CN102952130A - Method for chiral synthesis of (S,S)-2-8-diazabicyclononane - Google Patents

Abstract

The invention provides a method for chiral synthesis of (S,S)-2-8-diazabicyclo[4.3.0]nonane. A target product with a desired structure is prepared by using pyridine 2,3-diformate as a raw material and carrying out a four-step reaction comprising hydrogenation, resolution, aminolysis and reduction. According to the method, a synthetic route is simple and short, the step of resolution is carried out at an early stage, and reaction raw materials and reagents are saved; thus, production cost is reduced, and production efficiency is improved.

Description

Chirality is synthesized (S, S)-2, the method for 8-diazabicyclo nonane

Technical field

The present invention relates to a kind of synthetic method of chipal compounds, be specifically related to chipal compounds (S, S)-2, a kind of synthetic method of 8-diazabicyclo [4.3.0] nonane.

Background technology

2,8-diazabicyclo [4.3.0] nonane is a kind of saturated heterocyclic compound, also is a kind of chipal compounds, has the multiple chiral isomers such as (2S, 8S), (2R, 8S), (2S, 8R), (2R, 8R).

A kind of configuration (S wherein, S)-2,8-diazabicyclo [4.3.0] nonane (formula I) is an important side chain (the Moxifloxacin chemical name: 1-cyclopropyl-7-(S of antibacterials Moxifloxacin, S-2,8-diazabicyclo [4.3.0] nonane-8-yl)-6-fluoro-8-methoxy-4-oxo-Isosorbide-5-Nitrae-dihydro-3-quinoline carboxylic acid).Therefore, the synthetic focus that also just becomes in the Moxifloxacin study on the synthesis of formula I.

Factor I is chipal compounds, must run into the step of multiple isomer products being carried out chiral separation in synthetic.In the prior art, synthetic compound of formula i all is to split in synthetic last several steps, because the chiral separation step is carried out lately, reaction raw materials and reagent waste are larger, cause production cost higher.

Below two kinds of synthetic routes be the methods of synthetic compound of formula i commonly used at present:

Route one (Chinese Journal of Pharmaceuticals.2004,35,129): be starting raw material with 2,3-dinicotinic acid, by six-step process, comprising twice pressurization and a chiral separation, obtain formula I compound.

Reaction formula is as follows:

Route two (patent US5770597): be raw material with 2,3-dinicotinic acid equally, need to carry out the reaction of eight steps, comprising once pressurizeing and a chiral separation, obtain formula I compound:

Can find out from art methods, not only step is many, and reaction scheme is long, and splitting step is late, causes the end product yield low, and production efficiency is lower, thereby production cost is higher.

Therefore, provide the method for the synthetic compound of formula i that a kind of cost is lower, efficient is higher very necessary.

Summary of the invention

The purpose of this invention is to provide synthetic (S, S)-2 that a kind of cost is lower, efficient is higher, the method for 8-diazabicyclo [4.3.0] nonane (formula I), specific purposes provide a kind of chiral separation step morning, the shorter synthetic method of general route.

The inventor finds: by with the chiral separation step in advance, and the mode of employing aminolysis Cheng Huan, synthetic route can be reduced to for four steps, not only improved efficient but also reduced cost, reached the foregoing invention purpose.

Technical scheme of the present invention is:

A kind of method of synthetic compound of formula i, step is:

A) hydrogenation

Formula II compound obtains cis 2 through pressurized catalysis hydrogenation, 3-piperidines-dicarboxylic acid esters (formula III);

B) split

With chiral resolving agent the formula III compound is split, and will split products therefrom and alkalize with weakly alkaline reagent, obtain 2R, 3S-piperidines-dicarboxylic acid esters (formula IV);

C) aminolysis

Formula IV compound carries out aminolysis reaction with ammonia under aluminum trichloride (anhydrous), Zinc Chloride Anhydrous or boron tribromide catalysis and pressurized conditions;

D) reduction

With c) step products and reductive agent carry out reduction reaction, obtains target product (S, S)-2,8-diazabicyclo [4.3.0] nonane (formula I);

Among formula II～IV, R is C _1-4Alkyl;

Step a) in, can select this area hydrogenation catalyst commonly used, such as palladium carbon, palladium hydroxide carbon or ruthenium black.

Step b) in, described chiral resolving agent can be selected from L-TARTARIC ACID, D-dibenzoyl tartaric acid, L-camphorsulfonic acid, L-N-acetyl phenyl alanine or L-N-Boc-leucine;

Steps d) in, can select this area carbonyl reduction agent commonly used, such as tetrahydrochysene lithium aluminium, borine, sodium borohydride, POTASSIUM BOROHYDRIDE or red aluminium.

