CN108752253A - A kind of polynary aza-cyclic Non-natural chiral amino acid and its synthetic method - Google Patents
A kind of polynary aza-cyclic Non-natural chiral amino acid and its synthetic method Download PDFInfo
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- CN108752253A CN108752253A CN201810680123.2A CN201810680123A CN108752253A CN 108752253 A CN108752253 A CN 108752253A CN 201810680123 A CN201810680123 A CN 201810680123A CN 108752253 A CN108752253 A CN 108752253A
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- 0 CCO*(CCCCCCl)OOC([N-])=O Chemical compound CCO*(CCCCCCl)OOC([N-])=O 0.000 description 2
- LFPKQLJTMTWPAQ-UHFFFAOYSA-N CCC(C)CCCCCCCCl Chemical compound CCC(C)CCCCCCCCl LFPKQLJTMTWPAQ-UHFFFAOYSA-N 0.000 description 1
- KAETVUXRWHGZRI-UHFFFAOYSA-N CCCC(C1(C(OCC)=O)NCCCCCCCCCC1)=[CH+] Chemical compound CCCC(C1(C(OCC)=O)NCCCCCCCCCC1)=[CH+] KAETVUXRWHGZRI-UHFFFAOYSA-N 0.000 description 1
- DQGPQUCMXRLDKF-UHFFFAOYSA-N CCOC(C1(C(OC)=O)NCCCCC1)=[U] Chemical compound CCOC(C1(C(OC)=O)NCCCCC1)=[U] DQGPQUCMXRLDKF-UHFFFAOYSA-N 0.000 description 1
- CODVFVXJORWVKO-UHFFFAOYSA-N OC(C1NCCCCCCCCCC1)O Chemical compound OC(C1NCCCCCCCCCC1)O CODVFVXJORWVKO-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
- C07D225/02—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom not condensed with other rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- 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
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Abstract
The present invention relates to a kind of polynary aza-cyclic Non-natural chiral amino acid and its synthetic methods, can be applied to the molecular building block of the drugs such as synthetic antibiotic.By the way that polynary aza-cyclic Non-natural chiral amino acid can be made with the replacing of 2- diethyl aminomalonates and halogenated alkane, cyclization, decarboxylic reaction, then by splitting.New synthetic method route of the present invention is succinct, it is at low cost, easy to operate, be easy to be commercially produced, products obtained therefrom chiral purity is high, there is good application prospect.
Description
Technical field
The present invention relates to chiral drugs to synthesize field, specially a series of polynary aza-cyclic Non-natural chiral amino acids
Synthesis, such non-natural amino acid are mainly used in pharmaceutical synthesis, have good application prospect in pharmaceutical synthesis field.
Background technology
With the rapid development of chiral drug synthetic technology, the type and structure of chiral non-natural amino acid propose more
High requirement, the appearance of some azepine chiral alpha-non-natural amino acids provide opportunity for the design of novel drugs.
The polynary cyclic annular non-natural amino acid reported in literature of chiral azepine mainly has following two synthetic methods, with heptatomic ring
For, but it is not limited solely to heptatomic ring：
This be one with (1S, 2R) -2- amino -1,2- diphenyl ethyl alcohol be substrate (Journal of Medicinal
Chemistry, 2003, Vol.46, No.11), by cyclization, the mode of chiral induction generates chiral centre.But this method is wanted
Anhydrous response has been sought, complicated for operation, expensive starting materials, and chiral purity is not high, yield is not high, is not suitable for amplification production etc..
Circuit two：
It with cycloheptanone is starting material (J.Org.Chem., Vol.66, No.26,2001) that this, which is one, passes through and resets, fourth
Base lithium pulls out hydrogen carbon dioxide and inserts carbonyl, induces hydrogenation to generate chiral centre finally by chiral reagent, this route is to reaction process
It is required that high, reagent is dangerous big, complicated for operation, and reaction raw materials are expensive, of high cost etc..
Invention content
In view of the problems of the existing technology, the present invention provides a kind of polynary aza-cyclic Non-natural chiral amino acid of series
And its synthetic method, with high, the complex process that solves existing aza-cyclic Non-natural chiral amino acid synthesis cost, ee values are not high
Technical problem.
To realize that above-mentioned target, the specific technical solution of the present invention are as follows：
A kind of polynary aza-cyclic Non-natural chiral amino acid of series, has the following structure general formula：
Wherein azacyclo- is from three-membered ring to twelve-ring.
In addition, the present invention also provides a kind of synthetic method of the above-mentioned polynary aza-cyclic Non-natural chiral amino acid of series,
Its route map is as follows, by taking azepine heptatomic ring as an example, but is not limited solely to heptatomic ring：
Wherein, X1=Cl, Br, I；X2=Cl, Br, I；
R bases are H, acyl group, Boc, Cbz or Fmoc amino protecting group.
