CN104262225B - 3-aminopyrrolidine compounds, and synthetic method and uses thereof - Google Patents
3-aminopyrrolidine compounds, and synthetic method and uses thereof Download PDFInfo
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Abstract
The invention relates to 3-aminopyrrolidine compounds, and a synthetic method and uses thereof. 3-pyrrolidone compounds (compounds IIIa or IIIb) are adopted as substrates and subjected to transaminase reactions under the actions of transaminase and an amino donator to obtain the (S)-3-aminopyrrolidine compounds (compounds II). Then intramolecular cyclization and removal of amino protective groups are performed to obtain (S,S)-2,8-diazabicyclo[4,3,0] nonane (a compound I). According to the 3-aminopyrrolidine compounds, the synthetic method and the uses, a synthetic technology that is low in cost, short in process steps and environmental friendly is provided for a moxifloxacin intermediate, and the synthetic technology will have great market application value and is suitable for large-scale industrial production.
Description
Technical field
The invention belongs to biomedicine technical field, it is related to 3- aminopyrrolidine compounds preparing technical field, especially relates to
And a kind of 3- aminopyrrolidine compounds and its preparation method and use,
Background technology
3- aminopyrrolidine compounds mainly for the preparation of carbostyril family antibacterial drugs Moxifloxacin chiral intermediate (s,
S) -2,8- diazabicyclo [4,3,0] nonane.
Moxifloxacin (moxifloxacin) is fluoroquinolone medicine, is ground by German Bayer AG earliest
System is succeeded in developing, and lists first in Germany in September, 1999, trade name avelox.In December in the same year, Moxifloxacin obtains fda and criticizes
Standard, in U.S.'s listing, lists in Quan Shi state many countries and regions later successively.Clinically it is widely used in treating respiratory tract
Infection such as acquired pneumonia, the outbreak of striving property of chronic bronchitiss, acute bacterial sinusitises etc..
(s, s) -2,8- diazabicyclo [4,3,0] nonane compound (i) is the crucial chiral intermediate of Moxifloxacin, point
Minor structure has piperidines and two framing structures of pyrrolidine and two chiral centres, and the preparation method of report is broadly divided into two kinds of conjunctions
Become route: piperidines route and pyrrolidines route (route one).
Route one
Piperidines route has more synthetic method to report, be also in current industrialized production adopt technique, mainly with
Pyridine-2,3-dicarboxylic acid to be prepared for raw material, sees route two and route three.
Route two
Route three
Above-mentioned two lines are directed to the reaction such as reduction of the high-pressure hydrogenation of pyridine, carboxylic acid carbonyl, and high-pressure hydrogenation is to equipment
Require higher, the reduction of carboxylic acid carbonyl will use the go back original reagent of costliness.Further relate to the fractionation of chirality, atom warp in building-up process
Ji utilization rate is very low.Although subsequently having patent and document report solving the racemization recycling of isomer, resolving agent recycles
The problems such as, but still there is complex process, the shortcomings of reactions steps are many, both uneconomical and not environmentally.
Patent wo2013053281 discloses a kind of method of asymmetric synthesis of pyrrolidines route (referring to route four), should
Route adopts the method for r- phenethylamine chiral induction, hydrogenation to build two chiral centres, and then intramolecular cyclization, removing occur
Chiral auxiliary and protection group obtain target product (i).
Route four
Content of the invention
No matter adopting method for splitting or method of asymmetric synthesis formula (i) compound, prior art has using high
Pressure hydrogenation technology and the problem of expensive reducing agent；Equally all exist process costs high, to environment disagreeableness shortcoming.Due to this change
Compound is the key intermediate preparing Moxifloxacin, therefore develops that a kind of low cost, technological process be short, environment amenable synthesis
Technology, will have huge market using value.
The invention aims to overcoming above-mentioned shortcoming of the prior art, provide a kind of life of moxifloxacin intermediate
Thing process for catalytic synthesis, related raw material and preparation method, especially a kind of 3- aminopyrrolidine compounds and its synthetic method and
Purposes, thus reaching the purpose of raw materials for production low cost, environmental protection, has huge market using value, is suitable to extensive work
Industry metaplasia is produced.
A kind of 3- aminopyrrolidine compounds ii structural formula is:
Wherein, r is amino protecting group；Z be oxygen or two hydrogen atoms, when z be two hydrogen atoms when, y be chlorine, bromine, iodine or
Hydroxyl sulfoacid ester；When z is for oxygen, y is hydrogen, hydroxyl or c1-6 alkoxyl.
Described 3- aminopyrrolidine compounds ii is 3- aminopyrrolidine compounds iia, the structural formula of compound iia
For:
Wherein, r is amino protecting group, and r1 is hydrogen or c1-6 alkyl.
