CN104387315B - Compound I and(R)3 amido piperidine hydrochlorate II, its preparation method and its application in Li Gelieting synthesis - Google Patents
Compound I and(R)3 amido piperidine hydrochlorate II, its preparation method and its application in Li Gelieting synthesis Download PDFInfo
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- CN104387315B CN104387315B CN201310561772.8A CN201310561772A CN104387315B CN 104387315 B CN104387315 B CN 104387315B CN 201310561772 A CN201310561772 A CN 201310561772A CN 104387315 B CN104387315 B CN 104387315B
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- FIYAVPKRSCPGHQ-UHFFFAOYSA-N Cc1nc(CN(C(C(N(CC#CC)C(N2)Br)=C2N2)=O)C2=O)nc2ccccc12 Chemical compound Cc1nc(CN(C(C(N(CC#CC)C(N2)Br)=C2N2)=O)C2=O)nc2ccccc12 FIYAVPKRSCPGHQ-UHFFFAOYSA-N 0.000 description 1
- GMGXUBNRROSXSF-GVHYBUMESA-N OC(CC1)N([C@H]2CNCCC2)C1=O Chemical compound OC(CC1)N([C@H]2CNCCC2)C1=O GMGXUBNRROSXSF-GVHYBUMESA-N 0.000 description 1
- 0 [B+]c1nc(N(C)*(N(Cc2nc(cccc3)c3c(C)n2)C2=*)=O)c2[n]1CC Chemical compound [B+]c1nc(N(C)*(N(Cc2nc(cccc3)c3c(C)n2)C2=*)=O)c2[n]1CC 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/56—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/02—Preparation by ring-closure or hydrogenation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
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- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation method with optically active 3 amino piperidine and its derivative, and its application in dipeptidy peptidase in inhibitors Li Gelieting synthesis.In the preparation method, 3 aminopyridines are used for raw material, are split by the protection of 3 bit aminos, catalytic hydrogen reduction pyridine ring, chiral reagent and are obtained chemical compounds I, and then are deprotected obtain (R) 3 amido piperidine hydrochlorate II again.In the application, the compound III prepared by chemical compounds I is the important intermediate for synthesizing Li Gelieting, and (R) 3 amido piperidine hydrochlorate II also can directly synthesize the Li Gelieting of high-purity.The raw materials used price of the present invention is low, in the market is readily obtained, each step unit is simple to operate, equipment requirement is low, safe, it is easy to industrialized production.
Description
Technical field
The present invention relates to a kind of new preparation process with optically active 3- amino piperidines and its derivative, and its
Dipeptidyl peptidase-IV(DPP-Ⅳ)Inhibitor Li Gelieting(Linagliptin)Application in synthesis.
Background technology
With optically active 3- amino piperidines and its derivative(Chemical compounds I)It is in the middle of the key of synthesis of chiral medicine
Body.Wherein(R)The hydrochloride of -3- amino piperidines(Ⅱ)And its derivative(Chemical compounds I)It is mainly used in the conjunction of DPP-IV inhibitor
Into.DPP-IV inhibitor can raise endogenous glucagon-like-peptide-1 by selective depression DPP-4(Glucagon-
LikePeptide-1, GLP-1)Polypeptide is discharged with glucose dependency pancreotropic hormone(Glucose-dependent
InsulinotropicPeptide, GIP)Level, so as to adjust blood glucose.
Them are for example described in patent US7807689 in synthesis Egelieting(Alogliptin, 1)In application.Ah
Ge Lieting is by Japanese military field(Takeda)The inhibitor of selective d PP- IV of company's exploitation, in December, 2010, FDA approvals exist
The U.S. is listed, trade name Nesina.Them are described in patent WO2004018468 and WO200604842 and is synthesizing another
New high selectivity DPP-IV inhibitor Li Gelieting(Linagliptin, 2)In application.Li Gelieting is Germany Bo Linge
Yin Ge writing brushes drugmaker(BoehringerIngelheimPharmaceuticalsInc.)The oral hypoglycemic drug of exploitation, in
Nikkei U.S. FDA approval listing May 2 in 2011, trade name Tradjenta.