Preferably, the synthetic method by taking heptatomic ring as an example, but is not limited solely to heptatomic ring, includes the following steps：
(a), the synthesis of 2-R- diethyl aminomalonates
Raw material 1 is dissolved in a certain amount of solvent, reacts, is changed with amido protecting agent under the catalytic action of alkali
Close object 2；
(b), the synthesis of 2-R- amino -2- (5-X- pentyls)-diethyl malonate
Compound 2 is dissolved in a certain amount of solvent, compound 4 is obtained by the reaction in the catalytic action of alkali and compound 3,
Wherein X1=Cl, Br, I；X2=Cl, Br, I；X=Cl, Br, I；
(c), the synthesis of 2- amino -2- (5-X- pentyls)-diethyl malonate
Compound 4 is dissolved in a certain amount of solvent, sloughing amino protecting group under the catalytic action of acid or alkali obtains
Compound 5, wherein X=Cl, Br, I；
(d), the synthesis of cycloheximide base -2,2- dicarboxylate
Compound 5 is dissolved in a certain amount of solvent, under the catalytic action of alkali cyclization obtain compound 6；
(e), the synthesis of cycloheximide base -2- formic acid
Compound 6 is dissolved in a certain amount of solvent, is hydrolyzed under the catalytic action of alkali, then in the catalytic action of acid
Lower decarboxylation obtains compound 7；
(f), the synthesis of N-R- cycloheximides base -2- formic acid
Compound 7 is dissolved in a certain amount of solvent, is obtained by the reaction with amido protecting agent under the catalytic action of alkali
Compound 8；
(g), the synthesis of (S) -2-N-R- cycloheximides base -1- formic acid and (R) -2-N-R- cycloheximide base -2- formic acid
Compound 8 is dissolved in a certain amount of solvent, is split under the catalytic action of resolving agent and obtains 9 He of compound
10；
(h), the synthesis of (R)-cycloheximide base -2- formic acid
Compound 9 is dissolved in a certain amount of solvent, sloughing R protecting groups under the catalytic action of acid or alkali obtains chemical combination
Object 11；
(i), the synthesis of (S)-cycloheximide base -2- formic acid
Compound 10 is dissolved in a certain amount of solvent, R protecting groups are sloughed under the catalytic action of acid or alkali
Close object 12.
Preferably, the alkali in step (a) described in reaction be selected from it is following any one or more：DIEA, TEA, piperidines, nitrogen
Methyl morpholine, NaHCO3、Na2CO3、K2CO3、NaOH、KOH。
Preferably, in step (b) the reaction alkali be selected from it is following any one or more：Sodium alkoxide, potassium alcoholate, Cs2CO3、
K2CO3、Na2CO3、NaH、CaH2。
Preferably, in step (c) the reaction acid be selected from it is following any one or more：Lead in ethyl acetate or first
The pickling catalyst of HCl gases, trifluoroacetic acid in alcoholic solvent；Alkali in step (c) described in reaction is selected from following any one
Kind is a variety of：The basic catalyst of concentrated ammonia liquor, NaOH aqueous solutions, KOH aqueous solutions.
Preferably, in step (d) the reaction alkali be selected from it is following any one or more：Sodium alkoxide, potassium alcoholate, Cs2CO3、
K2CO3、Na2CO3、NaH、CaH2。
Preferably, the alkali in step (e) described in reaction be selected from it is following any one or more：K2CO3、Na2CO3、
NaOH,KOH；In step (e) the reaction acid be selected from it is following any one or more：Acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid,
Phosphoric acid.
Preferably, in step (f) the reaction amido protecting agent be selected from it is following any one or more：R bases be H,
Acyl group, Boc, Cbz or Fmoc amino protecting group.
Preferably, in step (g) the reaction resolving agent be selected from it is following any one or more：(1S, 2R)-(+) -2- ammonia
Base -1,2- diphenyl ethyl alcohol, L-arginine hydrochloride, L-lysine propylhomoserin hydrochloride, (S)-(-) -1- phenyl ethylamines, R- (+) -1-
Phenyl ethylamine, R- (+)-α -1- naphthalene ethylamines, L- phenylalaninols.
Preferably, in step (h) the reaction acid be selected from it is following any one or more：Trifluoroacetic acid, hydrochloric acid, sulfuric acid
Acidic catalyst；Alkali in step (h) described in reaction be selected from it is following any one or more：K2CO3、Na2CO3、NaOH、
The basic catalyst of KOH, ammonium hydroxide.
Preferably, in step (i) the reaction acid be selected from it is following any one or more：Trifluoroacetic acid, hydrochloric acid, sulfuric acid
Acidic catalyst；Alkali in step (i) described in reaction be selected from it is following any one or more：K2CO3、Na2CO3、NaOH、
The basic catalyst of KOH, ammonium hydroxide.
Technical solution using the present invention, has the advantages that：
(1), synthetic method craft of the invention is simple, and raw material are cheap, and product chiral purity is high；
(2), this method has a wide range of application in the synthesis of azacyclo- Non-natural chiral amino acid, and sintetics type is more；
(3), this method technical maturity is easy to be commercially produced.
Description of the drawings
Fig. 1 is the ee values of (S)-cycloheximide base -2- formic acid in the present invention；
Fig. 2 is the ee values of (R)-cycloheximide base -2- formic acid in the present invention.
Specific implementation mode
Below in conjunction with the drawings and specific embodiments, the present invention is further described.
Referring to Fig.1 with Fig. 2, following embodiment only has chosen several representational aza-cyclic Non-natural chiral amino acids
Preparation process and test result, in practical operation, the selection of design parameter can be in proper range according to art technology
Common sense carries out various reasonable matching.
Embodiment 1 completely embodies the synthesis of (S)-azacyclopropane base -2- formic acid and (R)-azacyclopropane base -2- formic acid
Journey.
Embodiment 1：
(1), the synthesis of 2-Boc- diethyl aminomalonates
Compound 1 (450g, 2.13mol) is dissolved in 1L dichloromethane, under ice-water bath be added dropwise triethylamine (646g,
6.39mol), room temperature reaction 0.5h is added dropwise；Under ice-water bath cooling, Boc acid anhydrides (512g, 2.34mol) is slowly added dropwise, is added dropwise
It finishes, is stirred overnight at room temperature.TLC shows that compound 1 disappears, reaction solution filtering, washs filter cake with dichloromethane, concentration filtrate obtains
Grease.Grease adds ethyl acetate to dissolve, and is washed with 1N aqueous hydrochloric acid solutions, then with saturated common salt water washing, organic phase nothing
Aqueous sodium persulfate is dried, and filtering, organic phase is concentrated to give 2 (yield of 518g yellow oilies compounds：88%) it, is not necessarily to further pure
Change, directly carries out next step reaction.