Described 3- aminopyrrolidine compounds ii is 3- aminopyrrolidine compounds iib, the structural formula of compound iib
For:
Wherein, r is amino protecting group, and r1 is hydrogen or c1-6 alkyl；Y is chlorine, bromine, iodine or hydroxyl sulfoacid ester.
Described amino protecting group r be phenyl, benzyl, benzenesulfonyl, mesyl, formoxyl, acetyl group, propiono,
Carbethoxyl group, methoxycarbonyl group, propylene carbonyl oxygen, butoxy carbonyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, 2- xenyl -2- propylene carbonyl oxygen,
Phthalimide-based, trityl or trifluoroacetyl group.
The purposes of described compound ii be for prepare (s, s) -2,8- diazabicyclo [4,3,0] nonane (compound i),
(preparation method of compound i) comprises the steps: (s, s) -2,8- diazabicyclo [4,3,0] nonane
1) compound ii carries out Intra-molecular condensation by functional group y, z and amino and obtains compound ia or compound
ib；
2) by reducing amide, deprotection base obtains compound i to compound ia again, or compound ib deprotection base obtains
To compound i；
The structural formula of described compound ia is:
The structural formula of described compound ib is:
Wherein, r is amino protecting group；As z=h2, y is chlorine, bromine, iodine or hydroxyl sulfoacid ester；As z=o, y be hydrogen,
Hydroxyl or c1-6 alkoxyl.
When the amino protecting group r of described compound ia or compound ib is benzyl or trityl, then described step
2) deprotection base under conditions of pd/c hydrogenation, described pd/c inventory is the 1～5% of substrate, reaction temperature is 25～
80 DEG C, reaction pressure is 0.1～1mpa；If r is benzyloxycarbonyl group, 2- xenyl -2- propylene carbonyl oxygen, butoxy carbonyl, tertiary fourth oxygen
Carbonyl, methoxycarbonyl group, carbethoxyl group or propylene carbonyl oxygen, then described step 2) in salt aqueous acid or sodium hydrate aqueous solution
In or hydrolytic enzyme in the presence of deprotection base, described aqueous hydrochloric acid solution is 2～6:1 with the mol ratio of substrate, and described is anti-
Temperature is answered to be 50～100 DEG C, described hydrolytic enzyme is candidantartica Digestive Enzyme novozym435, operation amount is substrate
1～10%.Reaction temperature is 25～80 DEG C, and described sodium hydroxide or potassium hydroxide aqueous solution are 1 with the mol ratio of substrate
～5:1, described reaction temperature is 50～100 DEG C.
The amino protecting group r of described compound ia or compound ib is benzenesulfonyl, mesyl, formoxyl, acetyl
Base, propiono, phthalimide-based or trifluoroacetyl group, then described step 2) sodium hydroxide or potassium hydroxide water
In solution heating deprotection base or in the presence of hydrolytic enzyme deprotection base, described sodium hydrate aqueous solution rubbed with substrate
Your ratio is 1～5:1, and described reaction temperature is 50～100 DEG C, and described hydrolytic enzyme is candidantartica Digestive Enzyme
Novozym435, operation amount is the 1～10% of substrate.Reaction temperature is 25～80 DEG C.
The preparation method of described compound (iia) is: compound iiia passes through transamination reaction, in amino group donor, turns ammonia
In the presence of enzyme and solvent, reacting generating compound iia, described amino group donor is 2-aminopropane., and described transaminase is ω-turn
Ammonia enzyme, described solvent is water and the mixed solvent of organic solvent or water, described organic solvent be dimethyl sulfoxide, oxolane or
Dmf, the ph value of described transamination reaction is 7～10, and the reaction temperature of described transamination reaction is 10～50 DEG C；
The structural formula of described compound iiia is:
Wherein, r is amino protecting group, and r1 is hydrogen or c1-6 alkyl.
The preparation method of described compound (iib) is: compound iiib passes through transamination reaction, in amino group donor, turns ammonia
In the presence of enzyme and solvent, reacting generating compound iib, described amino group donor is 2-aminopropane., and described transaminase is ω-turn
Ammonia enzyme, described solvent is water and the mixed solvent of organic solvent or water, described organic solvent be dimethyl sulfoxide, oxolane or
Dmf, the ph value of described transamination reaction is 7～10, and the reaction temperature of described transamination reaction is 10～50 DEG C；
The structural formula of described compound iiib is:
Wherein, r is amino protecting group, and y is chlorine, bromine, iodine or hydroxyl sulfoacid ester.
A kind of enzymatic synthesis method of (s, s) -2,8- diazabicyclo [4,3,0] nonane (i) is: compound iiia or
Compound iiib in the presence of transaminase and hydrolytic enzyme, one pot process compound i.
