CN104262225A - 3-aminopyrrolidine compounds, and synthetic method and uses thereof - Google Patents
3-aminopyrrolidine compounds, and synthetic method and uses thereof Download PDFInfo
- Publication number
- CN104262225A CN104262225A CN201410418987.9A CN201410418987A CN104262225A CN 104262225 A CN104262225 A CN 104262225A CN 201410418987 A CN201410418987 A CN 201410418987A CN 104262225 A CN104262225 A CN 104262225A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- compounds
- transaminase
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 *[C@](c1ccccc1)N1[C@](CN(Cc2ccccc2)C2)[C@]2CCC1 Chemical compound *[C@](c1ccccc1)N1[C@](CN(Cc2ccccc2)C2)[C@]2CCC1 0.000 description 3
- KSCPLKVBWDOSAI-NKWVEPMBSA-N C1NC[C@H]2NCCC[C@@H]12 Chemical compound C1NC[C@H]2NCCC[C@@H]12 KSCPLKVBWDOSAI-NKWVEPMBSA-N 0.000 description 1
- BOELLHUZTHYKEK-UHFFFAOYSA-N CCO[NH+](CCC(CC(CCc1ccccc1)CC1)C1=O)[O-] Chemical compound CCO[NH+](CCC(CC(CCc1ccccc1)CC1)C1=O)[O-] BOELLHUZTHYKEK-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
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, relate to 3-aminopyrrolidine compounds preparing technical field, particularly relate to a kind of 3-aminopyrrolidine compounds and preparation method and use thereof,
Background technology
3-aminopyrrolidine compounds is mainly for the preparation of chiral intermediate (S, S)-2,8-diazabicyclo [4,3, the 0] nonane of carbostyril family antibacterial drugs Moxifloxacin.
Moxifloxacin (Moxifloxacin) is fluoroquinolone medicine, develops successfully the earliest by German Bayer AG, first goes on the market in September, 1999 in Germany, trade(brand)name Avelox.In December in the same year, Moxifloxacin obtains FDA approval in U.S.'s listing, afterwards successively in the many countries and regions listing of Quan Shi state.Be widely used in treatment respiratory tract infection clinically as acquired pneumonia, the outbreak of striving property of chronic bronchitis, acute bacterial sinusitis etc.
(S, S)-2,8-diazabicyclo [4,3,0] nonane compound (I) is the crucial chiral intermediate of Moxifloxacin, molecular structure has piperidines and tetramethyleneimine two skeleton structures and two chiral centres, and the preparation method reported mainly is divided into two kinds of synthetic routes: piperidines route and tetramethyleneimine route (route one).
Route one
Piperidines route has more synthetic method report, is also the technique adopted in current suitability for industrialized production, is mainly prepared by raw material with pyridine-2,3-dicarboxylic acid, sees route two and route three.
Route two
Route three
Above-mentioned two lines all relate to the reaction such as the high-pressure hydrogenation of pyridine, the reduction of carboxylic acid carbonyl, and high-pressure hydrogenation is higher to equipment requirements, and the reduction of carboxylic acid carbonyl will be used and expensive be gone back original reagent.Also relate to the fractionation of chirality in building-up process, atom economy utilization ratio is very low.Have although follow-up patent and bibliographical information to solve the problem such as racemization recycling, resolving agent recycling of isomer, still there is complex process, the shortcomings such as reactions steps is many, both uneconomical also not environmentally.
Patent WO2013053281 discloses a kind of method of asymmetric synthesis (referring to route four) of tetramethyleneimine route; this route adopts R-phenylethylamine chiral induction, the method for hydrogenation builds two chiral centres, then intramolecular cyclization occurs, removes chiral auxiliary and protecting group obtains target product (I).
Route four
Summary of the invention
No matter adopt method for splitting or method of asymmetric synthesis preparation formula (I) compound, prior art has the problem using high-pressure hydrogenation technology and expensive reductive agent; Equally all exist process costs high, to the disagreeableness shortcoming of environment.Because this compound is the key intermediate preparing Moxifloxacin, therefore develop that a kind of cost is low, technical process is short, environment amenable synthetic technology, will huge market using value be had.
The object of the invention is to overcome above-mentioned shortcoming of the prior art, a kind of biocatalytic synthesis of moxifloxacin intermediate, related raw material and preparation method are provided, especially a kind of 3-aminopyrrolidine compounds and preparation method and use thereof thus reach that raw materials for production cost is low, the object of environmental protection, there is huge market using value, be suitable for large-scale industrial production.
A kind of 3-aminopyrrolidine compounds II 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 sulfoacid ester; When Z is oxygen, Y is hydrogen, hydroxyl or C1-6 alkoxyl group.
Described 3-aminopyrrolidine compounds II is the structural formula of 3-aminopyrrolidine compounds IIa, Compound II per a:
Wherein, R is amino protecting group, and R1 is hydrogen or C1-6 alkyl.
Described 3-aminopyrrolidine compounds II is the structural formula of 3-aminopyrrolidine compounds IIb, Compound II per b:
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 is phenyl, benzyl, p-toluenesulfonyl, methylsulfonyl, formyl radical, ethanoyl, propionyl, ethoxycarbonyl, methoxycarbonyl, the third oxygen carbonyl, butoxy carbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), 2-xenyl-2-third oxygen carbonyl, phthalimide-based, trityl or trifluoroacetyl group.