Above-mentioned steps is hydrogenation a), can carry out in benzene, normal hexane, sherwood oil, toluene, dimethylbenzene or trimethylbenzene equal solvent; Temperature of reaction is room temperature to 100 ℃, preferred 50～60 ℃; Reaction pressure can be for the pressure of common catalytic hydrogenation, such as 0.11～10MPa, and preferred 0.5-1MPa; Reaction times can be 2-10 hour, preferred 5 hours.

Above-mentioned steps b), comprise splitting step and alkalinization step.

In the splitting step, the mol ratio of described chiral resolving agent and formula III compound can be 1～2: 1; Reaction can be at C _1～4Alkyl alcohol, C _1～4Haloalkyl alcohol, DMF, ethylene glycol monomethyl ether, ethyl acetate or tetrahydrofuran (THF) equal solvent in carry out; Temperature of reaction is the boiling point of solvent; Reaction times can be 1-5 hour, preferred 1 hour.

In the alkalinization step, described weakly alkaline reagent is specifically as follows salt of wormwood, yellow soda ash, sodium-acetate or lithium acetate, and the consumption of described weakly alkaline reagent can be 7-8 for the pH value to reaction system.

For making the better effects if of fractionation, can also between splitting step and alkalinization step, increase re-crystallization step, recrystallization solvent can be C _1～4Alkyl alcohol, C _1～4Haloalkyl alcohol, DMF, ethylene glycol monomethyl ether, ethyl acetate or tetrahydrofuran (THF) equal solvent, the recrystallization number of times can be for once or once.

Above-mentioned steps c) aminolysis reaction, solvent can be toluene, methyl-sulphoxide or equal triethyl-benzene etc.; Temperature of reaction is 30～150 ℃, preferred 120 ℃; Reaction pressure is 0.1～5MPa, preferred 1MPa; Reaction times can be 5-18 hour, preferred 10 hours.

Above-mentioned steps d) reduction reaction can be carried out in tetrahydrofuran (THF), toluene or normal hexane equal solvent; Temperature of reaction is-40 ℃～10 ℃, preferred-10 ℃～0 ℃.

Can find out from embodiment, the method for synthetic compound of formula i provided by the invention is raw material with 2,3-dinicotinic acid ester, only needs to adopt hydrogenation, fractionation, aminolysis, reduction four-step reaction, can obtain product, and route is brief; Simultaneously, because splitting step is carried out early, saved raw material and the reagent of subsequent reactions, reduced cost, improved efficient.

Embodiment:

The following examples have proved the feasibility of technical solution of the present invention, also are illustrating technical solution of the present invention.In fact, adopt other solvents, catalyzer, temperature, the pressure specifically do not mentioned among the embodiment, also might obtain technique effect of the present invention.

Among each embodiment, the detection method of product optical purity (HPLC method) is as follows:

Get a certain amount of testing sample, be dissolved in the methylene dichloride, testing sample) and the triethylamine of 2 times of mol ratios (triethylamine: testing sample), at room temperature stirring reaction 1-2 hour, obtain testing sample behind the derivatize benzyl chlorine (the benzyl chlorine: that adds again 1.5 times of mol ratios.Measure again the content of testing sample behind the derivatize with the HPLC method.The HPLC testing conditions is:

Chromatographic column: AD-H post

Flow velocity: 1.0mL/min

Moving phase: normal hexane-Virahol (7: 3)

Embodiment 1 (S, S)-2, the preparation of 8-diazabicyclo [4.3.0] nonane (formula I)

1.1 hydrogenation

With 100g 2,3-dinicotinic acid methyl esters is dissolved in the 500mL toluene, then is transferred in the autoclave, add 5g 10% palladium carbon, system sealing, fill change hydrogen three times after, kept under 500 rev/mins of stirring velocitys, system pressure 1MPa, the temperature 50-60 ℃ condition reaction 5 hours, cooling, discharge excessive hydrogen, with reacting liquid filtering, toluene is removed in the filtrate distillation, obtain almost colourless liquid 101g, productive rate 98%.

Product is accredited as cis 2 through nuclear-magnetism, 3-piperidines-dioctyl phthalate methyl esters, and nuclear magnetic data is:

¹H?NMR(500MHz，CDCl ₃)：δ1.48-1.53(m，2H)，1.77-1.82(m，1H)，2.14-2.18(m，1H)，2.26(br，1H)，2.67-2.72(m，1H)2.99-3.07(m，2H)，3.65(d，J＝3.5Hz，1H)，3.70(s，3H)，3.75(s，3H)。

1.2 resolution reaction

Get the cis 2 that obtains in 1.1,3-teneraic acid methyl esters 60g is dissolved in the 100mL ethanol, then adds 43gL-tartrate, reflux to solid all dissolves, and continues back flow reaction after 1 hour, is cooled to room temperature, after stirring was spent the night, reacting liquid filtering obtained white crystal.