The present invention with formula (iii) pyrrolidone-2 compounds as raw material, the chiral amino that obtained by living things catalysis, intramolecular
The easy steps such as cyclization, deprotection base, prepare in the middle of Moxifloxacin especially by one kettle way method described above
Body, its chiral purity reaches more than 99%.The present invention is that a kind of low cost, technological process be short, environment amenable synthetic technology,
To have huge market using value, suitable large-scale industrial production.
Specific embodiment
In order to be better understood from present disclosure, it is described further with reference to specific embodiment.It should be understood that it is following
Instantiation is merely to illustrate the present invention, rather than limitation of the present invention.
The preparation of embodiment one (3s) -1- benzyl -3- amino -4- (3- ethoxycarbonyl-ethyl)-pyrrolidine
2-aminopropane. 100g is dissolved in 100ml water, under ice-water bath cooling, adjusts ph value to 8.0 with aqueous hydrochloric acid solution, and
Add 20ml oxolane, be then diluted to 700ml with the tris-hcl buffer of 0.1m and be preheating to 30 DEG C, add containing
The tetrahydrofuran solution 200ml of 1- benzyl -4- (3- ethoxycarbonyl-ethyl) -3- ketopyrrolidine (3-1) 50g, finally plus
Enter 1g ω-transaminase's cold-dry powder and plp (phosphoric acid Vitamin B6) 0.8g, reaction with 20% isopropylamine solution control ph=7～
10, temperature converts more than 24 hours at 10～50 DEG C, and tlc monitoring reaction finishes.Solids removed by filtration, mother solution ethyl acetate extracts
Take 3 times, the organic faciess anhydrous sodium sulfate drying after merging, be concentrated to give grease (2-1) 45g, yield is about 90%.
1h-nmr(400mhz,cdcl3):δ7.14(2h),7.06(3h),4.12(2h),3.62(2h),2.71(1h),
2.60(2h),2.34(2h)2.25(2h),2.0(2h),1.81(1h),1.64(2h),1.30(3h).Ms-esi:m/z:275 (m
++1).
The preparation of embodiment two (1s, 6s) 8- benzyl -2,8- diazabicyclo [4,3,0] nonane
By (3s) -1- benzyl -3- amino -4- (3- ethoxycarbonyl-ethyl)-pyrrolidine (compound 2-1 in embodiment 1,
27.4g, 100mmol), 270ml toluene, 35ml acetic acid, be warming up to 70 DEG C reaction 16h.After reaction is carried out completely, use sodium bicarbonate
Solution washing is about 8 to ph, merges aqueous phase, and 100ml toluene extracts, combining methylbenzene phase, washing, toluene phase anhydrous sodium sulfate
It is dried, the dry solvent of concentrating under reduced pressure obtains oil product (1-2) (21.2g, yield 92%).
1h-nmr(400mhz,cdcl3):δ7.14(2h),7.07(1h),7.06(2h),3.68(1h),3.62(2h),
2.60(2h),2.34(2h),2.23(2h),2.20(1h),1.65(2h).Ms-esi:m/z:229 (m++1).
Lithium aluminium hydride reduction 35.0g is added the anhydrous tetrahydro furan of 50ml, be slowly added dropwise step product under nitrogen protection and (change
Compound 1-2,21.2g, 92mmol) it is dissolved in the solution of 110ml oxolane, maintain temperature at -10～-15 DEG C, completion of dropping liter
Temperature backflow 3 hours, is down to 0 DEG C after reaction completely, and Deca saturated aqueous ammonium chloride is quenched reaction, and ethyl acetate extracts (50ml
× 3 times), washing, anhydrous sodium sulfate drying, filters, filtrate reduced in volume is done to obtain grease, column chromatography for separation obtains oil product
Compound 1-1,15.7g, yield is about 72.6%.
The preparation of embodiment three (s, s) -2,8- diazabicyclo [4,3,0] nonane
Upper step product (compound 1-1,10.8g, 50mmol) is dissolved in 250ml methanol, 10% palladium carbon 0.5g adds pressure
Power kettle, room temperature hydrogenation reaction 24 hours under 1.0mpa pressure, it is filtered to remove palladium carbon after reaction completely, filtrate is with Feldalat NM/first
Alcoholic solution adjusts ph=10.0, filters, and filtrate concentrates dry rear vacuum distillation and obtains product (s, s) -2,8- diazabicyclo [4,3,0]
Nonane 5.3g, yield is about 84%, ee value 98.1%.