The purposes of described Compound II per is for the preparation of (S, S)-2,8-diazabicyclo [4,3,0] nonane (Compound I), (S, S)-2, the preparation method of 8-diazabicyclo [4,3,0] nonane (Compound I) comprises the steps:
1) Compound II per carries out Intra-molecular condensation by functional group Y, Z and amino and obtains Compound I a or compounds ib;
2) Compound I a by reducing amide again deprotection base obtain Compound I, or compounds ib deprotection base obtains Compound I;
The structural formula of described Compound I a is:
The structural formula of described compounds 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 group.
The amino protecting group R of described Compound I a or compounds ib be benzyl or trityl time, then described step 2) deprotection base under the condition of Pd/C hydrogenation, described Pd/C charging capacity is 1 ~ 5% of substrate, and temperature of reaction is 25 ~ 80 DEG C, and reaction pressure is 0.1 ~ 1MPa; If R is carbobenzoxy-(Cbz), 2-xenyl-2-third oxygen carbonyl, butoxy carbonyl, tertbutyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl or the third oxygen carbonyl; then described step 2) deprotection base in salt aqueous acid or aqueous sodium hydroxide solution or under the existence of lytic enzyme; described aqueous hydrochloric acid and the mol ratio of substrate are 2 ~ 6:1; described temperature of reaction is 50 ~ 100 DEG C; described lytic enzyme is Candidantartica lipase Novozym435, and operation amount is 1 ~ 10% of substrate.Temperature of reaction is 25 ~ 80 DEG C, and the mol ratio of described sodium hydroxide or potassium hydroxide aqueous solution and substrate is 1 ~ 5:1, and described temperature of reaction is 50 ~ 100 DEG C.
The amino protecting group R of described Compound I a or compounds ib is p-toluenesulfonyl, methylsulfonyl, formyl radical, ethanoyl, propionyl, phthalimide-based or trifluoroacetyl group; then described step 2) the heated in water solution deprotection base of sodium hydroxide or potassium hydroxide or under lytic enzyme exists deprotection base; described aqueous sodium hydroxide solution and the mol ratio of substrate are 1 ~ 5:1; described temperature of reaction is 50 ~ 100 DEG C; described lytic enzyme is Candidantartica lipase Novozym435, and operation amount is 1 ~ 10% of substrate.Temperature of reaction is 25 ~ 80 DEG C.
The preparation method of described compound (IIa) is: compound III a passes through transamination reaction, under amino group donor, transaminase and solvent exist, reacting generating compound IIa, described amino group donor is Isopropylamine, described transaminase is ω-transaminase, described solvent is mixed solvent or the water of water and organic solvent, described organic solvent is methyl-sulphoxide, tetrahydrofuran (THF) or DMF, the pH value of described transamination reaction is 7 ~ 10, and the temperature of reaction of described transamination reaction is 10 ~ 50 DEG C;
The structural formula of described compound III a is:
Wherein, R is amino protecting group, and R1 is hydrogen or C1-6 alkyl.
The preparation method of described compound (IIb) is: compound III b passes through transamination reaction, under amino group donor, transaminase and solvent exist, reacting generating compound IIb, described amino group donor is Isopropylamine, described transaminase is ω-transaminase, described solvent is mixed solvent or the water of water and organic solvent, described organic solvent is methyl-sulphoxide, tetrahydrofuran (THF) or DMF, the pH value of described transamination reaction is 7 ~ 10, and the temperature of reaction of described transamination reaction is 10 ~ 50 DEG C;
The structural formula of described compound III b is:
Wherein, R is amino protecting group, and Y is chlorine, bromine, iodine or hydroxyl sulfoacid ester.
A kind of (S, S)-2,8-the enzymatic synthesis method of diazabicyclo [4,3,0] nonane (I) be: compound III a or compound III b under the effect of transaminase and lytic enzyme, one pot process Compound I.
The present invention with formula (III) pyrrolidone-2 compounds for raw material; by the chiral amino that biocatalysis obtains; the easy steps such as intramolecular cyclization, deprotection base; particularly prepare moxifloxacin intermediate by one kettle way method described above, its chiral purity reaches more than 99%.The present invention is that a kind of cost is low, technical process is short, environment amenable synthetic technology, will have huge market using value, is applicable to large-scale industrial production.
Embodiment
Content for a better understanding of the present invention, is described further below in conjunction with specific embodiment.Should be understood that following specific examples is only for illustration of the present invention, instead of limitation of the present invention.
