CN111995624A - Process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane - Google Patents
Process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane Download PDFInfo
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Abstract
The present invention provides a process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of: step S1: preparing a platinum dehydrogenation catalyst; step S2: catalyzing piperidine ring dehydrogenation reaction by using a platinum dehydrogenation catalyst; step S3: the hydrogenation reaction is catalyzed by a chiral bronsted acid catalyst. The invention provides a method for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane with high racemic body purity and high reaction yield.
Description
Technical Field
The invention relates to the field of preparation of medical intermediates, in particular to a method for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane.
Background
Moxifloxacin is a novel fluoroquinolone drug, the chemical structure of the moxifloxacin is obviously different from other fluoroquinolone drugs, methoxy is introduced into the 8-position carbon atom of a quinolone mother nucleus, and benzyl-2, 8-diazabicyclo [4,3,0] nonane is introduced into the 7-position carbon atom of the quinolone mother nucleus, so that the gram-positive aerobic bacteria resistance of the moxifloxacin drug is enhanced, obvious phototoxicity is not generated, the solubility of moxifloxacin drug is increased, and the risk of formation of crystalluria is reduced. The presence of these substituents provides the drug with a broad spectrum of antimicrobial activity and has been used as a chemotherapeutic agent for humans and animals, and is effective in treating infections caused by a variety of bacteria.
(S, S) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is a key intermediate for synthesizing a new generation of fluoroquinolone drugs, moxifloxacin, a nonane mother liquor for synthesizing (S, S) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane often contains a chiral by-product (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is unstable and is not beneficial for the subsequent synthesis of moxifloxacin, so that the racemic preparation of (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane to obtain a racemic cis product, and the racemic cis product is used as a raw material to be resolved again to obtain a target product (S, s) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane. Currently, the research on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is less, the recovery yield and the purity of reactants are generally not high in the industrial production process for recycling (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, and the cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane racemate is prepared by adopting a method of dehydrogenation before hydrogenation in the prior art, but the catalyst dosage is larger in the second hydrogenation step, the catalytic efficiency is still not ideal, and the total yield of the reaction and the purity of the product are influenced.
Therefore, there is a need to develop a method for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane with high racemic purity and high reaction yield.
Disclosure of Invention
The invention aims to provide a method for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane with high racemic body purity and high reaction yield.
The technical purpose of the invention is realized by the following technical scheme:
a process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparation of platinum dehydrogenation catalyst: loading noble metal platinum carbon on a solid carrier by dipping into a dipping solution containing noble metal ions by adopting a dipping method;
step S2: dehydrogenation reaction of piperidine ring: subjecting (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, which is subjected to optical resolution, to a piperidine ring dehydrogenation reaction with a platinum dehydrogenation catalyst;
step S3: hydrogenation reaction: and (2) carrying out hydrogenation reaction on the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step (S2) and a chiral bronsted acid catalyst in the environment of a reaction solvent under certain reaction conditions to obtain the target product, namely the racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane.
As a further configuration of the present invention, the ratio of the chiral bronsted acid catalyst to the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine in the step S3 by weight parts is: 0.005:1-0.01:1.
As a further arrangement of the invention, the chiral bronsted acid catalyst is a thiourea derivative catalyst.
As a further configuration of the present invention, the ratio of the weight of the platinum dehydrogenation catalyst of step S2 to the weight of (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane is 0.1:1 to 2: 1.
As a further configuration of the present invention, the reaction solvent in step S3 includes, by weight, 40-50 parts of tetrahydrofuran and 5-8 parts of lauryl glycol hydroxypropyl ether.
As a further configuration of the present invention, the reaction solvent in step S3 further includes 1 to 5 parts by weight of linoleyl lactate.
As a further configuration of the present invention, the loading amount of the platinum carbon on the solid support in the step S2 is 0.2% to 5% by weight of the solid support.
As a further configuration of the present invention, the solid support of step S1 is one of silica, porous alumina and silica alumina gel.
As a further configuration of the invention, the reaction temperature in the piperidine ring dehydrogenation reaction of the step S3 is 130-140 ℃, and the reaction time is 3-5 h.
As a further configuration of the present invention, the reaction conditions in the hydrogenation reaction of step S3 are: after nitrogen is used for oxygen removal, hydrogen is introduced for reaction, the reaction temperature is 60-80 ℃, and the reaction time is 3-5 h.