(2), the synthesis of 2-Boc-2- (5- bromomethyls)-diethyl aminomalonate
Compound 2 (518g, 1.88mol) is dissolved in the there-necked flask equipped with 3.5L DMF solvents, cesium carbonate is added
Compound 3 (344.1g, 1.98mol), N is added in (797.4g, 2.45mol)2Under protection, it is stirred overnight at room temperature.TLC displayizations
Object 2 is closed to disappear.Reaction solution is slowly added into 4L ice water, is then extracted with ethyl acetate, organic phase is merged, organic phase is used full
With brine It, anhydrous sodium sulfate drying, filtering, it is concentrated to give 4 (yield of 692g yellow oilies compounds：100%) it, is not necessarily to
Purifying directly carries out in next step.
(3), the synthesis of 2- amino -2- (5- bromomethyls)-diethyl malonate
Compound 4 (692g, 1.88mol) is dissolved in 1L ethyl acetate, ice-water bath cooling, under nitrogen protection, slowly
Homemade HCl gases ethyl acetate solution is added dropwise, is added dropwise, is stirred overnight at room temperature.TLC shows that compound 4 disappears, filtering,
Then solid uses water dissolution, water phase NaHCO3PH=9-10 is adjusted, is extracted with ethyl acetate three times, organic phase is merged, it is organic
It is mutually dried with saturated common salt water washing, anhydrous sodium sulfate, filters, is concentrated to give 5 (yield of 403g yellow oilies compounds：
80%) it, is not necessarily to purifying and directly carries out next step reaction.
(4), the synthesis of azacyclopropane base -2,2- dicarboxylate
Compound 5 (403g, 1.50mol) is dissolved in 2L acetonitriles, sodium iodide (286.7g, 1.91mol), potassium carbonate is added
(304.6g, 2.21mol), under nitrogen protection, oil bath is warming up to 80 DEG C and is stirred overnight.TLC shows 5 residue about 30% of compound,
It is cooled to concentration after room temperature and falls acetonitrile and obtains yellow oil；2L water is added into grease, so that solution is clarified, is extracted with ethyl acetate
It takes, merges organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying are concentrated to give grease 233g compounds 6
(yield：83%).
(5), the synthesis of 2-Boc- azacyclopropanes base -2- formic acid
Under ice-water bath, compound 6 (233g, 1.24mol) is dissolved in 5%NaOH aqueous solutions, is stirred overnight at room temperature.TCL
It shows that compound 6 disappears, adjusts pH=5-6 with acetic acid, 1L acetic acid is then added, be warming up to 90 DEG C, stir 4h, TLC detections are changed
Object 7 is closed to generate.The addition NaOH aqueous solutions adjusting pH=8-9 into reaction solution, addition 1L tetrahydrofurans, NaOH (57.2g,
1.43mol) aqueous solution.10 DEG C or less are added dropwise Boc acid anhydrides (272.7g, 1.25mol), are added dropwise, are stirred overnight at room temperature.TLC
Detection, compound 7 disappear.Reaction solution saturation NaHSO4Aqueous solution adjusts pH=4-5, has a large amount of white solids to be precipitated, filtering,
Filter cake is dissolved in 1L ethyl acetate, and filtrate is extracted with ethyl acetate 3 times, merges organic phase, and organic phase is washed with saturated common salt
It washs, anhydrous sodium sulfate is dry, is concentrated to give grease.Grease with PE/EA=10/1-1/1 elutes column chromatography for separation, and to obtain 153g white
(the two step total recoverys of color solid chemical compound 8：66%).
(6), the synthesis of (S) -2-Boc- azacyclopropanes base -2- formic acid
Compound 8 (50g, 267mmol) is dissolved in 1L ether, S- (-)-is slowly added dropwise into above-mentioned ether clarified solution
α -1- naphthalene ethylamines (36g, 214mmol), are stirred at room temperature, and have a large amount of white solids to be precipitated, filtering, filter cake 200mL washed with ether,
Mother liquor is for use.White solid is dissolved in 500mL water, 1N HCl/water solution is added, adjusts PH=1-2, there are a large amount of whites solid
Body is precipitated, and filtering, filter cake is rinsed with 100mL water, and filtration cakes torrefaction obtains 9 (yield of 23g compound as white solid：45%).[α]20=+
87.4 (c=1.0, CH3OH), [M+=188.1].
(R) synthesis of -2-Boc- azacyclopropanes base -2- formic acid
The mother liquor merging for splitting R configurations is concentrated to give 33g white solids, solid is dissolved in 300mL water, with 1N HCl/waters
Solution adjusts PH=1-2, has a large amount of solids to be precipitated, solid filtering, and filter cake 25mL water washings obtain 27g after solid drying.It will
Above-mentioned 27g solids are dissolved in 340mL ether, into above-mentioned ether clarified solution be added dropwise R- (+)-α -1- naphthalene ethylamines (24.4g,
144mmol), 1h is stirred at room temperature, there are a large amount of white solids to be precipitated, filtering, filter cake 100mL washed with ether, mother liquor reservation.Solid
It is dissolved in 200mL water, 1N HCl/water solution is added, adjust PH=1-2, there are a large amount of white solids to be precipitated, filtering, filter cake is used
50mL water rinses, and filtration cakes torrefaction obtains 10 (yield of 20.5g white solids：40%).[α]20=-86.2 (c=1.0, CH3OH), [M+
=188.1].