The preparation of embodiment one (3S)-1-benzyl-3-amino-4-(3-ethoxycarbonylpropyl)-tetramethyleneimine
Isopropylamine 100g is dissolved in 100ml water, under ice-water bath cooling, regulate pH value to 8.0 with aqueous hydrochloric acid, and add 20ml tetrahydrofuran (THF), then be diluted to 700ml with the Tris-HCl damping fluid of 0.1M and be preheating to 30 DEG C, add the tetrahydrofuran solution 200ml containing 1-benzyl-4-(3-ethoxycarbonylpropyl)-3-pyrrolidone (3-1) 50g again, finally add 1g ω-transaminase cold-dry powder and PLP (phosphoric acid Vitamin B6) 0.8g, react isopropylamine solution control PH=7 ~ 10 with 20%, temperature transforms more than 24 hours at 10 ~ 50 DEG C, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor is extracted with ethyl acetate 3 times, the organic phase anhydrous sodium sulfate drying after merging, and concentrate and obtain oily matter (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-ethoxycarbonylpropyl)-tetramethyleneimine (in embodiment 1 compound 2-1,27.4g, 100mmol), 270ml toluene, 35ml acetic acid, is warming up to 70 DEG C of reaction 16h.Reaction is carried out completely, is about 8, merges aqueous phase with sodium bicarbonate aqueous solution washing to pH, 100ml toluene extracts, combining methylbenzene phase, washing, toluene uses anhydrous sodium sulfate drying mutually, and the dry solvent of concentrating under reduced pressure obtains oil product (1-2) (21.2g, yield 92%).
1H-NMR(400MHz,CDCl
3):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 aluminum hydride 35.0g is added the anhydrous tetrahydro furan of 50ml, product (compound 1-2 is walked on slowly dripping under nitrogen protection, 21.2g, 92mmol) be dissolved in the solution of 110ml tetrahydrofuran (THF), holding temperature is at-10 ~-15 DEG C, dropwise temperature rising reflux 3 hours, 0 DEG C is down to after reacting completely, drip saturated aqueous ammonium chloride cancellation reaction, extraction into ethyl acetate (50ml × 3 time), washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is done to obtain oily matter, 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 methyl alcohol, 10% palladium carbon 0.5g adds autoclave pressure, room temperature hydrogenation reaction 24 hours under 1.0MPa pressure, crosses and filter palladium carbon after reacting completely, filtrate regulates PH=10.0 with sodium methylate/methanol solution, filters, and the concentrated dry rear underpressure distillation of filtrate obtains product (S, S)-2,8-diazabicyclo [4,3,0] nonane 5.3g, yield is about 84%, ee value 98.1%.
The preparation of embodiment four (3S)-1-benzyl-3-amino-4-(3-chloropropyl)-tetramethyleneimine
Isopropylamine 100g is dissolved in 100ml water, under ice-water bath cooling, regulate pH value to 8.0 with aqueous hydrochloric acid, and add 20ml tetrahydrofuran (THF), then be diluted to 700ml with the Tris-HCl damping fluid of 0.1M and be preheating to 30 DEG C, add the tetrahydrofuran solution 200ml containing 1-benzyl-4-(3-ethoxycarbonylpropyl)-3-pyrrolidone (3-2) 50g again, finally add 1g ω-transaminase cold-dry powder and PLP (phosphoric acid Vitamin B6) 0.8g, react isopropylamine solution control PH=7 ~ 10 with 20%, temperature transforms more than 24 hours at 10 ~ 50 DEG C, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor is extracted with ethyl acetate 3 times, the organic phase anhydrous sodium sulfate drying after merging, and concentrate and obtain oily matter (2-2) 45.25g, yield is about 90.5%.
1H-NMR(400MHz,CDCl
3)：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)-tetramethyleneimine (compound 2-2 in embodiment 1,12.6g, 50mmol) potassium tert.-butoxide (6.8g, 60mmol), tetrabutylammonium iodide (0.38g, 1.0mmol) be dissolved in 150ml tetrahydrofuran (THF), back flow reaction 1 hour, the dry solvent of concentrating under reduced pressure, obtain oily matter and be dissolved in 100ml ethyl acetate, washing, anhydrous sodium sulfate drying, filters, filtrate reduced in volume is done to obtain oily matter (1-1) 10.0g, and yield is about 92.5%.
1H-NMR(400MHz,CDCl
3):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 five (S, S)-2,8-diazabicyclo [4,3,0] nonane
Isopropylamine 50g is dissolved in 50ml water, under ice-water bath cooling, regulate pH value to 8.0 with aqueous hydrochloric acid, and add 20ml tetrahydrofuran (THF), then be diluted to 400ml with the Tris-HCl damping fluid of 0.1M and be preheating to 30 DEG C, add the tetrahydrofuran solution 200ml containing 1-benzyl-4-(3-ethoxycarbonylpropyl)-3-pyrrolidone (3-2) 25g (95mmol) again, finally add 0.6g ω-transaminase cold-dry powder and PLP (phosphoric acid Vitamin B6) 0.4g, react isopropylamine solution control PH=7 ~ 10 with 20%, temperature transforms more than 24 hours at 10 ~ 50 DEG C, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor 1N sodium hydroxide regulates PH=12 at 10 ~ 30 DEG C, stirs 2 hours.Regulate pH value=7 ~ 8 with 2N hydrochloric acid, then add 1g amidohydrolase, stir 24 hours temperature 10 ~ 40 DEG C, TLC monitoring reaction is complete, solids removed by filtration, filtrate is concentrated into dry, and finally distillation obtains (S, S)-2,8-diazabicyclo [4,3,0] nonane 8.8g, yield is about 73.3%, ee value 96.8%.