The invention has the beneficial effects that:
1. the hydrogenation reaction of the pyridine ring adopts a thiourea derivative chiral bronsted acid catalyst, the thiourea derivative catalyst can realize ultrahigh-efficiency catalysis only depending on weak intermolecular forces such as hydrogen bonds, van der waals force and the like, the high-efficiency catalysis can be realized only by using a small amount in the hydrogenation reaction, the chiral selectivity of the thiourea derivative catalyst is high, and the catalytic hydrogenation is carried out on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, so that the selectivity of the reaction is effectively improved, and the yield and the product purity of the reaction are improved.
2. According to the invention, in the hydrogenation reaction solvent, the lauryl glycol hydroxypropyl ether can improve the contact area of the thiourea derivative catalyst and two phases of the reactant, improve the reaction degree of the catalytic reaction of the catalyst at the interface, and improve the yield and the product purity of the reaction.
3. The ester group and the hydroxyl optical energy group of the linolenol lactate in the hydrogenation reaction solvent can improve the hydrogen bond acting force in the reaction system, thereby improving the catalytic activity of the thiourea derivative catalyst, effectively improving the hydrogenation reaction degree, and further improving the reaction yield and the product purity.
Detailed Description
The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without any inventive step, are within the scope of the present invention.
First, an embodiment
Example 1
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparation of platinum dehydrogenation catalyst: loading noble metal platinum carbon on solid carrier silicon dioxide by dipping into dipping solution containing noble metal ions by adopting a dipping method, wherein the loading amount of the platinum carbon on the solid carrier is 0.2 percent of the weight of the solid carrier;
step S2: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 130 ℃ in a weight part ratio of 1:0.1 for 3 h;
step S3: hydrogenation reaction: mixing a chiral bronsted acid catalyst with the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step S2 in parts by weight: 0.005:1, and carrying out hydrogenation reaction for 3h in the environment of reaction solvents of 40 parts of tetrahydrofuran, 5 parts of lauryl glycol hydroxypropyl ether and 1 part of linoleol lactate and in the environment of nitrogen gas introduction at the reaction temperature of 60 ℃ to obtain the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 86.5 percent and the purity of the product is 99.1 percent.
Example 2
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparation of platinum dehydrogenation catalyst: loading noble metal platinum carbon on the solid carrier porous alumina by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the loading amount of the platinum carbon on the solid carrier is 5 percent of the weight of the solid carrier;
step S2: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 140 ℃ for 5h, wherein the weight part of the catalyst is 1: 2;
step S3: hydrogenation reaction: mixing a chiral bronsted acid catalyst with the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step S2 in parts by weight: 0.01:1, and carrying out hydrogenation reaction for 5h in the environment of reaction solvents of 50 parts of tetrahydrofuran, 8 parts of lauryl glycol hydroxypropyl ether and 5 parts of linoleol lactate and in the environment of nitrogen gas introduction at the reaction temperature of 80 ℃ to obtain the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 89.4 percent and the purity of the product is 99.6 percent.
Example 3
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparation of platinum dehydrogenation catalyst: loading noble metal platinum carbon on a solid carrier silica-alumina gel by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the loading amount of the platinum carbon on the solid carrier is 2 percent of the weight of the solid carrier;
step S2: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 135 ℃ for 4h in a weight part ratio of 1: 1;
step S3: hydrogenation reaction: mixing a chiral bronsted acid catalyst with the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step S2 in parts by weight: 0.008:1, carrying out hydrogenation reaction for 4h in the environment of reaction solvents of 45 parts of tetrahydrofuran, 6 parts of lauryl glycol hydroxypropyl ether and 3 parts of linoleol lactate and in the environment of nitrogen gas introduction at the reaction temperature of 70 ℃ to obtain the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 87.2 percent and the purity of the product is 99.3 percent.
Example 4
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparation of platinum dehydrogenation catalyst: loading noble metal platinum carbon on solid carrier silicon dioxide by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the loading amount of the platinum carbon on the solid carrier is 2 percent of the weight of the solid carrier;
step S2: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 135 ℃ for 4h in a weight part ratio of 1: 1;
step S3: hydrogenation reaction: mixing a chiral bronsted acid catalyst with the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step S2 in parts by weight: 0.008:1, carrying out hydrogenation reaction for 4h in the environment of reaction solvents of 45 parts of tetrahydrofuran and 3 parts of linoleol lactate and in the environment of nitrogen gas introduction at the reaction temperature of 70 ℃, and obtaining the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 78.4 percent and the purity of the product is 90.1 percent.