(7), the synthesis of (S)-azacyclopropane base -2- formic acid
Compound 10 (10g, 53mmol) is dissolved in ethyl acetate, it is molten that 20mL 4NHCl ethyl acetate is added dropwise under ice-water bath
Liquid is stirred overnight at room temperature, and has a large amount of white solids to be precipitated.TCL shows that compound 10 disappears, and 50mL is added into solid for filtering
1N NaOH aqueous solutions are added in water dissolution, adjust PH=5 or so, have a large amount of white solids to be precipitated, filter to obtain 3.9g white solids
12 (yield of compound：85%).
1H NMR (400MHz, D2O)：δ 3.0 (m, 1H), 1.84 (m, 2H).
(R) synthesis of-azacyclopropane base -2- formic acid
Compound 9 (10g, 53mmol) is dissolved in ethyl acetate, it is molten that 20mL 4N HCl ethyl acetate is added dropwise under ice-water bath
Liquid is stirred overnight at room temperature, and has a large amount of white solids to be precipitated.TCL shows that 50mL water dissolutions are added into solid for 10 disappearances, filtering,
1N NaOH aqueous solutions are added, adjust PH=5 or so, there are a large amount of white solids to be precipitated, filters to obtain 11 (yield of 4.1g white solids：
88%).
1H NMR (400MHz, D2O)：δ 3.0 (m, 1H), 1.84 (m, 2H).
Embodiment 2 completely embodies the synthesis of (S)-cycloheximide base -2- formic acid and (R)-cycloheximide base -2- formic acid
Journey.
Embodiment 2：
(1), the synthesis of 2-Boc- diethyl aminomalonates
Compound 1 (450g, 2.13mol) is dissolved in 1L dichloromethane, under ice-water bath be added dropwise triethylamine (646g,
6.39mol), room temperature reaction 0.5h is added dropwise；Under ice-water bath cooling, Boc acid anhydrides (512g, 2.34mol) is slowly added dropwise, is added dropwise
It finishes, is stirred overnight at room temperature.TLC shows compound and shows that 1 disappearance, reaction solution filtering wash filter cake with dichloromethane, and concentration filtrate obtains
Grease.Grease adds ethyl acetate to dissolve, and is washed with 1N aqueous hydrochloric acid solutions, then with saturated common salt water washing, organic phase nothing
Aqueous sodium persulfate is dried, and filtering, organic phase is concentrated to give 2 (yield of 518g yellow oilies compounds：88%) it, is not necessarily to further pure
Change, directly carries out next step reaction.
(2), the synthesis of 2-Boc-2- (5- chloropentanes base)-diethyl aminomalonate
Compound 2 (518g, 1.88mol) is dissolved in the there-necked flask equipped with 3.5L DMF solvents, cesium carbonate is added
Compound 3 (364.7g, 1.98mol), N is added in (797.4g, 2.45mol)2Under protection, it is stirred overnight at room temperature.TLC displayizations
Object 2 is closed to disappear.Reaction solution is slowly added into 4L ice water, is then extracted with ethyl acetate, organic phase is merged, organic phase is used full
With brine It, anhydrous sodium sulfate drying, filtering, it is concentrated to give 4 (yield of 711g yellow oilies compounds：100%) it, is not necessarily to
Purifying directly carries out in next step.
(3), the synthesis of 2- amino -2- (5- chloropentanes base)-diethyl malonate
Compound 4 (711g, 1.87mol) is dissolved in 1L ethyl acetate, ice-water bath cooling, under nitrogen protection, slowly
Homemade HCl gases ethyl acetate solution is added dropwise, is added dropwise, is stirred overnight at room temperature.TLC shows that compound 4 disappears, filtering,
Then solid uses water dissolution, water phase NaHCO3PH=9-10 is adjusted, is extracted with ethyl acetate three times, organic phase is merged, it is organic
It is mutually dried with saturated common salt water washing, anhydrous sodium sulfate, filters, is concentrated to give 5 (yield of 410g yellow oilies compounds：
78%) it, is not necessarily to purifying and directly carries out next step reaction.
(4), the synthesis of cycloheximide base -2,2- dicarboxylate
Compound 5 (410g, 1.47mol) is dissolved in 2L acetonitriles, sodium iodide (286.7g, 1.91mol), potassium carbonate is added
(304.6g, 2.21mol), under nitrogen protection, oil bath is warming up to 80 DEG C and is stirred overnight.TLC shows 5 residue about 30% of compound,
It is cooled to concentration after room temperature and falls acetonitrile and obtains yellow oil；2L water is added into grease, so that solution is clarified, is extracted with ethyl acetate
It takes, merges organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying are concentrated to give 290g colorless oil chemical combination
6 (yield of object：80%).
(5), the synthesis of 2-Boc- cycloheximides base -2- formic acid
Under ice-water bath, compound 6 (290g, 1.2mol) is dissolved in 5%NaOH aqueous solutions, is stirred overnight at room temperature.TCL is aobvious
Show that compound 6 disappears, adjust pH=5-6 with acetic acid, 1L acetic acid is then added, be warming up to 90 DEG C, stirs 4h, TLC detections, chemical combination
Object 7 generates.The addition NaOH aqueous solutions adjusting pH=8-9 into reaction solution, addition 1L tetrahydrofurans, NaOH (57.2g,
1.43mol) aqueous solution.10 DEG C or less are added dropwise Boc acid anhydrides (272.7g, 1.25mol), are added dropwise, are stirred overnight at room temperature.TLC
Detection, compound 7 disappear.Reaction solution adjusts pH=4-5 with saturation NaHSO4 aqueous solutions, has a large amount of white solids to be precipitated, filtering,
Filter cake is dissolved in 1L ethyl acetate, and filtrate is extracted with ethyl acetate 3 times, merges organic phase, and organic phase is washed with saturated common salt
It washs, anhydrous sodium sulfate is dry, is concentrated to give grease.Grease with PE/EA=10/1-1/1 elutes column chromatography for separation, and to obtain 190g white
(the two step total recoverys of color solid 8：65%).