The preparation of embodiment six (3S)-1-benzyl-3-amino-4-(3-ethoxycarbonylpropyl)-tetramethyleneimine
Isopropylamine 100g is dissolved in 100ml water, under ice-water bath cooling, regulate pH value to 8.0 with aqueous hydrochloric acid, and add 20ml tetrahydrofuran (THF), then be diluted to 700ml with the Tris-HCl damping fluid of 0.1M and be preheating to 30 DEG C, add the tetrahydrofuran solution 200ml containing 1-benzyl-4-(3-ethoxycarbonylpropyl)-3-pyrrolidone (3-1) 50g again, finally add 1g ω-transaminase cold-dry powder and PLP (phosphoric acid Vitamin B6) 0.8g, react isopropylamine solution control PH=8 ~ 10 with 20%, temperature transforms more than 24 hours at 10 ~ 50 DEG C, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor is extracted with ethyl acetate 3 times, the organic phase anhydrous sodium sulfate drying after merging, and concentrate and obtain oily matter (2-1) 46g, yield is about 92%.
1H-NMR(400MHz,CDCl
3):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 seven (1S, 6S)-8-ethanoyl-2,8-diazabicyclo [4,3,0] nonane
By (3S)-1-ethanoyl-3-amino-4-(3-ethoxycarbonylpropyl)-tetramethyleneimine (in embodiment six compound 2-4,22.8g, 100mmol), 270ml toluene, 33ml acetic acid, is warming up to 70 DEG C of reaction 16h.Reaction is carried out completely, is about 8, merges aqueous phase with sodium bicarbonate aqueous solution washing to pH, 100ml toluene extracts, combining methylbenzene phase, washing, toluene uses anhydrous sodium sulfate drying mutually, and the dry solvent of concentrating under reduced pressure obtains oil product (1-5) (17.3g, yield 95%).
1H-NMR(400MHz,CDCl
3):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 aluminum hydride 35.0g is added the anhydrous tetrahydro furan of 50ml, product (compound 1-5 is walked on slowly dripping under nitrogen protection, 16.8g, 92mmol) be dissolved in the solution of 110ml tetrahydrofuran (THF), holding temperature is at-10 ~-15 DEG C, dropwise temperature rising reflux 3 hours, 0 DEG C is down to after reacting completely, drip saturated aqueous ammonium chloride cancellation reaction, extraction into ethyl acetate (50ml × 3 time), washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is done to obtain oily matter, 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 eight (S, S)-2,8-diazabicyclo [4,3,0] nonane
Will
-8-ethanoyl-2; 8-diazabicyclo [4; 3; 0] nonane (compound 1-4 in embodiment seven; 12g, 100mmol) and the mixture aqueous solution of SODIUM PHOSPHATE, MONOBASIC/Sodium phosphate dibasic buffer reagent of mixture 150mM of 1gCandidantartica lipase (Novozym435) to be mixed with volume be 200ml.Be warming up to 40 DEG C of reaction 16h.Reaction is carried out completely, is about 10, solids removed by filtration with aqueous sodium hydroxide solution washing to pH, after filtrate reduced in volume is extremely dry, underpressure distillation obtains product (S, S)-2,8-diazabicyclo [4,3,0] nonane 11.1g, yield is about 87.8%, ee value 98.5%.
The preparation of embodiment nine (3S)-1-p-toluenesulfonyl-3-amino-4-(3-ethoxycarbonylpropyl)-tetramethyleneimine
Phenylethylamine 100g is dissolved in 100ml water, under ice-water bath cooling, regulate pH value to 8.0 with aqueous sodium hydroxide solution, and add 20mlDMF, then be diluted to 700ml with the Tris-HCl damping fluid of 0.1M and be preheating to 30 DEG C, add the DMF solution 200ml containing 1-p-toluenesulfonyl-4-(3-ethoxycarbonylpropyl)-3-pyrrolidone (4-1) 50g again, finally add 1g ω-transaminase cold-dry powder and PLP (phosphoric acid Vitamin B6) 0.8g, react phenylethylamine aqueous solution control PH=8 ~ 10 with 20%, temperature transforms more than 24 hours at 10 ~ 50 DEG C, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor dichloromethane extraction 3 times, the organic phase anhydrous sodium sulfate drying after merging, concentratedly obtains oily matter (4-2) 61g, and yield is about 93.5%.
1H-NMR(400MHz,CDCl
3):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 ten (1S, 6S)-8-p-toluenesulfonyl-2,8-diazabicyclo [4,3,0] nonane
By (3S)-1-p-toluenesulfonyl-3-amino-4-(3-ethoxycarbonylpropyl)-tetramethyleneimine (in embodiment nine compound 4-2,32.6g, 100mmol), 270ml toluene, 33ml acetic acid, is warming up to 70 DEG C of reaction 16h.Reaction is carried out completely, is about 8, merges aqueous phase with sodium bicarbonate aqueous solution washing to pH, 100ml toluene extracts, combining methylbenzene phase, washing, toluene uses anhydrous sodium sulfate drying mutually, and the dry solvent of concentrating under reduced pressure obtains oil product (4-3) (26.3g, yield 94%).