Current compound I synthetic method, is usually carried out by synthesizing racemic 3- amino piperidines and its hydrochloride
Split, or directly synthesized with optically active 3- amino piperidines and its derivative by chiral raw material.Primary synthetic methods
It is as follows:
Patent WO2006048427 discloses the synthetic route 1 of Boehringer Ingelheim company exploitation.This method has following lack
Fall into:(1)The first step needs high pressure(100 atmospheric pressure, i.e. 10MPa), harsh is required to production equipment, is unfavorable for scale metaplasia
Production;(2)Metallic catalyst used(Platinum, rhodium)Expensive, cost of material and production cost are high.
Moreover, chemical compounds I -1 or its tartrate can be produced when being spliced with compound 3 it is more(More than 3%)Bromo
Impurity, the bromo impurity can hydrolyze generation impurity 1 and impurity 2 in downstream reaction, and the two impurity are all difficult to remove(1% very
To the above).The removing of last phthalyl protection group is, it is necessary in ethanol amine toluene(80℃)Under conditions of carry out, reaction
Liquid impurity is more, and crude product after treatment still has the impurity for being difficult to remove, and influences Li Gelieting purity, it is necessary to by post layer
Analysis can just obtain the Li Gelieting of more than 99% purity.
Patent JP2007262040 discloses one kind using D-Glu as raw material, and light is synthesized using natural chiral centre
The method for learning the compound I of activity(Synthetic route 2).This method has a disadvantage that:(1)Step is more, and the production cycle is long;(2)The
Product after the reduction of three steps is water-soluble big, it is difficult to separating-purifying;(3)5th step ammoniacal liquor cyclization, yield is low, and ammoniacal liquor is easily waved
Hair, operating environment is poor, it is difficult to realize industrialized production.
Moreover, chemical compounds I -2 to be used for Li Gelieting synthesis, bromo impurity takes off tertiary fourth oxygen 2% or so by last
Carbonyl(-Boc)Protection, impurity 1, impurity 2 are all more than 1%.Moreover, removing tertbutyloxycarbonyl is needed with trifluoroacetic acid as de-
Protect reagent, during again can produce the distinctive impurity of this route, impurity 3, impurity 4.These impurity pass through general purifying
Method is difficult to remove, and influences Li Gelieting purity, it is necessary to which column chromatography can just obtain qualified products.
Patent CN101955457 discloses the synthetic route 3 of Haimen Huiju Pharmaceutical Co., Ltd.'s exploitation.In this method, use
Benzylamine replaces ammoniacal liquor to carry out ring-closure reaction, although improve yield, but this method still has following deficiency:(1)Step is more, operation
It is cumbersome;(2)Raw material N-Cbz-D- glutamic acid dimethyl esters are difficult to commercially available, it is necessary to react system from D-Glu by 2 steps
;(3)The N-Boc protection products of 5th step need to purify through column chromatography, could carry out the Pd/C catalytic hydrogenations of next step,
Otherwise metallic catalyst Pd can be made to be poisoned and be difficult to obtain chemical compounds I.
Moreover, chemical compounds I -2 to be used for Li Gelieting synthesis, finally de- tertbutyloxycarbonyl protection group can produce distinctive
Impurity, impurity 3 and impurity 4, are difficult to remove by general purification process, influence Li Gelieting purity.Need column chromatography pure
Change.
The synthetic route 4 using 1- benzyl -3R- amino piperidines as raw material is disclosed in patent CN102516225.This method institute
Few with raw materials market supply, expensive, production cost is high.
Moreover, the hydrochloride of chemical compounds I -1 is spliced with compound 3, during synthesis applied to Li Gelieting, finally take off
Except phthalyl protection group, it is necessary in ethanol amine toluene(80℃)Under conditions of removed, reaction solution impurity is more,
Crude product after treatment has the impurity for being difficult to remove, and influences Li Gelieting purity, it is necessary to can just obtain 99% by column chromatography
The Li Gelieting of above purity.