The preparation of example IV (3s) -1- benzyl -3- amino -4- (3- chloropropyl)-pyrrolidine
2-aminopropane. 100g is dissolved in 100ml water, under ice-water bath cooling, adjusts ph value to 8.0 with aqueous hydrochloric acid solution, and
Add 20ml oxolane, be then diluted to 700ml with the tris-hcl buffer of 0.1m and be preheating to 30 DEG C, add containing
The tetrahydrofuran solution 200ml of 1- benzyl -4- (3- chloropropyl) -3- ketopyrrolidine (3-2) 50g, is eventually adding 1g
ω-transaminase's cold-dry powder and plp (phosphoric acid Vitamin B6) 0.8g, reaction controls ph=7～10 with 20% isopropylamine solution,
Temperature converts more than 24 hours at 10～50 DEG C, and tlc monitoring reaction finishes.Solids removed by filtration, mother solution is extracted with ethyl acetate 3
Secondary, after merging organic faciess anhydrous sodium sulfate drying, is concentrated to give grease (2-2) 45.25g, and yield is about 90.5%.
1h-nmr(400mhz,cdcl3):
δ4.08(2h),3.69(2h),3.43(2h),3.38(2h),2.71(1h),1.81(1h),1.57(2h),1.33
(2h),1.25(2h),0.96(3h).Ms-esi:m/z:251 (m++1).
The preparation of embodiment five (1s, 6s) 8- benzyl -2,8- diazabicyclo [4,3,0] nonane
By (3s) -1- benzyl -3- amino -4- (3- chloropropyl)-pyrrolidine (compound 2-2,12.6g in embodiment 1,
50mmol) potassium tert-butoxide (6.8g, 60mmol), tetrabutylammonium iodide (0.38g, 1.0mmol) are dissolved in 150ml oxolane,
Back flow reaction 1 hour, the dry solvent of concentrating under reduced pressure, obtain grease and be dissolved in 100ml ethyl acetate, washing, anhydrous sodium sulfate drying,
Filter, filtrate reduced in volume is done to obtain grease (1-1) 10.0g, yield is about 92.5%.
1h-nmr(400mhz,cdcl3):δ7.14(2h),7.07(1h),7.06(2h),3.68(1h),3.62(2h),
2.60(2h),2.34(2h),2.23(2h),2.20(1h),1.65(2h).Ms-esi:m/z:215 (m++1).
The preparation of embodiment six (s, s) -2,8- diazabicyclo [4,3,0] nonane
2-aminopropane. 50g is dissolved in 50ml water, under ice-water bath cooling, adjusts ph value to 8.0 with aqueous hydrochloric acid solution, and plus
Enter 20ml oxolane, be then diluted to 400ml with the tris-hcl buffer of 0.1m and be preheating to 30 DEG C, add containing
The tetrahydrofuran solution of 1- butyl formate base -4- (3- chloropropyl) -3- ketopyrrolidine (3-3) 25g (95mmol)
200ml, is eventually adding 0.6g ω-transaminase's cold-dry powder and plp (phosphoric acid Vitamin B6) 0.4g, reacts the isopropyl aqueous amine with 20%
Solution controls ph=7～10, and temperature converts more than 24 hours at 10～50 DEG C, and tlc monitoring reaction finishes.Solids removed by filtration,
Mother solution adjusts ph=12 with 1n sodium hydroxide at 10～30 DEG C, stirs 2 hours.With 2n hydrochloric acid adjust ph value=7～8, then plus
Enter 1g amidohydrolase, 10～40 DEG C are stirred 24 hours in temperature, tlc monitoring reaction finishes, solids removed by filtration, and filtrate concentrates
To dry, finally distill and obtain (s, s) -2,8- diazabicyclo [4,3,0] nonane 8.8g, yield is about 73.3%, ee value
96.8%.
The preparation of embodiment seven (3s) -1- benzyl -3- amino -4- (3- ethoxycarbonyl-ethyl)-pyrrolidine
2-aminopropane. 100g is dissolved in 100ml water, under ice-water bath cooling, adjusts ph value to 8.0 with aqueous hydrochloric acid solution, and
Add 20ml oxolane, be then diluted to 700ml with the tris-hcl buffer of 0.1m and be preheating to 30 DEG C, add containing
The tetrahydrofuran solution 200ml of 1- acetyl group -4- (3- ethoxycarbonyl-ethyl) -3- ketopyrrolidine (3-1) 50g, finally
Add 1g ω-transaminase's cold-dry powder and plp (phosphoric acid Vitamin B6) 0.8g, reaction controls ph=8 with 20% isopropylamine solution
～10, temperature converts more than 24 hours at 10～50 DEG C, and tlc monitoring reaction finishes.Solids removed by filtration, mother solution ethyl acetate
Extraction 3 times, the organic faciess anhydrous sodium sulfate drying after merging, it is concentrated to give grease (2-4) 46g, yield is about 92%.
1h-nmr(400mhz,cdcl3):δ4.12(2h),3.81(2h),3.55(2h),3.09(1h),2.25(2h),
2.19(1h),2.02(3h),1.64(2h),1.30(3h).Ms-esi:m/z:227 (m++1).