1H-NMR(400MHz,CDCl
3):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 aluminum hydride 35.0g is added the dry DMF of 50ml; product (compound 1-5 is walked on slowly dripping under nitrogen protection; 24.2g; 94mmol) be dissolved in the solution of 110ml DMF; holding temperature is at-10 ~-15 DEG C; dropwise temperature rising reflux 3 hours, after reacting completely, be down to 0 DEG C, drip saturated aqueous ammonium chloride cancellation reaction; dichloromethane extraction (50ml × 3 time); washing, anhydrous sodium sulfate drying, filters; filtrate reduced in volume is done to obtain oily matter; column chromatography for separation obtains oil product compound 4-4, and 13.5g, yield is about 78.1%.
1H-NMR(400MHz,CDCl
3):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 11 (S, S)-2,8-diazabicyclo [4,3,0] nonane
By (1S; 6S)-8-p-toluenesulfonyl-2; 8-diazabicyclo [4; 3; 0] nonane (compound 4-4 in embodiment ten; 26.6g, 100mmol) and the mixture aqueous solution of potassium primary phosphate/dipotassium hydrogen phosphate buffer reagent of mixture 150mM of 5gCandidantartica lipase (Novozym435) to be mixed with volume be 200ml, be warming up to 40 DEG C of reaction 15h.Reaction is carried out completely, is about 9, solids removed by filtration with potassium hydroxide aqueous solution washing to pH, after filtrate reduced in volume is extremely dry, underpressure distillation obtains 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 12 (S, S)-2,8-diazabicyclo [4,3,0] nonane
Phenylethylamine 50g is dissolved in 50ml water, under ice-water bath cooling, regulate pH value to 8.0 with aqueous sodium hydroxide solution, and add 20ml methyl-sulphoxide, then be diluted to 400ml with the Tris-HCl damping fluid of 0.1M and be preheating to 30 DEG C, add the dimethyl sulfoxide solution 200ml containing 1-benzyl-4-(3-ethanoyl)-3-pyrrolidone (5-1) 19.5g (95mmol) again, finally add 0.6g ω-transaminase cold-dry powder and PLP (phosphoric acid Vitamin B6) 0.4g, react phenylethylamine aqueous solution control PH=7 ~ 10 with 20%, temperature transforms more than 24 hours at 10 ~ 50 DEG C, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor 1N sodium hydroxide regulates PH ≈ 12 at 10 ~ 30 DEG C, stirs 2 hours.Regulate pH value ≈ 8.0 with 2N hydrochloric acid, then add 1g amidohydrolase, stir 24 hours temperature 10 ~ 40 DEG C, TLC monitoring reaction is complete, solids removed by filtration, filtrate is concentrated into dry, and finally distillation obtains (S, S)-2,8-diazabicyclo [4,3,0] nonane 8.9g, yield is about 74.2%, ee value 96.8%.
The preparation of embodiment 13 (3S)-1-carbobenzoxy-(Cbz)-3-amino-4-(3-ethoxycarbonylpropyl)-tetramethyleneimine
D-alanine 100g is dissolved in 100ml water, under ice-water bath cooling, regulate pH value to 8.0 with aqueous sodium hydroxide solution, and add 20mlDMF, then be diluted to 700ml with the Tris-HCl damping fluid of 0.1M and be preheating to 30 DEG C, add the DMF solution 200ml containing 1-carbobenzoxy-(Cbz)-4-(3-ethoxycarbonylpropyl)-3-pyrrolidone (6-1) 31.9g again, finally add 1g ω-transaminase cold-dry powder and PLP (phosphoric acid Vitamin B6) 0.8g, react D-alanine aqueous solution control PH=8 ~ 10 with 20%, temperature transforms more than 24 hours at 10 ~ 50 DEG C, TLC monitoring reaction is complete.Solids removed by filtration, mother liquor dichloromethane extraction 3 times, the organic phase anhydrous sodium sulfate drying after merging, concentratedly obtains oily matter (6-2) 29.8g, and yield is about 93.1%.
1H-NMR(400MHz,CDCl
3):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 14 (1S, 6S)-8-carbobenzoxy-(Cbz)-2,8-diazabicyclo [4,3,0] nonane
By (3S)-1-carbobenzoxy-(Cbz)-3-amino-4-(3-ethoxycarbonylpropyl)-tetramethyleneimine (in embodiment 13 compound 6-3,32.0g, 100mmol), 270ml toluene, 33ml acetic acid, is warming up to 70 DEG C of reaction 16h.Reaction is carried out completely, is about 8, merges aqueous phase with sodium bicarbonate aqueous solution washing to pH, 100ml toluene extracts, combining methylbenzene phase, washing, toluene uses anhydrous sodium sulfate drying mutually, and the dry solvent of concentrating under reduced pressure obtains oil product (6-4) (25.8g, yield 94%).