A kind of synthetic route 5 using D-Orn hydrochloride as initiation material is disclosed in patent WO2007112368.Should
Method has a disadvantage that:(1)The first step needs ultralow temperature to react, high to equipment requirement;(2)The reduction of 3rd step will use lithium hydride
, there is potential safety hazard in aluminium, it is difficult to realize industrialized production;(3)Product enters aqueous phase in last handling process, exists with a large amount of aluminium salts
Together, it is difficult to separate;(4)Raw material D-Orn hydrochloride is alpha-non-natural amino acid, expensive, and production cost is high.
The synthetic route 6 that a kind of 3- piperidine formamides are raw material is disclosed in patent WO2008102720.Will in this method
Enzyme resolving agent is used, there is presently no domestic enzyme, import is required for, while requiring harsh to working condition, it is difficult to realize work
The big production of industryization.Also, first step catalytic hydrogenation needs to use platinum(Pt or Rh)Catalysis, cost is higher.
A kind of preparation and its fractionation of piperidines -3- aminocarbamic acid ester type compounds are disclosed in patent WO2009119700
Method(Synthetic route 7).The 3- amino protecting groups used in this method are not sufficiently stable, and are just held in first step catalytic hydrogenation
Easily it is removed, the impurity in hydrogenated products is more.
A kind of synthetic method using 3- acetylaminos pyridine as raw material is disclosed in patent WO2011160037(Synthetic route
8).In this method, first step catalytic hydrogenation is needed in~20 atmospheric pressures(20bar)Under, 80 DEG C, react in acetate solvate
More than 24hr, still there is the incomplete impurity of hydrogenation, influences the purity of 3- amino piperidines and splits effect.
Moreover, the intermediate of the acetyl group protection in the route is applied in Li Gelieting synthesis, even if using highly basic
Property condition(Sodium hydroxide)Backflow is for a long time(48 hours)Also acetyl group can not be removed, while producing substantial amounts of impurity, therefore
Be not suitable for.This method carries out chiral resolution in final step to 3- amino piperidines, into salt poor reproducibility, splits effect poor.
Patent CN101565397 discloses one kind using ethyl nipecotate as initiation material, passes through amido protecting, ammonia
Solution, Hoffman are degraded, split, being deprotected into salt and obtain(R)The synthetic method of -3- amino -1-Boc- piperidines(Synthetic route 9).
Initiation material market supply used in this method is not enough, and production cost is high;Second step carries out the ammonolysis reaction of ester with ammoniacal liquor, reaction
Not exclusively, hydrolysing carboxylic's impurity is tended to have, and workshop operating environment is poor;3rd step Hoffman degradation reactions need to use bromine
Water, volatile, operating environment is poor.
Document Adv.Synth.Catal.2008,350,807-812 reports one kind and utilizes transaminase(ω-
Transaminases)The method for splitting 1-N- protection group -3- amino piperidines(Synthetic route 10).Belong to field of bioconversion.
Patent JP2012240958 discloses one kind and its individual isomer is obtained by resolving racemic 3- amino piperidines
Method(Synthetic route 11).The market price of the raw materials used 3- amino piperidines of this method is expensive, and N- pairs of resolving agent used
Toluyl groups glutamic acid is also required to oneself and prepared, and production cost is higher, is not suitable for industrialization.
The content of the invention
The technical problems to be solved by the invention are to design that one novel, raw material is easy to get, cost is low, technique is easy
General hydrochloride II and its derivative of the preparation with optically active 3- amino piperidines(Chemical compounds I)Method.And by profit
The chemical compounds I that is prepared with the method for the invention and(R)- 3- amido piperidine hydrochlorates II is successfully applied to dipeptidyl peptidase-IV
(DPP-Ⅳ)Inhibitor Li Gelieting(Linagliptin)Synthesis in, prepare the Li Gelieting of high-purity.