The preparation of embodiment eight (1s, 6s) 8- acetyl group -2,8- diazabicyclo [4,3,0] nonane
By (3s) -1- acetyl group -3- amino -4- (3- ethoxycarbonyl-ethyl)-pyrrolidine (compound 2-4 in embodiment six,
22.8g, 100mmol), 270ml toluene, 33ml acetic acid, be warming up to 70 DEG C reaction 16h.After reaction is carried out completely, use sodium bicarbonate
Solution washing is about 8 to ph, merges aqueous phase, and 100ml toluene extracts, combining methylbenzene phase, washing, toluene phase anhydrous sodium sulfate
It is dried, the dry solvent of concentrating under reduced pressure obtains oil product (1-5) (17.3g, yield 95%).
1h-nmr(400mhz,cdcl3):δ4.06(1h),3.81(2h),3.55(2h),2.58(1h),2.23(2h),
2.02(3h),1.65(2h).Ms-esi:m/z:181 (m++1).
Lithium aluminium hydride reduction 35.0g is added the anhydrous tetrahydro furan of 50ml, be slowly added dropwise step product under nitrogen protection and (change
Compound 1-5,16.8g, 92mmol) it is dissolved in the solution of 110ml oxolane, maintain temperature at -10～-15 DEG C, completion of dropping liter
Temperature backflow 3 hours, is down to 0 DEG C after reaction completely, and Deca saturated aqueous ammonium chloride is quenched reaction, and ethyl acetate extracts (50ml
× 3 times), washing, anhydrous sodium sulfate drying, filters, filtrate reduced in volume is done to obtain grease, column chromatography for separation obtains oil product
Compound 1-4,11.3g, yield is about 73.3%.1h-nmr(400mhz,cdcl3):δ3.66(2h0,3.55(2h),3.09
(1h),2.79(2h),2.19(1h),2.02(3h),1.59(2h),1.55(2h).Ms-esi:m/z:167 (m++1).
The preparation of embodiment nine (s, s) -2,8- diazabicyclo [4,3,0] nonane
By 8- acetyl group -2,8- diazabicyclo [4,3,0] nonane (compound 1-4,12g in embodiment seven,
100mmol) and 1gcandidantartica Digestive Enzyme (novozym435) the mixture sodium dihydrogen phosphate/phosphoric acid of 150mm
It is 200ml that the mixture aqueous solution of disodium hydrogen buffer agent is configured to volume.It is warming up to 40 DEG C of reaction 16h.After reaction is carried out completely,
Washed with sodium hydrate aqueous solution and be about 10 to ph, solids removed by filtration, to after dry, vacuum distillation obtains product to filtrate reduced in volume
(s, s) -2,8- diazabicyclo [4,3,0] nonane 11.1g, yield is about 87.8%, ee value 98.5%.
The preparation of embodiment ten (3s) -1- benzenesulfonyl -3- amino -4- (3- ethoxycarbonyl-ethyl)-pyrrolidine
Phenethylamine 100g is dissolved in 100ml water, under ice-water bath cooling, adjusts ph value with sodium hydrate aqueous solution and arrive
8.0, and add 20mldmf, then it is diluted to 700ml with the tris-hcl buffer of 0.1m and is preheating to 30 DEG C, add and contain
Have the dmf solution 200ml of 1- benzenesulfonyl -4- (3- ethoxycarbonyl-ethyl) -3- ketopyrrolidine (4-1) 50g, finally plus
Enter 1g ω-transaminase's cold-dry powder and plp (phosphoric acid Vitamin B6) 0.8g, reaction with 20% phenethylamine aqueous solution control ph=8～
10, temperature converts more than 24 hours at 10～50 DEG C, and tlc monitoring reaction finishes.Solids removed by filtration, mother solution dichloromethane extracts
Take 3 times, the organic faciess anhydrous sodium sulfate drying after merging, be concentrated to give grease (4-2) 61g, yield is about 93.5%.
1h-nmr(400mhz,cdcl3):δ4.12(2h),3.1(2h),2.84(3h),2.8(2h),2.71(1),2.25
(2h),2.0(2h),1.81(1h),1.64(2h),1.30(3h).Ms-esi:m/z:325 (m++1).
The preparation of embodiment 11 (1s, 6s) 8- benzenesulfonyl -2,8- diazabicyclo [4,3,0] nonane
By (3s) -1- benzenesulfonyl -3- amino -4- (3- ethoxycarbonyl-ethyl)-pyrrolidine (compound 4- in embodiment nine
2,32.6g, 100mmol), 270ml toluene, 33ml acetic acid, be warming up to 70 DEG C reaction 16h.After reaction is carried out completely, use bicarbonate
Sodium water solution washs and is about 8 to ph, merges aqueous phase, and 100ml toluene extracts, combining methylbenzene phase, washing, toluene phase anhydrous slufuric acid
Sodium is dried, and the dry solvent of concentrating under reduced pressure obtains oil product (4-3) (26.3g, yield 94%).