(6), the synthesis of (S) -2-Boc- cycloheximides base -2- formic acid
Compound 8 (70g, 288mmol) is dissolved in 1L ether, S- (-)-is slowly added dropwise into above-mentioned ether clarified solution
α -1- naphthalene ethylamines (39g, 230mmol), are stirred at room temperature, and have a large amount of white solids to be precipitated, filtering, filter cake 200mL washed with ether,
Mother liquor is for use.White solid is dissolved in 500mL water, 1N HCl/water solution is added, adjusts PH=1-2, there are a large amount of whites solid
Body is precipitated, and filtering, filter cake is rinsed with 100mL water, and filtration cakes torrefaction obtains 9 (yield of 30g white solids：41%).[α]20=+62.1 (c
=1.0, CH3OH), [M+=242.5].
(R) synthesis of -2-Boc- cycloheximides base -2- formic acid
The mother liquor merging for splitting R configurations is concentrated to give 50g white solids, solid is dissolved in 400mL water, with 1N HCl/waters
Solution adjusts PH=1-2, has a large amount of solids to be precipitated, solid filtering, and filter cake 30mL water washings obtain 35g after solid drying.It will
Above-mentioned 35g solids are dissolved in 500mL ether, into above-mentioned ether clarified solution be added dropwise R- (+)-α -1- naphthalene ethylamines (19.6g,
115mmol), 1h is stirred at room temperature, there are a large amount of white solids to be precipitated, filtering, filter cake 100mL washed with ether, mother liquor reservation.Solid
It is dissolved in 200mL water, 1N HCl/water solution is added, adjust PH=1-2, there are a large amount of white solids to be precipitated, filtering, filter cake is used
50mL water rinses, and filtration cakes torrefaction obtains 10 (yield of 27g compound as white solid：38.6%).[α]20=-60.1 (c=1.0,
CH3OH), [M+=242.5].
(7), the synthesis of (S)-cycloheximide base -2- formic acid
Compound 10 (10g, 41mmol) is dissolved in ethyl acetate, 20mL4 N HCl ethyl acetate is added dropwise under ice-water bath
Solution is stirred overnight at room temperature, and has a large amount of white solids to be precipitated.TCL shows that compound 10 disappears, and filtering is added into solid
1N NaOH aqueous solutions are added in 50mL water dissolutions, adjust PH=5 or so, have a large amount of white solids to be precipitated, filter 5g whites are solid
12 (yield of body compound：86%).
1H NMR (400MHz, D2O)：δ 4.59-4.64,4.42-4.46 (m, 1H), 3.99-4.02,3.85-3.81 (m,
1H), 3.01-3.10,2.93-2.99 (m, 1H), 2.34-2.39 (m, 1H), 1.94-1.97 (m, 1H), 1.76-1.83 (m,
3H), 1.47-1.52 (m, 1H), 1.25-1.38 (m, 2H).
(R) synthesis of-cycloheximide base -2- formic acid
Compound 9 (10g, 41mmol) is dissolved in ethyl acetate, 4 N HCl ethyl acetate of 20mL is added dropwise under ice-water bath
Solution is stirred overnight at room temperature, and has a large amount of white solids to be precipitated.TCL shows that compound 10 disappears, and filtering is added into solid
1N NaOH aqueous solutions are added in 50mL water dissolutions, adjust PH=5 or so, have a large amount of white solids to be precipitated, and filter to obtain 5.1g whites
11 (yield of solid chemical compound：88%).
1H NMR (400MHz, D2O)：δ 4.59-4.64,4.42-4.46 (m, 1H), 3.99-4.02,3.85-3.81 (m,
1H), 3.01-3.10,2.93-2.99 (m, 1H), 2.34-2.39 (m, 1H), 1.94-1.97 (m, 1H), 1.76-1.83 (m,
3H), 1.47-1.52 (m, 1H), 1.25-1.38 (m, 2H).
Embodiment 3 completely embodies the conjunction of 11 imido grpup -2- formic acid of (S)-ring and 11 imido grpup -2- formic acid of (R)-ring
At process.
Embodiment 3：
(1), the synthesis of 2-Boc- diethyl aminomalonates
Compound 1 (500g, 2.36mol) is dissolved in 1L dichloromethane, under ice-water bath be added dropwise triethylamine (716g,
7.08mol), room temperature reaction 0.5h is added dropwise；Under ice-water bath cooling, Boc acid anhydrides (567g, 2.60mol) is slowly added dropwise, is added dropwise
It finishes, is stirred overnight at room temperature.TLC shows that compound 1 disappears, reaction solution filtering, washs filter cake with dichloromethane, concentration filtrate obtains
Grease.Grease adds ethyl acetate to dissolve, and is washed with 1N aqueous hydrochloric acid solutions, then with saturated common salt water washing, organic phase nothing
Aqueous sodium persulfate is dried, and filtering, organic phase is concentrated to give 2 (yield of 578g yellow oilies compounds：89%) it, is not necessarily to further pure
Change, directly carries out next step reaction.
(2), the synthesis of 2-Boc-2- (5- chlorodecanes base)-diethyl aminomalonate
Compound 2 (578g, 2.10mol) is dissolved in the there-necked flask equipped with 3.8L DMF solvents, cesium carbonate is added
Compound 3 (565g, 2.21mol), N is added in (889g, 2.73mol)2Under protection, it is stirred overnight at room temperature.TLC shows compound 2
It disappears.Reaction solution is slowly added into 4.3L ice water, is then extracted with ethyl acetate, organic phase, organic phase saturation are merged
Brine It, anhydrous sodium sulfate are dry, filter, and are concentrated to give 4 (yield of 936g yellow oilies compounds：99%) it, is not necessarily to pure
Change and directly carries out in next step.
