CN106588771A - Besifloxacin hydrochloride key intermediate preparation method - Google Patents
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Abstract
The invention discloses a besifloxacin hydrochloride key intermediate (R)-alpha-t-butyloxycarboryl-amino-epsilon-caprolactam preparation method. The preparation method comprises the steps of taking (R)-N-Boc-allylglycine and allyl amine as starting materials, and performing amide condensation, RCM reaction, and catalytic hydrogenation reduction to synthesize and prepare the (R)-alpha-t-butyloxycarboryl-amino-epsilon-caprolactam. The preparation method has the characteristics of high reaction selectivity, less side reactions, high total recovery and product quality, convenient and simple technological operation, and high stability and controllability, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthesis preparation method of besifloxacin hydrochloride key intermediate, belongs to pharmaceutical synthesis field.
Background technology
Besifloxacin hydrochloride (Besifloxacin hydrochloride) is fluoroquinolone medicine, by
Bausch ＆ Lomb Inc of the U.S. (bausch ＆ lomb Inc.) develops, and is approved by the FDA in the United States listing in May, 2009, is first
Exclusively for the non-systemic fluoroquinolones of ophthalmic remedy exploitation.Besifloxacin hydrochloride listing dosage form and specification be
0.6% besifloxacin hydrochlorate suspension, trade nameClinically it is used for the treatment of bacterial conjunctivitis.Salt
Sour besifloxacin chemical name is (R) -7- [3- amino hexahydro -1H- azepines- 1- bases] the fluoro- 1,4- of the chloro- 1- cyclopropyl -6- of -8-
Dihydro -4- oxo -3- quinoline carboxylic acid hydrochlorides, its chemical structural formula are as follows：
Besifloxacin hydrochloride system has the 8- chlorine flouroquinolone drugs of N- cyclopropyl, by suppress DNA of bacteria gyrase and
Topoisomerase Ⅳ plays anti-gram positive bacteria and negative bacterium effect.DNA gyrases are bacterium DNA replication, transcription and repair institute
The key enzyme for needing；Topoisomerase Ⅳ is that chromosomal DNA separates required key enzyme when antibacterial is divided.Besifloxacin hydrochloride is facing
Extraordinary bactericidal effect is shown in bed test, and the eye pathogenic bacterium to causing bacterial conjunctivitis have broad-spectrum antiseptic to live
Property.
The synthetic method of besifloxacin hydrochloride, existing many document reports.With the chloro- two fluoro- 1,4- of 1- cyclopropyl -6,7- of 8-
Dihydro -4- oxo -3- quinolinecarboxylic acids (compound II) is parent nucleus, with (R) -3- t-butoxycarbonyl amino hexahydro azepines(chemical combination
Thing III) condensation, the besifloxacin (compound IV) of BOC protections, then the method that deprotection obtains besifloxacin hydrochloride are obtained, is
One of wherein important synthetic method (Hebei chemical industry, 2011,34 (7), 13-15；Chinese patent, CN200780037522.7).
Synthetic route is as follows：
In superincumbent synthetic route, (R) -3- t-butoxycarbonyl aminos hexahydro azepineIt is synthetic hydrochloric acid besifloxacin
Crucial side chain.(R) -3- t-butoxycarbonyl aminos hexahydro azepineSynthesis, document report can be by (R)-α-tertbutyloxycarbonyl ammonia
Base-epsilon-caprolactams (compound I) comes synthetically prepared (PCT Patent, WO2004098589A1) through the carbonyl of reducing amide.Close
It is as follows into route：
Therefore, (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams shown in Formulas I are a synthetic hydrochloric acid besifloxacins
Key intermediate.With regard to the synthetic method of (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams, the method for document report mainly by
The compound Jing intramolecular condensations cyclization of straight chain is preparing.The most method of document report is with N- α-Boc-D- lysines as original
Material, in the presence of condensing agent, molecule inner ring condensation obtain (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams (Chinese patent,
CN101090883A；PCT Patent, WO2005042489A1；PCT Patent, WO2004098589A1).Synthetic route is as follows：
The method has that maximum is that intermolecular condensation is unavoidable so that the purity of finished product is not high.Additionally, institute
Using raw material N- α-Boc-D- lysines and condensing agent BTA -1- bases epoxide three (dimethylamino) phosphorus hexafluoro phosphorus
Hydrochlorate (BOP) it is expensive.Therefore the method be not suitable for industrialization large-scale production (R)-α-t-butoxycarbonyl amino-ε-oneself
Lactams.