One kind has optically active 3- amino piperidines alkane derivatives(Chemical compounds I)And its hydrochloride II, i.e., with optics
The preparation method of the 3- amido piperidine hydrochlorates of activity, it is technically characterized in that:Using 3- aminopyridines as raw material, pass through 3- ammonia
Base protection, catalytic hydrogen reduction pyridine ring, chiral reagent, which are split, obtains chemical compounds I, then is deprotected and obtains(R)- 3- amino piperidines
Hydrochloride II;Its reaction scheme is as follows:
Wherein,
Initiation material 3- aminopyridines are conventional chemical intermediate, ample supply of commodities on the market, and cheap.According to experiment knot
Really, the hydrogenation of 3- amino piperidines is corresponding piperidines, it is necessary to noble metal catalyst such as 100bar high pressure and expensive Pt/C etc.
Condition, and after amino is protected using acyl group, required hydrogenation pressure can be down to 1~20bar.In addition, general acetyl
Base protection group, it is more difficult to remove, and after it is connected on Li Gelieting molecules, it more difficult to remove, even in very strong alkalescence condition(Hydrogen
Sodium oxide molybdena)Lower back flow reaction(48 hours)Also difficult removing.But this class diacyl guarantor such as diacyl protection group, such as succinyl
Base is protected, removing is easier than acetyl group, can be used for the synthesis of DDP-IV inhibitor;Or the acyl group of halogenated hydrocarbons substitution, such as
Trifluoroacetyl group, chloracetyl, tribromo-acetyl base etc., it can remove under very mild conditions.Therefore it is suitable for arranging spit of fland class medicine
The preparation of thing.
First step substitution reaction, uses R1And R2Group is protected to N.Protection reagent used is with following structure
Acyl chlorides or acid anhydrides:
Wherein, R can be with identical or different group from R ';R, R ' it is containing the aliphatic hydrocarbon that C numbers are 1-12, takes
Fat subsitutes hydrocarbon or C numbers are 6-12 aromatic hydrocarbons, substituted arene, such as methyl, ethyl, trichloromethyl, trifluoromethyl, phenyl or to methyl
Phenyl etc.;When R and R ' constitutes cyclic structure, acid anhydrides is cyclic acid anhydride, such as R, when R ' is all methylene, is succinic anhydride.R, R '
Preferably methyl, ethyl, trifluoromethyl, methylene(R, R ' circlewise)Deng.Solvent for use is tetrahydrofuran, 2- methyl tetrahydrochysene furans
Mutter, one kind in ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, toluene, dimethylbenzene etc..Preferably tetrahydrochysene furan
Mutter, toluene.The range of reaction temperature is -10 DEG C of reflux temperatures to solvent for use.
The R1And R2It is N blocking groups, it is each independently selected from H, succinyl base, glutaryl, the acyl of butylene two
Base, glutaconyl, phthalyl, hexahydro phthalyl, 3- chlore O-phthalic acids acyl group, 4- chlore O-phthalic acid acyls
Base, R "-C=O, and R1And R2It is not simultaneously H;Wherein, R " is that aliphatic hydrocarbon or substituted fatty hydrocarbon base or C numbers that C numbers are 1~16 are
6~16 aromatic hydrocarbon or substituted aroma alkyl, the substituent of the substituted fatty hydrocarbon base and substituted aroma alkyl is methyl, one
Chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 1- chloroethyls, 1,1- Dichloroethyls, propyl group, isopropyl, butyl, isobutyl
Base, cyclopropyl, cyclopenta, cyclohexyl, phenyl, 4- chlorphenyls, 4- methoxyphenyls, benzyl or phenethyl etc.;R1And R2Wherein
One be H when, another is preferably benzoyl, 2,2,2- trifluoroacetyl groups etc.;When R1 and R2 are not H, it is each independent
Ground is preferably benzoyl, acetyl group, 2,2,2- trifluoroacetyl groups or R1And R2Cyclization, collectively forms succinyl base, glutaryl
Base, hexahydro phthalyl etc..