Example 5
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparation of platinum dehydrogenation catalyst: loading noble metal platinum carbon on solid carrier silicon dioxide by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the loading amount of the platinum carbon on the solid carrier is 2 percent of the weight of the solid carrier;
step S2: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 135 ℃ for 4h in a weight part ratio of 1: 1;
step S3: hydrogenation reaction: mixing a chiral bronsted acid catalyst with the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step S2 in parts by weight: 0.008:1, carrying out hydrogenation reaction for 4h in the environment of reaction solvents of 45 parts of tetrahydrofuran and 6 parts of lauryl glycol hydroxypropyl ether at the temperature of 70 ℃ in the environment of nitrogen gas introduction to obtain the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, wherein the yield is 76.8 percent and the purity of the product is 91.6 percent.
Example 6
A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane comprising the steps of:
step S1: preparation of platinum dehydrogenation catalyst: loading noble metal platinum carbon on solid carrier silicon dioxide by dipping into a dipping solution containing noble metal ions by adopting a dipping method, wherein the loading amount of the platinum carbon on the solid carrier is 2 percent of the weight of the solid carrier;
step S2: dehydrogenation reaction of piperidine ring: carrying out piperidine ring dehydrogenation reaction on (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane subjected to optical resolution and a platinum dehydrogenation catalyst at the reaction temperature of 135 ℃ for 4h in a weight part ratio of 1: 1;
step S3: hydrogenation reaction: mixing a chiral bronsted acid catalyst with the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step S2 in parts by weight: 0.008:1, in the environment of 45 parts of reaction solvent tetrahydrofuran, in the environment of nitrogen gas introduction, at the reaction temperature of 70 ℃, carrying out hydrogenation reaction for 4 hours to obtain the target product racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, with the yield of 72.4% and the product purity of 87.4%.
The principles and embodiments of the present invention are explained herein using specific examples, which are set forth only to help understand the method and its core ideas of the present invention. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (10)
1. A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, which comprises the steps of:
step S1: preparation of platinum dehydrogenation catalyst: loading noble metal platinum carbon on a solid carrier by dipping into a dipping solution containing noble metal ions by adopting a dipping method;
step S2: dehydrogenation reaction of piperidine ring: subjecting (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane, which is subjected to optical resolution, to a piperidine ring dehydrogenation reaction with a platinum dehydrogenation catalyst;
step S3: hydrogenation reaction: and (2) carrying out hydrogenation reaction on the 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine obtained in the step (S2) and a chiral bronsted acid catalyst in the environment of a reaction solvent under certain reaction conditions to obtain the target product, namely the racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane.
2. The process for preparing racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the ratio of parts by weight of the chiral bronsted acid catalyst to the weight of 6-benzyl-1, 2,3, 4-tetrahydro-pyrrolo [3, 4-b ] pyridine in step S3 is: 0.005:1-0.01:1.
3. A process for the preparation of racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, characterised in that the chiral bronsted acid catalyst is a thiourea derivative catalyst.
4. The process for preparing racemic cis 8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the ratio of the weight of the platinum dehydrogenation catalyst to the weight of (R, R) -8-benzyl-2, 8-diazabicyclo [4,3,0] nonane in parts by weight of step S2 is from 0.1:1 to 2: 1.
5. The process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the reaction solvent in step S3 comprises 40 to 50 parts by weight of tetrahydrofuran and 5 to 8 parts by weight of lauryl glycol hydroxypropyl ether.
6. The process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 5, wherein the reaction solvent in step S3 further comprises 1 to 5 parts by weight of linoleyl lactate.
7. The process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the loading of the platinum carbon in step S2 is from 0.2% to 5% by weight of the solid support, based on the weight percentage.
8. The process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the solid support of step S1 is one of silica, porous alumina and silica alumina gel.
9. The process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the reaction temperature in the step S3 piperidine ring dehydrogenation reaction is 130 ℃ to 140 ℃ and the reaction time is 3 to 5 hours.
10. The process for preparing racemic cis-8-benzyl-2, 8-diazabicyclo [4,3,0] nonane according to claim 1, wherein the reaction conditions in the hydrogenation reaction of step S3 are: after nitrogen is used for oxygen removal, hydrogen is introduced for reaction, the reaction temperature is 60-80 ℃, and the reaction time is 3-5 h.
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| CN112574197A (en) * | 2020-12-07 | 2021-03-30 | 泰安汉威集团有限公司 | Chiral purification method of compound C |
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