There is the synthesis of the α-t-butoxycarbonyl amino-epsilon-caprolactams of some document reports S configurations or racemization, it is and upper
The method stated is similar to, and adopts lysine of S configurations or racemization or derivatives thereof or its analog for raw material, through molecule inner ring condensation
Obtain caprolactam ring.Boc-Lys (Z)-OH are such as adopted for raw material, through with N-hydroxy-succinamide (HOSu) or N, N '-
Succinimidyl carbonate (DSC) or N- succinimido diphenyl phosphoesters (SDPP) form active ester, then in catalysis
Cbz protection groups are sloughed under hydroconversion condition, while molecule inner ring condensation, obtains (S)-α-t-butoxycarbonyl amino-epsilon-caprolactams
(J.Am.Chem.Soc.,2006,128,15394-15395；Heterocycles, 1981,15,467-468).Synthetic route
It is as follows：
United States Patent (USP) (US4474778A) reports that with Boc-Lys (Z)-OH as raw material catalytic hydrogenation is sloughed again after esterification
Cbz protection groups, while molecule inner ring condensation, obtains (S)-α-t-butoxycarbonyl amino-epsilon-caprolactams.The following institute of synthetic route
Show：
William J.Boyle etc. are direct with 1B dihydrochloride as raw material, after esterification, in the effect of Feldalat NM
Direct molecule inner ring condensation obtains (S)-alpha-amido-epsilon-caprolactams hydrochlorate (J.Org.Chem., 1979,44,4841- down
4847.).The compound can use (Boc)2(S)-α-t-butoxycarbonyl amino-epsilon-caprolactams are obtained after O protection primary amino radicals.
Synthetic route is as follows：
L-type lysine or its hydrochlorate, in Lewis acid Al2O3Or SiO2Catalysis under (Tetrahedron Lett.,
1980,21,2443-2446.), or with hexamethyldisiloxane make condensing agent, under the catalysis of a small amount of trim,ethylchlorosilane
(Synthesis, 1978,614-616.), it is also possible to direct intramolecular cyclization, obtain (S)-alpha-amido-epsilon-caprolactams or its
Hydrochlorate.Synthetic route is as follows：
The method of synthesis (S)-α-t-butoxycarbonyl amino-epsilon-caprolactams can be used for reference for (R)-α-tertiary fourth above
The synthesis of oxygen carbonyl amino-e-caprolactam.But, as being previously noted, the synthesis strategy used by these methods is equal
Employ the ring-closure reaction that intramolecular forms amido link.Such method cannot avoid emulative intermolecular condensation secondary anti-
Should, in causing target product, impurity is raised, and is difficult to remove.In order to reduce intermolecular condensation side reaction, the method typically taken
It is the concentration for reducing raw material substrate in reaction system, the decline and production cost that can so cause preparation efficiency is raised.Additionally, with
On method used in highly basic or strong acid condition, in reaction, highly basic or strong acid can cause the chiral part racemization of α bit aminos
Change, so as to the chiral purity of product can be caused relatively low.