1H-NMR(400MHz,CDCl
3):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 aluminum hydride 35.0g is added the dry DMF of 50ml; product (compound 6-4 is walked on slowly dripping under nitrogen protection; 27.0g; 98mmol) be dissolved in the solution of 110mlDMF; holding temperature is at-10 ~-15 DEG C; dropwise temperature rising reflux 3 hours, after reacting completely, be down to 0 DEG C, drip saturated aqueous ammonium chloride cancellation reaction; dichloromethane extraction (50ml × 3 time); washing, anhydrous sodium sulfate drying, filters; filtrate reduced in volume is done to obtain oily matter; column chromatography for separation obtains oil product compound 6-5, and 20.5g, yield is about 78.8%.
The preparation of embodiment 15 (S, S)-2,8-diazabicyclo [4,3,0] nonane
By (1S, 6S)-8-carbobenzoxy-(Cbz)-2,8-diazabicyclo [4,3,0] nonane (compound 6-5 in embodiment 14,26.0g, 100mmol) and the mixture aqueous solution of SODIUM PHOSPHATE, MONOBASIC/Sodium phosphate dibasic buffer reagent of mixture 150mM of 5gCandidantartica lipase (Novozym435) to be mixed with volume be 200ml, be warming up to 40 DEG C of reaction 15h.Reaction is carried out completely, is about 9, solids removed by filtration with aqueous sodium hydroxide solution washing to pH, after filtrate reduced in volume is extremely dry, underpressure distillation obtains product (S, S)-2,8-diazabicyclo [4,3,0] nonane 11.2g, yield is about 88.9%, ee value 98.5%.
Claims (10)
1. a 3-aminopyrrolidine compounds (II), is characterized 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 sulfoacid ester; When Z is oxygen, Y is hydrogen, hydroxyl or C1-6 alkoxyl group.
2. a kind of 3-aminopyrrolidine compounds as claimed in claim 1, is characterized in that described 3-aminopyrrolidine compounds II is the structural formula of 3-aminopyrrolidine compounds IIa, Compound II per a and is:
Wherein, R is amino protecting group, and R1 is hydrogen or C1-6 alkyl.
3. a kind of 3-aminopyrrolidine compounds as claimed in claim 1, is characterized in that described 3-aminopyrrolidine compounds II is the structural formula of 3-aminopyrrolidine compounds IIb, Compound II per b and 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 according to any one of claim 1-3, is characterized in that described amino protecting group R is phenyl, benzyl, p-toluenesulfonyl, methylsulfonyl, formyl radical, ethanoyl, propionyl, ethoxycarbonyl, methoxycarbonyl, the third oxygen carbonyl, butoxy carbonyl, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), 2-xenyl-2-third oxygen carbonyl, phthalimide-based, trityl or trifluoroacetyl group.
5. the purposes of a Compound II per as claimed in claim 1, it is characterized in that for the preparation of (S, S)-2,8-diazabicyclos [4,3,0] nonane (Compound I), (S, S)-2,8-diazabicyclo [4,3,0] preparation method of nonane (Compound I) comprises the steps:
1) Compound II per carries out Intra-molecular condensation by functional group Y, Z and amino and obtains Compound I a or compounds ib;
2) Compound I a by reducing amide again deprotection base obtain Compound I, or compounds ib deprotection base obtains Compound I;
The structural formula of described Compound I a is:
The structural formula of described compounds 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 group.
6. purposes as claimed in claim 5, it is characterized in that the amino protecting group R of described Compound I a or compounds ib be benzyl or trityl time, then described step 2) deprotection base under the condition of Pd/C hydrogenation, described Pd/C charging capacity is 1 ~ 5% of substrate, temperature of reaction is 25 ~ 80 DEG C, and reaction pressure is 0.1 ~ 1MPa; If R is carbobenzoxy-(Cbz), 2-xenyl-2-third oxygen carbonyl, butoxy carbonyl, tertbutyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl or the third oxygen carbonyl; then described step 2) deprotection base in salt aqueous acid or aqueous sodium hydroxide solution or under the existence of lytic enzyme; described aqueous hydrochloric acid and the mol ratio of substrate are 2 ~ 6:1; described temperature of reaction is 50 ~ 100 DEG C; described lytic enzyme is Candidantartica lipase Novozym435, and operation amount is 1 ~ 10% of substrate.Temperature of reaction is 25 ~ 80 DEG C, and the mol ratio of described sodium hydroxide or potassium hydroxide aqueous solution and substrate is 1 ~ 5:1, and described temperature of reaction is 50 ~ 100 DEG C.
7. purposes as claimed in claim 5, it is characterized in that the amino protecting group R of described Compound I a or compounds ib is p-toluenesulfonyl, methylsulfonyl, formyl radical, ethanoyl, propionyl, phthalimide-based or trifluoroacetyl group, then described step 2) the heated in water solution deprotection base of sodium hydroxide or potassium hydroxide or under lytic enzyme exists deprotection base, described aqueous sodium hydroxide solution and the mol ratio of substrate are 1 ~ 5:1, described temperature of reaction is 50 ~ 100 DEG C, described lytic enzyme is Candidantartica lipase Novozym435, operation amount is 1 ~ 10% of substrate.Temperature of reaction is 25 ~ 80 DEG C.