1h-nmr(400mhz,cdcl3):δ7.93(2h),7.54(2h),7.3(1h),3.60(1h),3.01(1h),2.38
(2h),2.23(2h),2.12(3h),1.65(2h).Ms-esi:m/z:279 (m++1).
Lithium aluminium hydride reduction 35.0g is added the anhydrous dmf of 50ml, be slowly added dropwise step product (compound under nitrogen protection
1-5,24.2g, 94mmol) it is dissolved in the solution of 110ml dmf, maintain temperature at -10～-15 DEG C, completion of dropping temperature rising reflux 3 is little
When, it is down to 0 DEG C after reaction completely, Deca saturated aqueous ammonium chloride is quenched reaction, dichloromethane extracts (50ml × 3 time), water
Wash, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is done to obtain grease, column chromatography for separation obtains oil product compound 4-
4,13.5g, yield is about 78.1%.
1h-nmr(400mhz,cdcl3):δ3.0(2h),2.84(3h),2.8(2h),2.79(2h),2.71(1h),1.81
(1h),1.59(2h),1.55(2h).Ms-esi:m/z:265 (m++1).
The preparation of embodiment 12 (s, s) -2,8- diazabicyclo [4,3,0] nonane
By (1s, 6s) 8- benzenesulfonyl -2,8- diazabicyclo [4,3,0] nonane (compound 4-4 in embodiment ten,
26.6g, 100mmol) and 5gcandidantartica Digestive Enzyme (novozym435) the mixture biphosphate of 150mm
It is 200ml that the mixture aqueous solution of potassium/dipotassium hydrogen phosphate buffer agent is configured to volume, is warming up to 40 DEG C of reaction 15h.Reaction is carried out
After completely, washed with potassium hydroxide aqueous solution and be about 9 to ph, solids removed by filtration, filtrate reduced in volume to after dry, vacuum distillation
Obtain product (s, s) -2,8- diazabicyclo [4,3,0] nonane 11.2g, yield is about 88.2%, ee value 98.5%.
The preparation of embodiment 13 (s, s) -2,8- diazabicyclo [4,3,0] nonane
Phenethylamine 50g is dissolved in 50ml water, under ice-water bath cooling, adjusts ph value to 8.0 with sodium hydrate aqueous solution,
And add 20ml dimethyl sulfoxide, then it is diluted to 400ml with the tris-hcl buffer of 0.1m and is preheating to 30 DEG C, add and contain
There is the dimethyl sulfoxide solution of 1- acetyl group -4- (3- chloropropyl) -3- ketopyrrolidine (5-1) 19.5g (95mmol)
200ml, is eventually adding 0.6g ω-transaminase's cold-dry powder and plp (phosphoric acid Vitamin B6) 0.4g, reacts the phenethylamine water with 20%
Solution controls ph=7～10, and temperature converts more than 24 hours at 10～50 DEG C, and tlc monitoring reaction finishes.Solids removed by filtration,
Mother solution adjusts ph ≈ 12 with 1n sodium hydroxide at 10～30 DEG C, stirs 2 hours.Adjust ph value ≈ 8.0 with 2n hydrochloric acid, be subsequently added into
1g amidohydrolase, in temperature, 10～40 DEG C are stirred 24 hours, and tlc monitoring reaction finishes, solids removed by filtration, and filtrate is concentrated into
Dry, finally distillation obtains (s, s) -2,8- diazabicyclo [4,3,0] nonane 8.9g, and yield is about 74.2%, ee value 96.8%.
The preparation of embodiment 14 (3s) -1- benzyloxycarbonyl group -3- amino -4- (3- ethoxycarbonyl-ethyl)-pyrrolidine
D- alanine 100g is dissolved in 100ml water, under ice-water bath cooling, adjusts ph value with sodium hydrate aqueous solution and arrive
8.0, and add 20mldmf, then it is diluted to 700ml with the tris-hcl buffer of 0.1m and is preheating to 30 DEG C, add and contain
There is the dmf solution 200ml of 1- benzyloxycarbonyl group -4- (3- ethoxycarbonyl-ethyl) -3- ketopyrrolidine (6-1) 31.9g, finally
Add 1g ω-transaminase's cold-dry powder and plp (phosphoric acid Vitamin B6) 0.8g, reaction controls ph with 20% d- alanine aqueous solution
=8～10, temperature converts more than 24 hours at 10～50 DEG C, and tlc monitoring reaction finishes.Solids removed by filtration, mother solution dichloro
Methane extracts 3 times, and the organic faciess anhydrous sodium sulfate drying after merging is concentrated to give grease (6-2) 29.8g, yield is about
93.1%.
1h-nmr(400mhz,cdcl3):δ7.19(5h),5.34(2h),3.69(2h),3.68(1h),3.43(2h),
2.23(2h),2.20(1h),1.65(2h).Ms-esi:m/z:319 (m++1).