Additionally, Sung-Hwan Moon etc. are also reported with (R)-alpha-Aminoadipic acid as initiation material, Jing is esterified and BOC
N- tertbutyloxycarbonyl dimethyl ester intermediate is obtained after protection, then Jing after calcium chloride/sodium borohydride reduction, methylsulfonyl protection, in ammonia
Molecule inner ring condensation is carried out in water, the side chain required for synthetic hydrochloric acid besifloxacin is directly obtained, i.e., (the R) -3- uncles shown in formula III
Butoxy carbonyl amino hexahydro azepine(Synthetic Communications,1998,28,3919-3926.).The method
Equally exist serious intermolecular side reaction.Synthetic route is as follows：
In addition to the synthesis strategy that above-mentioned employing molecule inner ring condensation forms amido link, Fuhshuku etc. employs methodology
Upper diverse cultural care (Ring Closing Metathesis, RCM) come synthesize (R)-α shown in Formulas I-
T-butoxycarbonyl amino-epsilon-caprolactams.The method is with (R)-N-Boc- allylglycines and N- benzyl allyls amine as former
Material, reacts through condensation, RCM and takes off benzyl, obtain target product (Tetrahedron, 2012,68,6651-6655.).Synthesis road
Line is as follows：
The method uses first-generation Grubbs catalyst in RCM reactions, in the precursor (diene of synthesis RCM reactions
Compound) when, it is necessary to using the allyl amine of benzyl protection.Therefore, after RCM reactions and double bond reduction, reacted with Birch
Slough the benzyl on nitrogen.But the RCM of document report reacts and the yield of two step of Birch debenzylations is very low, only 32%, and
Birch reactions need to be carried out at -78 DEG C of ultralow temperature.It will be apparent that the method is not suitable for industrialization prepares (R)-α-tertiary fourth on a large scale
Oxygen carbonyl amino-e-caprolactam.
The method that Gardiner etc. reports the α-t-butoxycarbonyl amino-epsilon-caprolactams of similar synthesising racemation
(Journal of Organometallic Chemistry,2006,691,5487-5496.).The method uses second
For Grubbs catalyst, the diene substrate of the RCM reactions which uses, can be unprotected secondary amide.The following institute of synthetic route
Show：
The method of the reports such as Gardiner can be used for the conjunction of (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams by reference
Into, but the RCM reactions in the method can also produce six in addition to generating (±)-α-t-butoxycarbonyl amino-epsilon-caprolactams
(±)-α of yuan of rings-t-butoxycarbonyl amino-δ-valerolactam.And the yield of two products is close to 1: 1, the selectivity of reaction is very
Difference.Its reason is the isomerization that the Grubbs catalyst of the second filial generation may cause double bond on unprotected pi-allyl secondary amide,
So as to the by-product of hexatomic ring is generated in reacting in RCM.It will be apparent that the method be not suitable for industrialization prepare on a large scale (R)-α-
T-butoxycarbonyl amino-epsilon-caprolactams.
The content of the invention
It is an object of the invention to provide a kind of besifloxacin hydrochloride key intermediate (R)-α-t-butoxycarbonyl amino-ε-
The preparation method of caprolactam, it is intended to overcome not enough present in method made above.
The present invention provides a kind of besifloxacin hydrochloride key intermediate (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams
Preparation method, its chemical structural formula is as shown in following formula I：
Besifloxacin hydrochloride key intermediate (R)-α-t-butoxycarbonyl amino-ε shown in Formulas I provided by the present invention-
The preparation method of caprolactam, its preparation methods steps are as follows：
Step 1：(R)-N-Boc- allylglycines and allyl amine, in the presence of condensing agent, are condensed to yield Formula V institute
The intermediate V for showing；
Step 2：Intermediate V shown in Formula V, in the presence of the RCM catalyst shown in Formula IV, cyclization obtains Formula VII institute
The intermediate VII for showing；
Step 3：Intermediate VII Jing catalytic hydrogenating reductions shown in Formula VII, obtain the besifloxacin hydrochloride shown in Formulas I and close
Key intermediate (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams.