Second step catalytic hydrogenation, used catalyst is Pd/C, Pt/C, PtO2Or Rh/C etc., preferably Pd/C, it is necessary to
Hydrogen Vapor Pressure is 1~20bar;Solvent for use is one or more mixed solvents in acetic acid, methanol, ethanol, propyl alcohol;Reaction
Temperature is 20~140 DEG C.
3rd step resolution reaction, obtains compound I, and resolving agent used includes:D- tartaric acid, D- mandelic acids, D- hexichol first
One or more mixtures in acyl tartaric acid, L- camphorsulfonic acids, and their optical isomer, preferably D- mandelic acids or
D- dibenzoyl tartaric acids;Solvent for use be water, acetone, butanone, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate,
One or more mixing in acetic acid, tetrahydrofuran, 2- methyltetrahydrofurans, methyl tertiary butyl ether(MTBE), toluene, dimethylbenzene etc.
Thing;Preferably acetone, ethanol or isopropanol.The reaction temperature is 30 DEG C of reflux temperatures to solvent for use, preferably 30-
100℃.The equivalent of resolving agent used is 0.4-1.0 equivalents, preferably 0.4-0.6 equivalents.
Four-step reaction, compound I is deprotected, has optically active 3- amino piperidines dihydrochloride into salt is obtained((R)-
3- amido piperidine hydrochlorates II).Compound I can be deprotected under acid or alkaline conditions.Wherein,
When compound I is deprotected in the basic conditions, pH value of reaction system is more than 10.Solvent for use be methanol, ethanol,
One or both of propyl alcohol, isopropanol, water mixed solvent.Preferably methanol, water;Alkali used be sodium hydroxide, potassium hydroxide,
One kind or its mixture in sodium carbonate, potassium carbonate, cesium carbonate etc..Preferably sodium hydroxide, sodium carbonate;The reaction temperature is
30 DEG C of reflux temperatures to solvent for use.Compound I is obtained after being deprotected in the basic conditions(R)- 3- amido piperidine hydrochlorates
II free alkali form, can in HCl aqueous isopropanol, ethyl acetate solution or the aqueous solution hydrochloric acid salt, finally obtain
(R)- 3- amido piperidine hydrochlorates II.
When compound I is deprotected in acid condition, pH value of reaction system is below 2.The salt that acid used is 4N~12N
Acid.Preferably 12N hydrochloric acid.Solvent for use is one kind or water and a kind of other mixtures in water, ethanol, isopropanol.Institute
Reaction temperature is stated for 50-100 DEG C.Compound I is deprotected under the acid condition, can be directly obtained(R)- 3- amino piperidine salt
Hydrochlorate II.
Wherein, deprotection base can produce more impurity under acid condition, therefore deprotection base effect under alkalescence condition
More preferably.
The mother liquor after the 3rd step is split is reclaimed, compound I S type optical isomers can be obtained, the isomers is further
Deprotection can obtain 3- amido piperidine hydrochlorates II S type optical isomers.The isomers can be used for 5-HT4 acceptor inhibitors
In synthesis Deng multi-medicament.
Present invention also offers the compound I with(R)- 3- amido piperidine hydrochlorates II answering in synthesis Li Gelieting
With.
There is optically active compound I after being split through the 3rd step, the medicines such as Li Gelieting, Egelieting are can be directly used for
The synthesis of thing.When compound I is used for Li Gelieting synthesis, by being reacted with compound 3, Li Gelieting midbody compounds are obtained
III, then obtain Li Gelieting by deprotection.(R)- 3- amido piperidine hydrochlorates II also can be directly used for Li Gelieting synthesis.
Synthetic route is:
(R)- 3- amido piperidine hydrochlorates II is in phase transfer catalyst(PTC)In the presence of react direct with compound 3
For Li Gelieting synthesis,
Wherein,
The phase transfer catalyst(PTC)For the compound with following structure:R1’R2’R3’R4’N+X4 -,
Wherein, R1’、R2’、R3' and R4' it is each independently C1-C18 alkyl or C6-C18 aryl, X4For halogen(For example
Fluorine, chlorine or bromine), bisulfate ion or hydroxyl;The phase transfer catalyst is preferably TBAB, benzyl triethyl ammonium bromination
Ammonium, benzyltriethylammoinium chloride, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide etc..