The preparation of embodiment 15 (1s, 6s) -8- benzyloxycarbonyl group -2,8- diazabicyclo [4,3,0] nonane
By (3s) -1- benzyloxycarbonyl group -3- amino -4- (3- ethoxycarbonyl-ethyl)-pyrrolidine (compound in embodiment 13
6-3,32.0g, 100mmol), 270ml toluene, 33ml acetic acid, be warming up to 70 DEG C reaction 16h.After reaction is carried out completely, use carbonic acid
Hydrogen sodium water solution washs and is about 8 to ph, merges aqueous phase, and 100ml toluene extracts, combining methylbenzene phase, washing, the anhydrous sulfur of toluene phase
Sour sodium is dried, and the dry solvent of concentrating under reduced pressure obtains oil product (6-4) (25.8g, yield 94%).
1h-nmr(400mhz,cdcl3):δ7.19(5h),5.34(2h),3.69(2h),3.68(1h),3.43(2h),
2.23(2h),2.20(1h),1.65(2h).Ms-esi:m/z:273 (m++1).
Lithium aluminium hydride reduction 35.0g is added the anhydrous dmf of 50ml, be slowly added dropwise step product (compound under nitrogen protection
6-4,27.0g, 98mmol) it is dissolved in the solution of 110mldmf, maintain temperature at -10～-15 DEG C, completion of dropping temperature rising reflux 3 is little
When, it is down to 0 DEG C after reaction completely, Deca saturated aqueous ammonium chloride is quenched reaction, dichloromethane extracts (50ml × 3 time), water
Wash, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is done to obtain grease, column chromatography for separation obtains oil product compound 6-
5,20.5g, yield is about 78.8%.
The preparation of embodiment 16 (s, s) -2,8- diazabicyclo [4,3,0] nonane
By (1s, 6s) 8- benzyloxycarbonyl group -2,8- diazabicyclo [4,3,0] nonane (compound 6- in embodiment 14
5,26.0g, 100mmol) and 5gcandidantartica Digestive Enzyme (novozym435) the mixture di(2-ethylhexyl)phosphate of 150mm
It is 200ml that the mixture aqueous solution of hydrogen sodium/phosphorus acid disodium hydrogen buffer agent is configured to volume, is warming up to 40 DEG C of reaction 15h.React into
Row completely after, washed with sodium hydrate aqueous solution and be about 9 to ph, solids removed by filtration, filtrate reduced in volume to after dry, steam by decompression
Evaporate to obtain product (s, s) -2,8- diazabicyclo [4,3,0] nonane 11.2g, yield is about 88.9%, ee value 98.5%.
Claims (9)
1. a kind of 3- aminopyrrolidine compounds (ii) are it is characterised in that its structural formula is:
Wherein, r is amino protecting group；Z is oxygen or two hydrogen atoms, and when z is two hydrogen atoms, y is chlorine, bromine, iodine or hydroxyl
Sulphonic acid ester；When z is for oxygen, y is hydrogen, hydroxyl or c1-6 alkoxyl.
2. as claimed in claim 1 a kind of 3- aminopyrrolidine compounds it is characterised in that described 3- amino-pyrroles alkanisation
Compound ii is 3- aminopyrrolidine compounds iia, and the structural formula of compound iia is:
Wherein, r is amino protecting group, and r1 is hydrogen or c1-6 alkyl.
3. as claimed in claim 1 a kind of 3- aminopyrrolidine compounds it is characterised in that described 3- amino-pyrroles alkanisation
Compound ii is 3- aminopyrrolidine compounds iib, and the structural formula of compound iib is:
Wherein, r is amino protecting group, and r1 is hydrogen or c1-6 alkyl；Y is chlorine, bromine, iodine or hydroxyl sulfoacid ester.
4. the 3- aminopyrrolidine compounds as any one of claim 1-3 are it is characterised in that described amido protecting
Base r be phenyl, benzyl, p-toluenesulfonyl, mesyl, formoxyl, acetyl group, propiono, carbethoxyl group, methoxycarbonyl group,
Propylene carbonyl oxygen, butoxy carbonyl, tertbutyloxycarbonyl, benzyloxycarbonyl group, 2- xenyl -2- propylene carbonyl oxygen, phthalimide-based, three
Benzyl or trifluoroacetyl group.
5. a kind of purposes of compound ii as claimed in claim 1 is it is characterised in that be used for preparing (s, s) -2,8- diaza pair
((preparation method of compound i) includes compound i), (s, s) -2,8- diazabicyclo [4,3,0] nonane ring [4,3,0] nonane
Following steps:
1) compound ii carries out Intra-molecular condensation by functional group y, z and amino and obtains compound ia or compound ib；
2) by reducing amide, deprotection base obtains compound i to compound ia again, or compound ib deprotection base
Compound i；
The structural formula of described compound ia is:
The structural formula of described compound ib is:
Wherein, r is amino protecting group；As z=h2, y is chlorine, bromine, iodine or hydroxyl sulfoacid ester；As z=o, y is hydrogen, hydroxyl
Or c1-6 alkoxyl.