The chemical constitution and synthetic route of compound shown in above-described Formulas I, Formula V, Formula IV and Formula VII is as follows：
On the synthesis road of above-mentioned besifloxacin hydrochloride key intermediate (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams
In line, with (R)-N-Boc- allylglycines and allyl amine as raw material, the method for list of references (Tetrahedron,
2012,68,6651-6655；Journal of Organometallic Chemistry, 2006,691,5487-5496.),
Condensing agent 1- ethyls-one water thing of (3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (EDC) and I-hydroxybenzotriazole
(HOBt) in the presence of, the intermediate V being condensed to yield shown in Formula V.The reaction is typical carboxylic acid and amine synthesizing amide compound
Condensation reaction, typically carry out under non-polar solven, room temperature, reaction yield is high, good product purity.Intermediate V has diene
Structure, is the important as precursors compound for carrying out RCM reactions.
Olefin metathesis reaction (Olefin Metathesis) is catalyzed by metal olefin complex (also known as metal carbene)
Unsaturated carbon-carbon double bond or three key between carbon skeleton rearrangement reaction.The reaction is caused under ordinary meaning in chemically inert
Double bond and three bond energy are enough coupled each other, are greatly expanded imagination space of the people in construction compound skeleton.Simultaneously as
Olefin metathesis reaction has the characteristics of reaction condition is gentle, yield is higher, and most of organic group is anti-at this
Without the need for protection in answering, so the reaction in recent years receives the extensive attention of academia and industrial quarters.The metathesis reaction of alkene
It is broadly divided into three directions of correlation：Ring-opening polymerization (Ring Opening Metathesis Polymerization,
), ROMP cultural care (Ring Closing Metathesis, RCM) and cross-metathesis (Cross
Metathesis,CM).RCM reacts namely intramolecular olefin metathesis reaction, containing two unsaturated carbon carbon bonds (generally
Terminal olefin) chain molecule there is double decomposition in the presence of metal carbene, obtain unsaturation with losing a molecular olefine
Member ring systems.Under RCM reaction conditions, be easier to higher yield synthesize 5～7 yuan of cyclenes (modern organic reaction, volume five,
Metal catalysed reaction, Hu Yuefei, Lin Guoqiang chief editor, Chemical Industry Press, 2008, p153-156.).
The conventional reaction dissolvent of RCM reactions is nonpolar organic solvent, such as benzene, toluene, dichloromethane, chloroform,
1,2- dichloroethanes etc., and RCM reaction in catalyst be RCM reaction research emphasis (organic chemistry, 2004,24,127-
129.).The catalyst of some not clear structures, such as WCl are used earliest6/Me4Sn、MoO3/SiO2And Re2O7/Al2O3Deng.But
It is that the RCM reactions are catalyzed by these catalyst generally need more exacting terms.Nowadays, it is widely used in organic synthesiss
RCM catalyst includes Schrock catalyst, first-generation Grubbs catalyst, second generation Grubbs catalyst and Grubbs-
Hoveyda catalyst.These catalyst are respectively provided with higher catalysis activity for RCM reactions, and wherein Schrock catalyst is to sky
Gas and water etc. are very sensitive, are difficult storage.First-generation Grubbs catalyst is with functional group's suitability widely, and stablize,
Easily prepare.Second generation Grubbs catalyst is higher than first-generation Grubbs catalyst activity, can shorten response time and reduction
The consumption of catalyst.Grubbs-Hoveyda catalyst equally has very high reactivity, in addition importantly, this kind of urge
Agent can realize recycling, can be effectively reduced heavy metal residual in the reaction product.The chemistry of above catalyst
Structure is as follows：
The above RCM catalyst, it is generally the case that for the catalysis activity containing primary amine, secondary amine and secondary amide is not
It is highly desirable.As described in the background art, Fuhshuku etc. is with (R)-N-Boc- allylglycines and N- benzyl allyl amine
For raw material, react through condensation, RCM and take off benzyl, obtain the synthetic method of (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams
In, first-generation Grubbs catalyst has been used, its RCM reaction substrate employs the teritary amide of benzyl protection, so as to result in the need for
Reacted sloughing benzyl with Birch finally, cause the method RCM reactions and debenzylation two-step reaction yield significantly under
Drop, only 32% (Tetrahedron, 2012,68,6651-6655.).Synthetic route is as follows：
And Gardiner etc. employs unprotected secondary amide as RCM reaction substrates, it is catalyzed using second filial generation Grubbs
Agent is preparing the α-t-butoxycarbonyl amino-epsilon-caprolactams of racemization.But, the method is except generating (±)-α-tertiary butyloxycarbonyl
Outside base amino-e-caprolactam, hexatomic ring (±)-α-t-butoxycarbonyl amino-δ-valerolactam can be also produced.And two products
The yield of thing is close to 1: 1, the selectivity of reaction it is very poor (Journal of Organometallic Chemistry, 2006,
691,5487-5496.).Synthetic route is as follows：
In order to solve this problem, the present invention has attempted a variety of new modified model Grubbs catalyst and Grubbs-
Hoveyda catalyst.When inventor attempts modified model Grubbs-Hoveyda catalyst (the catalyst VI) shown in Formula IV, send out
A person of good sense is it has surprisingly been found that the RCM tools of catalyst VI catalytic intermediary V have an unexpected effect.The reaction not only reaction yield
High (>90%), and choose, almost do not found that hexatomic ring by-product and intermolecular reaction by-product are generated, course of reaction
Middle chiral centre occurs without racemization, and the optical purity of product is high.The synthetically prepared existing document report of catalyst VI
(Tetrahedron, 2013,69,7408-7415.), its synthetic route is as follows：
There is RCM reactions, high selectivity, obtained containing alkene in high yield in intermediate V in the presence of catalyst Formula IV
The intermediate VII of double bond.Intermediate VII Jing catalytic hydrogenating reductions, can easily obtain the besifloxacin hydrochloride shown in Formulas I
Key intermediate (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams.Catalytic hydrogenation reaction is be in daily use in organic synthesiss anti-
Should, post-reaction treatment is easy, is the synthetic technology of non-evergreen color, very high for the reduction selectivity of olefinic double bonds.It is general conventional
Catalyst be Pd/C and Raney-Ni, conventional solvent is methanol, ethanol, DMF polar solvents.
Specifically, besifloxacin hydrochloride key intermediate (R)-α-tertbutyloxycarbonyl shown in Formulas I provided by the present invention
The synthesis preparation method of amino-e-caprolactam I can be realized in accordance with the following steps：
Step 1：Under room temperature, a certain amount of (R)-N-Boc- allylglycines and allyl amine are added to into organic solvent
In dichloromethane, open stirring, add a certain amount of 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate,
One water thing of I-hydroxybenzotriazole and diisopropyl ethyl amine, react under room temperature, TLC detections, until (R)-N-Boc- pi-allyls
Glycine raw material point disappears, and is subsequently added a certain amount of water, separates organic faciess, and water is mutually extracted with ethyl acetate again, is merged organic
Phase, washing are dried, and filter, after filtrate decompression is evaporated off solvent, that is, obtain the intermediate V shown in Formula V.
Step 2：Under room temperature and nitrogen protection, in the organic solvent A after a certain amount of degassing, a certain amount of formula is added
Intermediate V and a certain amount of catalyst VI shown in V, is warming up to reaction temperature A and is reacted, TLC detection reactions, until middle
The raw material point of body V disappears, and is cooled to room temperature, and Jing silica gel is filtered, after filtrate decompression is evaporated off solvent, that is, in obtaining shown in Formula VII
Mesosome VII.
Organic solvent A described in step 2 is may be selected in benzene, toluene, dichloromethane, chloroform, 1,2- dichloroethanes
One or more mixed solvent.
The scope of reaction temperature A described in step 2 is 25 DEG C to solvent of reflux temperature.
Concentration of the intermediate V shown in Formula V described in step 2 in organic solvent A is 0.01～0.10M.