(3), the synthesis of 2- amino -2- (5- chlorodecanes base)-diethyl malonate
Compound 4 (936g, 2.07mol) is dissolved in 1.2L ethyl acetate, ice-water bath cooling, under nitrogen protection, is delayed
Slowly homemade HCl gases ethyl acetate solution is added dropwise, is added dropwise, is stirred overnight at room temperature.TLC shows that compound 4 disappears, mistake
Then filter, solid use water dissolution, water phase NaHCO3PH=9-10 is adjusted, is extracted with ethyl acetate three times, is merged organic phase, have
Machine mutually uses saturated common salt water washing, anhydrous sodium sulfate to dry, and filters, is concentrated to give 5 (yield of 558g yellow oilies compounds：
77%) it, is not necessarily to purifying and directly carries out next step reaction.
(4), the synthesis of 11 imido grpup -2,2- dicarboxylate of ring
Compound 5 (558g, 1.59mol) is dissolved in 2.3L acetonitriles, sodium iodide (342g, 2.06mol), potassium carbonate is added
(330g, 2.39mol), under nitrogen protection, oil bath is warming up to 80 DEG C and is stirred overnight.TLC shows 5 residue about 30% of compound, cold
It concentrates acetonitrile after to room temperature and obtains yellow oil；2.2L water is added into grease, so that solution is clarified, is extracted with ethyl acetate
It takes, merges organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying are concentrated to give grease, use EA/PE=1/
Elution column chromatography for separation obtains 6 (yield of 398g colorless oils compounds：80%).
(5), the synthesis of 11 imido grpup -2- formic acid of 2-Boc- rings
Under ice-water bath, compound 6 (398g, 1.26mol) is dissolved in 5%NaOH aqueous solutions, is stirred overnight at room temperature.TCL
Display compound 6 disappears, and adjusts pH=5-6 with acetic acid, 1.2L acetic acid is then added, be warming up to 90 DEG C, stirs 4h, and TLC is detected,
Compound 7 generates.The addition NaOH aqueous solutions adjusting pH=8-9 into reaction solution, addition 1.2L tetrahydrofurans, NaOH (57.2g,
1.43mol) aqueous solution.10 DEG C or less are added dropwise Boc acid anhydrides (272.7g, 1.25mol), are added dropwise, are stirred overnight at room temperature.TLC
Detection, 7 disappear.Reaction solution adjusts pH=4-5 with saturation NaHSO4 aqueous solutions, has a large amount of white solids to be precipitated, filtering, and filter cake is molten
In 1.2L ethyl acetate, filtrate is extracted with ethyl acetate 3 times solution, merges organic phase, organic phase saturated common salt water washing, nothing
Aqueous sodium persulfate is dry, is concentrated to give grease.Grease elutes column chromatography for separation with PE/EA=10/1-1/1 and obtains 245g white solids
(the two step total recoverys of compound 8：62%).
(6), the synthesis of 11 imido grpup -2- formic acid of (S) -2-Boc- rings
Compound 8 (100g, 319mmol) is dissolved in 1.1L ether, S- is slowly added dropwise into above-mentioned ether clarified solution
(-)-α -1- naphthalene ethylamines (43g, 254mmol), are stirred at room temperature, and have a large amount of white solids to be precipitated, filtering, filter cake 230mL ether
It rinses, mother liquor is for use.White solid is dissolved in 500mL water, 1N HCl/water solution is added, adjusts PH=1-2, is had a large amount of white
Color solid is precipitated, and filtering, filter cake is rinsed with 100mL water, and filtration cakes torrefaction obtains 9 (yield of 40g compound as white solid：40%).
[α]20=+42.7 (c=1.0, CH3OH), [M+=313.2].
(R) synthesis of 11 imido grpup -2- formic acid of -2-Boc- rings
The mother liquor merging for splitting R configurations is concentrated to give 70g white solids, solid is dissolved in 430mL water, with 1N HCl/waters
Solution adjusts PH=1-2, has a large amount of solids to be precipitated, solid filtering, and filter cake 40mL water washings obtain 49g after solid drying.It will
Above-mentioned 49g solids are dissolved in 550mL ether, into above-mentioned ether clarified solution be added dropwise R- (+)-α -1- naphthalene ethylamines (29.3g,
173mmol), 1h is stirred at room temperature, there are a large amount of white solids to be precipitated, filtering, filter cake 120mL washed with ether, mother liquor reservation.Solid
It is dissolved in 220mL water, 1N HCl/water solution is added, adjust PH=1-2, there are a large amount of white solids to be precipitated, filtering, filter cake is used
60mL water rinses, and filtration cakes torrefaction obtains 10 (yield of 30g compound as white solid：30.0%).[α]20=-44.5 (c=1.0,
CH3OH), [M+=313.2].
(7), the synthesis of 11 imido grpup -2- formic acid of (S)-ring
Compound 10 (15g, 32mmol) is dissolved in ethyl acetate, it is molten that 25mL4 NHCl ethyl acetate is added dropwise under ice-water bath
Liquid is stirred overnight at room temperature, and has a large amount of white solids to be precipitated.TCL shows that compound 10 disappears, and 55mL is added into solid for filtering
1N NaOH aqueous solutions are added in water dissolution, adjust PH=5 or so, have a large amount of white solids to be precipitated, filter to obtain 5.8g white solids
12 (yields：85%).
1H NMR (400MHz, D2O)：δ 4.59-4.64,4.42-4.46 (m, 1H), 3.99-4.02,3.85-3.81 (m,
1H), 3.01-3.10,2.93-2.99 (m, 1H), 2.34-2.39 (m, 1H), 1.94-1.97 (m, 1H), 1.76-1.83 (m,
3H), 1.47-1.52 (m, 1H), 1.25-1.38 (m, 2H).