8. the preparation method of a compound (IIa) as claimed in claim 2, it is characterized in that, compound III a passes through transamination reaction, under amino group donor, transaminase and solvent exist, reacting generating compound IIa, described amino group donor is Isopropylamine, described transaminase is ω-transaminase, described solvent is mixed solvent or the water of water and organic solvent, described organic solvent is methyl-sulphoxide, tetrahydrofuran (THF) or DMF, the pH value of described transamination reaction is 7 ~ 10, and the temperature of reaction of described transamination reaction is 10 ~ 50 DEG C;
The structural formula of described compound III a is:
Wherein, R is amino protecting group, and R1 is hydrogen or C1-6 alkyl.
9. the preparation method of a compound (IIb) as claimed in claim 2, it is characterized in that, compound III b passes through transamination reaction, under amino group donor, transaminase and solvent exist, reacting generating compound IIb, described amino group donor is Isopropylamine, described transaminase is ω-transaminase, described solvent is mixed solvent or the water of water and organic solvent, described organic solvent is methyl-sulphoxide, tetrahydrofuran (THF) or DMF, the pH value of described transamination reaction is 7 ~ 10, and the temperature of reaction of described transamination reaction is 10 ~ 50 DEG C;
The structural formula of described compound III b is:
Wherein, R is amino protecting group, and Y is chlorine, bromine, iodine or hydroxyl sulfoacid ester.
10. one kind (S, S)-2,8-enzymatic synthesis method of diazabicyclo [4,3,0] nonane (I), is characterized in that compound III a or compound III b is under the effect of transaminase and lytic enzyme, one pot process Compound I.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410418987.9A CN104262225B (en) | 2014-08-24 | 2014-08-24 | 3-aminopyrrolidine compounds, and synthetic method and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410418987.9A CN104262225B (en) | 2014-08-24 | 2014-08-24 | 3-aminopyrrolidine compounds, and synthetic method and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104262225A true CN104262225A (en) | 2015-01-07 |
| CN104262225B CN104262225B (en) | 2017-02-01 |
Family
ID=52153844
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410418987.9A Active CN104262225B (en) | 2014-08-24 | 2014-08-24 | 3-aminopyrrolidine compounds, and synthetic method and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104262225B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106086148A (en) * | 2016-06-20 | 2016-11-09 | 苏州汉酶生物技术有限公司 | A kind of chemical-enzymatic prepares the method for dehydroepiandros-sterone |
| CN106399418A (en) * | 2015-07-29 | 2017-02-15 | 苏州汉酶生物技术有限公司 | Method for preparing moxifloxacin side chain through biological method |
| CN107686852A (en) * | 2016-08-04 | 2018-02-13 | 上海朴颐化学科技有限公司 | A kind of preparation method of moxifloxacin intermediate compound |
| 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 |
| CN111349667A (en) * | 2016-11-01 | 2020-06-30 | 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 |
| CN113789310A (en) * | 2021-01-25 | 2021-12-14 | 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 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830898A (en) * | 2009-03-13 | 2010-09-15 | 上海普渡生化科技有限公司 | Preparation method of (S, S)-octahydro-6H-pyrrolo[3, 4-b] pyridine |
| CN102399219A (en) * | 2011-11-18 | 2012-04-04 | 太仓市运通化工厂 | Method for preparing moxifloxacin hydrochloride intermediate |
| CN102964346A (en) * | 2011-09-01 | 2013-03-13 | 中国中化股份有限公司 | Preparation method of (S, S)-octahydro-6H-pyrrolo[3, 4-b]pyridine |
| CN103030638A (en) * | 2012-11-29 | 2013-04-10 | 中国科学院成都生物研究所 | Preparation method of (S, S)-8H-6H-pyrrolo [3, 4-b] pyridine |
| CN103044418A (en) * | 2011-10-14 | 2013-04-17 | 上海朴颐化学科技有限公司 | Asymmetric synthesis method, relevant raw materials and preparation method of (S,S)-2,8-diazabicyclo[4,3,0] nonane |
| CN103183673A (en) * | 2011-12-30 | 2013-07-03 | 浙江新和成股份有限公司 | Synthesizing method of (S,S)-2,8-diazabicyclo[4.3.0]nonane |
-
2014
- 2014-08-24 CN CN201410418987.9A patent/CN104262225B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830898A (en) * | 2009-03-13 | 2010-09-15 | 上海普渡生化科技有限公司 | Preparation method of (S, S)-octahydro-6H-pyrrolo[3, 4-b] pyridine |
| CN102964346A (en) * | 2011-09-01 | 2013-03-13 | 中国中化股份有限公司 | Preparation method of (S, S)-octahydro-6H-pyrrolo[3, 4-b]pyridine |
| CN103044418A (en) * | 2011-10-14 | 2013-04-17 | 上海朴颐化学科技有限公司 | Asymmetric synthesis method, relevant raw materials and preparation method of (S,S)-2,8-diazabicyclo[4,3,0] nonane |