The molar ratio of intermediate V and catalyst VI shown in the Formula V described in step 2 is 1: 0.005～0.10.
Step 3：Under room temperature, a certain amount of catalyst is added in autoclave, add organic solvent B and a certain amount of formula
Intermediate VII shown in VII, opens stirring, hydrogen exchange back end hydrogenation pressure to 1MPa, TLC detection reactions, until raw material point disappears
Lose, filter, after filtrate decompression is evaporated off solvent, recrystallizing methanol, obtain (R)-α-t-butoxycarbonyl amino-ε shown in Formulas I-oneself
Lactams.
Organic solvent B described in step 3 may be selected one or more mixed solvent in methanol, ethanol, isopropanol.
Catalyst described in step 3 may be selected Pd/C or Raney-Ni.
The charged material weight ratio of the compound shown in Formula VII and catalyst described in step 3 is 1: 0.05～0.10.
Besifloxacin hydrochloride key intermediate (R)-α-t-butoxycarbonyl amino-ε shown in Formulas I provided by the present invention-
Caprolactam, Jing after reducing amide carbonyl, obtains the crucial side chain of synthetic hydrochloric acid besifloxacin, i.e. (R) -3- tertbutyloxycarbonyl ammonia
Base hexahydro azepine(PCT Patent, WO2004098589A1).Synthetic route is as follows：
Besifloxacin hydrochloride key intermediate (R)-α-t-butoxycarbonyl amino-ε shown in Formulas I provided by the present invention-
The synthesis preparation method of caprolactam, its novelty be embodied in it is following some：
(1) adopt (the R)-N-Boc- allylglycines being easy to get on market with allyl amine for raw material, merely through three steps
Reaction, you can obtain target product, reactions steps are few, simple to operate, high income；
(2) selectivity of the RCM reactions of the intermediate V of catalyst VI catalysis is high, has not almost found hexatomic ring by-product
Thing and intermolecular reaction by-product are generated, and in course of reaction, chiral centre occurs without racemization, and the optical purity of product is high；
(3), without special harsh reaction condition, technology stability is good, and controllability is high, is adapted to the big life of industrialization for synthesis technique
Produce.
In a word, (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams shown in Formulas I provided by the present invention is synthetically prepared
Method, with reaction selectivity height, few side reaction, high total recovery and product quality, easy technological operation and stability and controllable
Property it is high the characteristics of, be adapted to industrialized great production.
Specific embodiment
Following exemplary embodiments are used for illustrating the present invention, the letter that technical staff in the art is the present invention
Single replacement or improvement etc. are belonged within the technical scheme protected by the present invention.
Embodiment 1：Intermediate V's is synthetically prepared
Reaction equation is as follows：
Under room temperature, (R)-N-Boc- allylglycines (430g, 2mol) are added with allyl amine (137g, 2.4mol)
To in dichloromethane (2L), stirring is opened, 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate is sequentially added
One water thing (306g, 2mol) of (460g, 2.4mol), I-hydroxybenzotriazole and diisopropyl ethyl amine (310g, 2.4mol).Plus
Finish, continue reaction, TLC detections, until (R)-N-Boc- allylglycines raw material point disappears is stirred at room temperature.It is subsequently added
The water of 2L, is sufficiently stirred for, and separates organic faciess, and water is mutually extracted with ethyl acetate (700mL ╳ 2) again.After merging organic faciess, wash with water
Wash (700mL ╳ 2), after organic faciess are with anhydrous calcium chloride drying, filter, after filtrate decompression is evaporated off solvent, obtain faint yellow oily
Thing be intermediate V (488.3g, 1.92mol), yield 96.1%.