6. purposes as claimed in claim 5 is it is characterised in that the amino protecting group r of described compound ia or compound ib is
When benzyl or trityl, then described step 2) deprotection base under conditions of pd/c hydrogenation, described pd/c inventory
For the 1～5% of substrate, reaction temperature is 25～80 DEG C, and reaction pressure is 0.1～1mpa；If r is benzyloxycarbonyl group, 2- biphenyl
Base -2- propylene carbonyl oxygen, butoxy carbonyl, tertbutyloxycarbonyl, methoxycarbonyl group, carbethoxyl group or propylene carbonyl oxygen, then described step 2)
Deprotection base in salt aqueous acid or sodium hydrate aqueous solution or in the presence of hydrolytic enzyme, described aqueous hydrochloric acid solution with
The mol ratio of substrate is 2～6:1, and described reaction temperature is 50～100 DEG C, and described hydrolytic enzyme is candidantartica
Digestive Enzyme novozym435, operation amount is the 1～10% of substrate.Reaction temperature is 25～80 DEG C, described sodium hydroxide or hydrogen
Oxidation aqueous solutions of potassium is 1～5:1 with the mol ratio of substrate, and described reaction temperature is 50～100 DEG C.
7. purposes as claimed in claim 5 is it is characterised in that the amino protecting group r of described compound ia or compound ib is
P-toluenesulfonyl, mesyl, formoxyl, acetyl group, propiono, phthalimide-based or trifluoroacetyl group, then institute
The step 2 stated) the heated in water solution deprotection base of sodium hydroxide or potassium hydroxide or in the presence of hydrolytic enzyme removing protect
Shield base, described sodium hydrate aqueous solution is 1～5:1 with the mol ratio of substrate, and described reaction temperature is 50～100 DEG C, institute
The hydrolytic enzyme stated is candidantartica Digestive Enzyme novozym435, and operation amount is the 1～10% of substrate.Reaction temperature is
25～80 DEG C.
8. a kind of preparation method of compound as claimed in claim 2 (iia) is it is characterised in that compound iiia is by turning ammonia
Enzyme reaction, in the presence of amino group donor, transaminase and solvent, reacting generating compound iia, described amino group donor is isopropyl
Amine, described transaminase is ω-transaminase, and described solvent is water and the mixed solvent of organic solvent or water, described organic molten
Agent is dimethyl sulfoxide, oxolane or dmf, and the ph value of described transamination reaction is 7～10, the reaction temperature of described transamination reaction
Spend for 10～50 DEG C；
The structural formula of described compound iiia is:
Wherein, r is amino protecting group, and r1 is hydrogen or c1-6 alkyl.
9. a kind of preparation method of compound as claimed in claim 3 (iib) is it is characterised in that compound iiib is by turning ammonia
Enzyme reaction, in the presence of amino group donor, transaminase and solvent, reacting generating compound iib, described amino group donor is isopropyl
Amine, described transaminase is ω-transaminase, and described solvent is water and the mixed solvent of organic solvent or water, described organic molten
Agent is dimethyl sulfoxide, oxolane or dmf, and the ph value of described transamination reaction is 7～10, the reaction temperature of described transamination reaction
Spend for 10～50 DEG C；
The structural formula of described compound iiib is:
Wherein, r is amino protecting group, and y is chlorine, bromine, iodine or hydroxyl sulfoacid ester.
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| CN106399418B (en) * | 2015-07-29 | 2020-09-25 | 苏州汉酶生物技术有限公司 | Method for preparing moxifloxacin side chain by biological method |
| CN106086148B (en) * | 2016-06-20 | 2020-10-02 | 苏州汉酶生物技术有限公司 | Method for preparing dehydroepiandrosterone by chemical-enzymatic method |
| CN107686852B (en) * | 2016-08-04 | 2022-08-02 | 上海朴颐化学科技有限公司 | Preparation method of moxifloxacin intermediate compound |
| CN111349667B (en) * | 2016-11-01 | 2022-05-06 | 凯莱英医药集团（天津）股份有限公司 | Preparation method of chiral amino heterocyclic compound and derivative thereof |
| CN108623580A (en) * | 2017-03-17 | 2018-10-09 | 北大医药股份有限公司 | The preparation method of moxifloxacin side chain and its intermediate |
| CN113789310B (en) * | 2021-01-25 | 2023-11-10 | 上海予君生物科技发展有限公司 | Transaminase and application thereof in preparation of moxifloxacin or intermediate thereof |
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