(R) synthesis of -11 imido grpup -2- formic acid of ring
Compound 9 (20g, 64mmol) is dissolved in ethyl acetate, it is molten that 30mL 4N HCl ethyl acetate is added dropwise under ice-water bath
Liquid is stirred overnight at room temperature, and has a large amount of white solids to be precipitated.TCL shows that compound 10 disappears, and 60mL is added into solid for filtering
1N NaOH aqueous solutions are added in water dissolution, adjust PH=5 or so, have a large amount of white solids to be precipitated, filter to obtain 11.7g white solids
11 (yield of compound：86%).
1H NMR (400MHz, D2O)：δ 4.59-4.64,4.42-4.46 (m, 1H), 3.99-4.02,3.85-3.81 (m,
1H), 3.01-3.10,2.93-2.99 (m, 1H), 2.34-2.39 (m, 1H), 1.94-1.97 (m, 1H), 1.76-1.83 (m,
3H), 1.47-1.52 (m, 1H), 1.25-1.38 (m, 2H).
The foregoing is merely the preferred embodiment of the present invention, are not intended to limit the scope of the invention, every at this
Under the inventive concept of invention, using equivalent structure transformation made by description of the invention and accompanying drawing content, or directly/use indirectly
In the scope of patent protection that other related technical areas are included in the present invention.
Claims (10)
1. a kind of polynary aza-cyclic Non-natural chiral amino acid of series, which is characterized in that have the following structure general formula：
Wherein, azacyclo- is from three-membered ring to twelve-ring.
2. a kind of synthetic method of the polynary aza-cyclic Non-natural chiral amino acid of series, route is as follows, with azepine heptatomic ring
For, but it is not limited solely to heptatomic ring：
Wherein, X1=Cl, Br, I；X2=Cl, Br, I；
R bases are H, acyl group, Boc, Cbz or Fmoc amino protecting group.
3. synthetic method according to claim 2 by taking heptatomic ring as an example, but is not limited solely to heptatomic ring, includes the following steps：
(a), the synthesis of 2-R- diethyl aminomalonates
Raw material 1 is dissolved in a certain amount of solvent, is reacted with amido protecting agent under the catalytic action of alkali, obtains compound
2；
(b), the synthesis of 2-R- amino -2- (5-X- pentyls)-diethyl malonate
Compound 2 is dissolved in a certain amount of solvent, compound 4 is obtained by the reaction in the catalytic action of alkali and compound 3, wherein
X1=Cl, Br, I；X2=Cl, Br, I；X=Cl, Br, I；
(c), the synthesis of 2- amino -2- (5-X- pentyls)-diethyl malonate
Compound 4 is dissolved in a certain amount of solvent, sloughing amino protecting group under the catalytic action of acid or alkali obtains chemical combination
Object 5, wherein X=Cl, Br, I；
(d), the synthesis of cycloheximide base -2,2- dicarboxylate
Compound 5 is dissolved in a certain amount of solvent, under the catalytic action of alkali cyclization obtain compound 6；
(e), the synthesis of cycloheximide base -2- formic acid
Compound 6 is dissolved in a certain amount of solvent, is hydrolyzed under the catalytic action of alkali, is then taken off under the catalytic action of acid
Carboxylic obtains compound 7；
(f), the synthesis of N-R- cycloheximides base -2- formic acid
Compound 7 is dissolved in a certain amount of solvent, under the catalytic action of alkali and chemical combination is obtained by the reaction in amido protecting agent
Object 8；
(g), the synthesis of (S) -2-N-R- cycloheximides base -1- formic acid and (R) -2-N-R- cycloheximide base -2- formic acid
Compound 8 is dissolved in a certain amount of solvent, is split under the catalytic action of resolving agent and obtains compound 9 and 10；
(h), the synthesis of (R)-cycloheximide base -2- formic acid
Compound 9 is dissolved in a certain amount of solvent, sloughing R protecting groups under the catalytic action of acid or alkali obtains compound
11；
(i), the synthesis of (S)-cycloheximide base -2- formic acid
Compound 10 is dissolved in a certain amount of solvent, sloughing R protecting groups under the catalytic action of acid or alkali obtains compound
12。
4. synthetic method according to claim 2, which is characterized in that the alkali in step (a) described in reaction is selected from following
Any one or more：DIEA, TEA, piperidines, N-methyl morpholine, NaHCO3、Na2CO3、K2CO3、NaOH、KOH。
5. synthetic method according to claim 2, which is characterized in that the reaction alkali is selected from following in step (b)
It anticipates one or more：Sodium alkoxide, potassium alcoholate, Cs2CO3、K2CO3、Na2CO3、NaH、CaH2。
6. synthetic method according to claim 2, which is characterized in that the reaction acid is selected from following in step (c)
It anticipates one or more：Lead to the pickling catalyst of HCl gases in ethyl acetate or methanol solvate, trifluoroacetic acid；Step (c)
Alkali described in middle reaction be selected from it is following any one or more：The base catalysis of concentrated ammonia liquor, NaOH aqueous solutions, KOH aqueous solutions
Agent.
7. synthetic method according to claim 2, which is characterized in that the reaction alkali is selected from following in step (d)
It anticipates one or more：Sodium alkoxide, potassium alcoholate, Cs2CO3、K2CO3、Na2CO3、NaH、CaH2。
8. synthetic method according to claim 2, which is characterized in that the alkali in step (e) described in reaction is selected from following
Any one or more：K2CO3、Na2CO3,NaOH,KOH；In step (e) the reaction acid be selected from it is following any one or it is more
Kind：Acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid.