Embodiment 2：Intermediate VII's is synthetically prepared
Reaction equation is as follows：
Under room temperature, in reaction bulb, toluene (20L), evacuation, logical nitrogen displacement three times is added simultaneously to keep nitrogen to protect, plus
Enter the intermediate V (254g, 1mol) shown in Formula V, after stirring and dissolving, add catalyst VI (7.14g, 0.01mol), heat temperature raising
React to 80 DEG C, TLC detection reactions, until the raw material point of intermediate V disappears.Reactant liquor is cooled to into room temperature, with being covered with silica gel
Filter cone for filtration, filter cake is washed with a small amount of toluene, after filtrate decompression is evaporated off solvent, obtains off-white powder for intermediate VII
(210.5g, 0.93mol), yield 93.1%.
Embodiment 3：Intermediate VII's is synthetically prepared
Reaction equation is as follows：
Under room temperature, in reaction bulb, dichloromethane (20L), evacuation, logical nitrogen displacement three times is added simultaneously to keep nitrogen to protect
Shield, adds the intermediate V (254g, 1mol) shown in Formula V, after stirring and dissolving, adds catalyst VI (7.14g, 0.01mol), plus
Heat is warming up to backflow, TLC detection reactions, until the raw material point of intermediate V disappears.Reactant liquor is cooled to into room temperature, with being covered with silicon
The filter cone for filtration of glue, filter cake are washed with a small amount of dichloromethane, after filtrate decompression is evaporated off solvent, obtain off-white powder for intermediate
VII (216.5g, 0.96mol), yield 95.7%.
Embodiment 4：(R)-α-t-butoxycarbonyl amino-epsilon-caprolactams I's is synthetically prepared
Reaction equation is as follows：
Under room temperature, 10% palladium carbon (22.6g) is added in autoclave, add methanol (2.5L) and intermediate VII
(452g, 2mol), opens stirring, and evacuation is passed through nitrogen displacement three times, then is passed through three back end hydrogenation pressure of hydrogen exchange extremely
1MPa, TLC detection reaction, until raw material point disappears, filters, and after filtrate decompression is evaporated off solvent, residue is obtained with recrystallizing methanol
White solid be (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams (437.2g, 1.92mol), yield 95.9%.HPLC is detected
Product purity is more than 99.5% more than 99%, ee values.
Embodiment 5：(R)-α-t-butoxycarbonyl amino-epsilon-caprolactams I's is synthetically prepared
Reaction equation is as follows：
Under room temperature, Raney-Ni (45g) is added in autoclave, methanol (2.5L) and intermediate VII is added
(452g, 2mol), opens stirring, and evacuation is passed through nitrogen displacement three times, then is passed through three back end hydrogenation pressure of hydrogen exchange extremely
1MPa, TLC detection reaction, until raw material point disappears, filters, and after filtrate decompression is evaporated off solvent, residue is obtained with recrystallizing methanol
White solid be (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams I (426.6g, 1.87mol), yield 93.6%.HPLC is examined
Survey product purity and be more than 99.5% more than 99%, ee values.
Claims (4)
1. the system of besifloxacin hydrochloride key intermediate (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams shown in a kind of Formulas I
Preparation Method, its preparation methods steps are as follows：
Step 1：(R)-N-Boc- allylglycines and allyl amine, in the presence of condensing agent, are condensed to yield shown in Formula V
Intermediate V；
Step 2：Intermediate V shown in Formula V, in the presence of the RCM catalyst shown in Formula IV, cyclization is obtained shown in Formula VII
Intermediate VII；
Step 3：Intermediate VII Jing catalytic hydrogenating reductions shown in Formula VII, obtain (R)-α-tertbutyloxycarbonyl ammonia shown in Formulas I
Base-epsilon-caprolactams；
The chemical constitution and synthetic route of wherein described Formulas I, Formula V, Formula IV and compound shown in Formula VII is as follows：
2. besifloxacin hydrochloride key intermediate (R)-α-tertbutyloxycarbonyl shown in a kind of Formulas I according to claim 1
The preparation method of amino-e-caprolactam, it is characterised in that the method for step 1 is as follows：
Under room temperature, a certain amount of (R)-N-Boc- allylglycines and allyl amine are added to into organic solvent dichloromethane
In, stirring is opened, a certain amount of 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate, 1- hydroxy benzeness are added
And one water thing of triazole and diisopropyl ethyl amine, react under room temperature, TLC detections, until (R)-N-Boc- allylglycines are former
Shots disappear, and are subsequently added a certain amount of water, separate organic faciess, and water is mutually extracted with ethyl acetate again, merges organic faciess, is washed,
It is dried, filters, after filtrate decompression is evaporated off solvent, that is, obtain the intermediate V shown in Formula V.