| CN102399219A (en) * | 2011-11-18 | 2012-04-04 | 太仓市运通化工厂 | Method for preparing moxifloxacin hydrochloride intermediate |
| CN103183673A (en) * | 2011-12-30 | 2013-07-03 | 浙江新和成股份有限公司 | Synthesizing method of (S,S)-2,8-diazabicyclo[4.3.0]nonane |
| CN103030638A (en) * | 2012-11-29 | 2013-04-10 | 中国科学院成都生物研究所 | Preparation method of (S, S)-8H-6H-pyrrolo [3, 4-b] pyridine |
Non-Patent Citations (5)
| Title |
|---|
| A. TORRES-GAVILAN, ET AL.: "The amidase activity of Candida Antarctica lipase B is dependent on specific structural features of the substrates.", 《JOURNAL OF MOLECULAR CATALYSIS B: ENZYMATIC》 * |
| JOHN WARD, ROLAND WOHLGEMUTH.: "High-yield biocatalytic amination reaction in organic synthesis", 《CURRENT ORGANIC CHEMISTRY》 * |
| 武钦佩，李善茂.: "《保护基化学》", 31 January 2007, 北京：化学工业出版社 * |
| 王潇莹,等.: "转氨酶在手性化合物合成中的研究进展", 《沈阳药科大学学报》 * |
| 贾红华,等.: "ω-转氨酶制备手性胺的研究进展", 《现代化工》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106399418A (en) * | 2015-07-29 | 2017-02-15 | 苏州汉酶生物技术有限公司 | Method for preparing moxifloxacin side chain through biological method |
| 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 |
| CN106086148A (en) * | 2016-06-20 | 2016-11-09 | 苏州汉酶生物技术有限公司 | A kind of chemical-enzymatic prepares the method for dehydroepiandros-sterone |
| 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 |
| CN107686852A (en) * | 2016-08-04 | 2018-02-13 | 上海朴颐化学科技有限公司 | A kind of preparation method of moxifloxacin intermediate compound |
| 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 |
| CN111349667A (en) * | 2016-11-01 | 2020-06-30 | 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 |
| CN113789310A (en) * | 2021-01-25 | 2021-12-14 | 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 |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104262225B (en) | 2017-02-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104262225A (en) | 3-aminopyrrolidine compounds, and synthetic method and uses thereof | |
| CN103282361B (en) | Asymmetric synthesis method, related raw material and preparation method of (S,S)-2,8-diazabicyclo[4,3,0]nonane | |
| CN108299296B (en) | Preparation method of phenanthridine heterocyclic compound | |
| CN108129288B (en) | Synthesis method of trans-3-hydroxycyclobutylformic acid | |
| CN103193779B (en) | A kind of preparation method of Lunesta | |
| CN104628808A (en) | Synthesis method and intermediates of pregnene-1,4,9 (11),16 (17)-tetraenol-3, 20-diketone | |
| CN107686852B (en) | Preparation method of moxifloxacin intermediate compound | |
| CN111499562B (en) | Process for producing 5-hydroxypiperidine-2-carboxylic acid | |
| Chrzanowska et al. | A concise synthesis of tetrahydroisoquinoline-1-carboxylic acids using a Petasis reaction and Pomeranz–Fritsch–Bobbitt cyclization sequence | |
| CN107793414B (en) | The synthetic method of (S, S) -2,8- diazabicyclo [4.3.0] nonane | |
| CN102887885B (en) | Preparation method of esomeprazole sodium | |
| CN105820101B (en) | A kind of preparation method of the pure 1- of optically-active (carbamoyl) methyl -4- hydroxy-2-pyrrolidinone | |
| CN106008316B (en) | A kind of method of synthesis Lei Dipawei chiral intermediates | |
| Yang et al. | A stereoselective approach to 6-alkylated piperidinone & 2-piperidine via three-component vinylogous Mannich reactions (VMR) and a concise synthesis of (S)-anabasine | |
| KR20090017316A (en) | ENANTIOSELECTIVE SYNTHESIS OF SUBSTITUTED gamma-BUTYROLACTONES | |
| CN102675313A (en) | Preparation method of moxifloxacin hydrochloride | |
| CN103554108A (en) | Improved tadalafil preparation method | |
| IL185015A (en) | Process for the manufacture of a camptothecin intermediate | |
| Chen et al. | Synthetic Studies on d-Biotin, Part 9. An Improved Asymmetric Synthetic Route to d-Biotin via Hoffmann–Roche Lactone–Thiolactone Approach | |
| CN109896980B (en) | Biosynthesis method of sitagliptin intermediate | |
| CN104478799B (en) | The preparation method of 1,4-diallyl isoquinolin | |
| CN105218477A (en) | A kind of polysubstituted benzo [b] [Isosorbide-5-Nitrae] oxygen azatropylidene piperidine derivatives and preparation method thereof | |
| CN105237492A (en) | Synthetic method for ezetimibe intermediate | |
| CN101691355B (en) | Substituted 4-quinolinone compounds and preparation method thereof | |
| CN103755710B (en) | One class 2,5-diazabicyclo iieptanes compound and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 318000 29 Binhai Road, Yan tou Industrial Zone, Jiaojiang District, Taizhou, Zhejiang. Patentee after: Zhejiang Le Pu pharmaceutical Limited by Share Ltd Address before: 318000 29 Binhai Road, Yan tou Industrial Zone, Jiaojiang District, Taizhou, Zhejiang. Patentee before: Xindonggang Pharmaceutical Co., Ltd., Zhejiang |