9. synthetic method according to claim 2, which is characterized in that the reaction resolving agent is selected from following in step (g)
Any one or more：(1S, 2R)-(+) -2- amino -1,2- diphenyl ethyl alcohol, L-arginine hydrochloride, L-lysine propylhomoserin
Hydrochloride, (S)-(-) -1- phenyl ethylamines, R- (+) -1- phenyl ethylamines, R- (+)-α -1- naphthalene ethylamines, L- phenylalaninols.
10. synthetic method according to claim 2, which is characterized in that step (h) is selected from following with the acid in (i)
It anticipates one or more：The acidic catalyst of trifluoroacetic acid, hydrochloric acid, sulfuric acid；Alkali be selected from it is following any one or more：K2CO3、
Na2CO3, NaOH, KOH, ammonium hydroxide basic catalyst.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108048317A (en) * | 2017-12-12 | 2018-05-18 | 凯莱英医药集团（天津）股份有限公司 | The continuous synthesis system and method for continuously synthesizing of a kind of alpha-non-natural amino acid |
| CN110627722A (en) * | 2019-10-17 | 2019-12-31 | 中国人民解放军国防科技大学 | Synthesis method of 7-alkynyl azepine derivative |
| CN115490606A (en) * | 2022-09-30 | 2022-12-20 | 安徽泽升科技有限公司 | Method for preparing medical intermediate from 2-chloromethylene-diethyl malonate |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000178253A (en) * | 1998-12-21 | 2000-06-27 | Daito Kagaku Kk | Production of optically active pipecolic acid |
| EP1179530A1 (en) * | 2000-02-17 | 2002-02-13 | Kaneka Corporation | Processes for preparing optically active amino acid derivatives |
| CN1529756A (en) * | 2001-06-08 | 2004-09-15 | 罗狄亚化学公司 | Steroselective preparation of cyclic L-amino acids |
| JP2004261086A (en) * | 2003-02-28 | 2004-09-24 | Kitakyushu Foundation For The Advancement Of Industry Science & Technology | Method for producing pipecolic acid |
| CN103288699A (en) * | 2012-02-24 | 2013-09-11 | 中国药科大学 | Preparation method of proline analogue |
| CN103467350A (en) * | 2013-09-16 | 2013-12-25 | 中国科学院嘉兴应用化学工程中心 | Method for preparing (S)-azetidine-2-carboxylic acid |
| CN105899487A (en) * | 2013-12-27 | 2016-08-24 | 株式会社Api | Method for producing 5-hydroxypiperidine-2-carboxylic acid |
-
2018
- 2018-06-27 CN CN201810680123.2A patent/CN108752253B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000178253A (en) * | 1998-12-21 | 2000-06-27 | Daito Kagaku Kk | Production of optically active pipecolic acid |
| EP1179530A1 (en) * | 2000-02-17 | 2002-02-13 | Kaneka Corporation | Processes for preparing optically active amino acid derivatives |
| CN1529756A (en) * | 2001-06-08 | 2004-09-15 | 罗狄亚化学公司 | Steroselective preparation of cyclic L-amino acids |
| JP2004261086A (en) * | 2003-02-28 | 2004-09-24 | Kitakyushu Foundation For The Advancement Of Industry Science & Technology | Method for producing pipecolic acid |
| CN103288699A (en) * | 2012-02-24 | 2013-09-11 | 中国药科大学 | Preparation method of proline analogue |
| CN103467350A (en) * | 2013-09-16 | 2013-12-25 | 中国科学院嘉兴应用化学工程中心 | Method for preparing (S)-azetidine-2-carboxylic acid |
| CN105899487A (en) * | 2013-12-27 | 2016-08-24 | 株式会社Api | Method for producing 5-hydroxypiperidine-2-carboxylic acid |
Non-Patent Citations (7)
| Title |
|---|
| FRED E. DUTTON等: "Restricted Conformation Analogues of an Anthelmintic Cyclodepsipeptide", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| H.T.NAGASAWA等: "Chromatographic properties of some cyclic α-imino acids homologous to proline, and their DNP-, DNS- and PTH-derivatives", 《JOURNAL OF CHROMATOGRAPHY A》 * |
| J. A. ELBERLING等: "The twelve to fifteen-membered ring homologs of proline", 《THE JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
| LOUIS A. WATANABE等: "An efficient access to both enantiomers of pipecolic acid", 《TETRAHEDRON: ASYMMETRY》 * |
| LOUIS M.-A. ROGERS等: "Enantioselective decarboxylation-reprotonation of an alpha-amino malonate derivative as a route to optically enriched cyclic alpha-amino acid", 《TETRAHEDRON LETTERS》 * |
| 朱葆佺: "《新编药物合成反应路线图设计与制备工艺新技术实务全书》", 31 December 2005 * |
| 李宗圣等: "氮杂环庚烷-2-甲酸的微波辅助合成", 《河北师范大学学报/自然科学版/》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108048317A (en) * | 2017-12-12 | 2018-05-18 | 凯莱英医药集团（天津）股份有限公司 | The continuous synthesis system and method for continuously synthesizing of a kind of alpha-non-natural amino acid |
| CN108048317B (en) * | 2017-12-12 | 2023-08-15 | 凯莱英医药集团（天津）股份有限公司 | Continuous synthesis system and continuous synthesis method of unnatural amino acid |
| CN110627722A (en) * | 2019-10-17 | 2019-12-31 | 中国人民解放军国防科技大学 | Synthesis method of 7-alkynyl azepine derivative |
| CN110627722B (en) * | 2019-10-17 | 2021-06-18 | 中国人民解放军国防科技大学 | Synthesis method of 7-alkynyl azepine derivative |
| CN115490606A (en) * | 2022-09-30 | 2022-12-20 | 安徽泽升科技有限公司 | Method for preparing medical intermediate from 2-chloromethylene-diethyl malonate |
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