3. besifloxacin hydrochloride key intermediate (R)-α-tertbutyloxycarbonyl shown in a kind of Formulas I according to claim 1
The preparation method of amino-e-caprolactam, it is characterised in that the method for step 2 is as follows：
Under room temperature under nitrogen protection, in the organic solvent A after a certain amount of degassing, the centre shown in a certain amount of Formula V is added
Body V and a certain amount of catalyst VI, is warming up to reaction temperature A and is reacted, TLC detection reactions, until the raw material point of intermediate V
Disappear, be cooled to room temperature, Jing silica gel is filtered, and after filtrate decompression is evaporated off solvent, that is, obtains the intermediate VII shown in Formula VII；
Wherein described organic solvent A may be selected the one kind in benzene, toluene, dichloromethane, chloroform, 1,2- dichloroethanes or
Various mixed solvents；
The scope of wherein described reaction temperature A is 25 DEG C to solvent of reflux temperature；
Concentration of the intermediate V shown in wherein described Formula V in organic solvent A is 0.01～0.10M；
The molar ratio of intermediate V and catalyst VI shown in wherein described Formula V is 1: 0.005～0.10.
4. besifloxacin hydrochloride key intermediate (R)-α-tertbutyloxycarbonyl shown in a kind of Formulas I according to claim 1
The preparation method of amino-e-caprolactam, it is characterised in that the method for step 3 is as follows：
Under room temperature, a certain amount of catalyst is added in autoclave, added shown in organic solvent B and a certain amount of Formula VII
Intermediate VII, opens stirring, and hydrogen exchange back end hydrogenation pressure to 1MPa, TLC detection reactions, until raw material point disappears, are filtered,
After filtrate decompression is evaporated off solvent, recrystallizing methanol obtains (R)-α-t-butoxycarbonyl amino-epsilon-caprolactams shown in Formulas I；
Wherein described organic solvent B may be selected one or more mixed solvent in methanol, ethanol, isopropanol；
Wherein described catalyst may be selected Pd/C or Raney-Ni；
The charged material weight ratio of the compound and catalyst shown in wherein described Formula VII is 1: 0.05～0.10.
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| CN108358845A (en) * | 2018-02-02 | 2018-08-03 | 广州仁恒医药科技股份有限公司 | A kind of new synthetic method of R-3- amino-hexahydro azepan hydrochloride |
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| CN101090883A (en) * | 2002-02-27 | 2007-12-19 | 艾伦药物公司 | Substituted hydroxyethylamines |
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| CN101090883A (en) * | 2002-02-27 | 2007-12-19 | 艾伦药物公司 | Substituted hydroxyethylamines |
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| JAMES GARDINER，ET AL.: "Ring closing metathesis of α- and β-amino acid derived dienes", 《JOURNAL OF ORGANOMETALLIC CHEMISTRY》 * |
| KEN-ICHI FUHSHUKU，ET AL: "Synthesis of optically active medium-sized α-aminolactams via ring-closing metathesis", 《TETRAHEDRON》 * |
| KRZYSZTOF SKOWERSKI，ET AL.: "Efficient, durable and reusable olefin metathesis catalysts with high affinity to silica gel", 《TETRAHEDRON》 * |
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| CN108358845A (en) * | 2018-02-02 | 2018-08-03 | 广州仁恒医药科技股份有限公司 | A kind of new synthetic method of R-3- amino-hexahydro azepan hydrochloride |
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