With this white crystal with the 30mL recrystallizing methanol once, obtain white crystal 45g, productive rate 44%.

The gained white crystal is dissolved in the 50mL ethanol, add 10% wet chemical to the pH value of system for behind the 7-8, with ethyl acetate extraction three times, merge organic phase, with the saturated sodium-chloride washing once, anhydrous magnesium sulfate drying filters, concentrated, obtain colourless viscous liquid 27g, productive rate 45%.Measure its optical purity, ee=98% with the HPLC method.

1.3 aminolysis reaction

Get the colourless viscous liquid 20g that obtains in 1.2, be dissolved in the 100mL sym-trimethylbenzene, then add the 4g aluminum trichloride (anhydrous), change in the autoclave, pass into ammonia, keep reacting 10 hours under 400 rev/mins of rotating speeds, pressure 1MPa, 120 ℃ of conditions of temperature.

The unstable products of this step reaction, after reaction was finished, exhaust cooling filtered, and filtrate is used for next step reaction.

1.4 reduction reaction

Gained filtrate in 1.3 is cooled to-10 ℃, then under agitation, slowly splash into the 20mL tetrahydrofuran solution of 5g LiAlH4, temperature of reaction is not higher than 0 ℃ in the maintenance dropping process, after dripping off (approximately 1 hour), being warming up to room temperature placed after 1 hour, be cooled to-10 ℃-0 ℃, after slowly dripping the 10mL pure water under this temperature, drip again 10%NaOH solution 20mL, reacted 1 hour, filter, filter cake and filtrate are used respectively ethyl acetate extraction three times, the combined ethyl acetate extracting solution, use anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure obtains red thick liquid, heat ℃ reaction of this liquid to 100 after 1 hour, underpressure distillation obtains pale pink oily matter 7.1g, productive rate 65%, measure its optical purity, ee=96% with the HPLC method.

Product is accredited as (S, S)-2 through nuclear-magnetism, 8-diazabicyclo [4.3.0] nonane, and nuclear magnetic data is:

H-NMR(300MHz，CDCl ₃)：δ1.41(m，1H)，1.52(m，1H)，1.60(m，2H)，2.23(br，2H)，2.51(m，1H)，2.55(td，1H)，2.72(d，1H)，2.95(m，4H)，3.12(t，1H)。

Claims (7)

1. the method for a chirality synthetic compound of formula i, step is:

A) hydrogenation

Formula II compound obtains cis 2 through pressurized catalysis hydrogenation, 3-piperidines-dicarboxylic acid esters (formula III);

B) chiral separation

With being selected from L-TARTARIC ACID, D-dibenzoyl tartaric acid, L-camphorsulfonic acid, L-N-acetyl phenyl alanine or the leucic chiral resolving agent of L-N-Boc-the formula III compound is split; Then will split products therefrom and alkalize with weakly alkaline reagent, obtain 2R, 3S-piperidines-dicarboxylic acid esters (formula IV);

C) aminolysis

Formula IV compound carries out aminolysis reaction with ammonia under the catalyzer that is selected from aluminum trichloride (anhydrous), Zinc Chloride Anhydrous or boron tribromide and pressurized conditions;

D) reduction

With step c) product and carbonyl reduction agent carry out reduction reaction, obtains target product (S, S)-2,8-diazabicyclo [4.3.0] nonane (formula I);

Among formula II～formula IV, R is C _1-4Alkyl.

2. method claimed in claim 1, step a) in, hydrogenation catalyst is selected from palladium carbon, palladium hydroxide carbon or ruthenium black.

3. claim 1 or 2 described methods, step a) in, reaction solvent is selected from benzene, normal hexane, sherwood oil, toluene, dimethylbenzene or trimethylbenzene; Temperature of reaction is room temperature to 100 ℃; Reaction times is 2～10 hours.

4. method claimed in claim 1, step b) in, the mol ratio of chiral resolving agent and formula III compound is 1～2: 1.

5. method claimed in claim 1, step b), described weakly alkaline reagent is selected from salt of wormwood, yellow soda ash, sodium-acetate or lithium acetate, and consumption is the pH value to 7～8 of conditioned reaction system.

6. method claimed in claim 1, step c), reaction solvent is selected from toluene, methyl-sulphoxide or equal triethyl-benzenes; Temperature of reaction is 30 ℃～150 ℃; Reaction pressure is 0.1MPa～5MPa; Reaction times is 5～18 hours.

7. method claimed in claim 1, steps d) in, described carbonyl reduction agent is selected from tetrahydrochysene lithium aluminium, borine, sodium borohydride, POTASSIUM BOROHYDRIDE or red aluminium.