazabicyclo [4.3.0] nonane according to claim 15, wherein in step (C), the catalyst for catalytic hydrogenation is ruthenium black, palladium on carbon hydroxide, palladium on carbon, or raney nickel; the solvent for catalytic hydrogenation is toluene, xylene, n-hexane, tetrahydrofuran or methanol; the reaction temperature is 60-130 ℃; the reaction time is 2-10 hours; the reaction pressure is 5-10 MPa.
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