Solvent for use is tetrahydrofuran, 2- methyltetrahydrofurans, ethyl acetate, propyl acetate, isopropyl acetate, acetic acid fourth
One or both of organic solvent that ester, isobutyl acetate, toluene, dimethylbenzene etc. can be layered with water, preferably tetrahydrochysene furan
Mutter, 2- methyltetrahydrofurans or isopropyl acetate.Alkali used is organic base or inorganic base, can be triethylamine (TEA), diisopropyl
Base ethylamine (DIPEA), pyridine, NMP, DBU, N- methylmorpholine, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, carbon
One or more in sour caesium, disodium hydrogen phosphate, sodium hydroxide, potassium hydroxide and sodium hydride.Preferably triethylamine or bicarbonate
Sodium.The reaction temperature is 40 DEG C of reflux temperatures to solvent for use.
Chemical compounds I is preferably:
Reactant can also use compound I with piperidinium salt formed by resolving agent;Resolving agent used includes:D- winestones
One or more in acid, D- mandelic acids, D- dibenzoyl tartaric acids, L- camphorsulfonic acids, and their optical isomer are mixed
Compound.Preferably D- mandelic acids or D- dibenzoyl tartaric acids.
Compound III is preferably:
Wherein, succinyl base protection group with document it has been reported that tertbutyloxycarbonyl, compared with phthalyl, in sharp lattice
In the synthesis for arranging spit of fland, last deprotection is more easy to removing, and reaction solution is cleaner, and impurity is less, it is easier to obtain purity higher
Product.
Reported in patent WO2013098775, the existing 3- amino protected by tertbutyloxycarbonyl, phthalyl
Piperidines has more impurity 1 and generated in the method to prepare Li Gelieting, it has been investigated that impurity 1 can further hydrolysis life
Into impurity 2, these impurity are all difficult to be removed, and can influence Li Gelieting purity., can be with complete using method of the present invention
The generation of the full impurity 3 and impurity 4 for avoiding producing by the deprotection of tertbutyloxycarbonyl, can also be avoided because of phthalyl
Deprotection and the peculiar impurity that produces.Moreover, impurity 1, impurity 2 also can be controlled in less than 0.5% in reaction solution, pass through rear place
Reason operation, without can obtain chemical purity more than 99.5% by special column chromatography purifying, optical isomer is not higher than
0.1%, single contaminant is not higher than 0.1%, and total impurities is not higher than the Li Gelieting of 0.5% high-purity.
Obtained by the present invention(R)- 3- amino piperidine alkane optical purity is high, and resolution yield is reachable~30%, and technique is reappeared
Property it is high.By gained compound I, II and Li Gelieting made from compound 3, chemical purity is high, easy to operate, it is easy to industrialize
Production.
What the present invention was provided(R)- 3- amido piperidine hydrochlorates II synthetic method compared with the conventional method, also with following
Advantage:
(1)The prices of raw materials respectively walked are relatively low, and ample supply of commodities on the market reduces cost;
(2)Step is few, the reaction of 3~4 steps.Technique is easy, shortens the production cycle;
(3)The introducing of electrophilic protection group, reduces pressure required during catalytic hydrogenation pyridine ring on the bit amino of pyridine 3,
Reaction condition is set to routinize, beneficial to industrialized production;
(4)Pd-C catalyst used in catalytic hydrogenation, it is possible to achieve circulating repetition is utilized and reclaimed, and reduces cost;
(5)Disposing mother liquor after fractionation can obtain chemical compounds I and II another optical isomer, further reduction
Cost.
Chemical compounds I that the present invention is provided, II are used for Li Gelieting synthesis compared with the conventional method, with advantages below:
(1)Starting compound I, preparation method is relatively convenient, cost is low, purity is high, be easy to obtain;
(2)Compound III structure is novel, and amino protecting group is easily deprotected, and reacts cleaner, can effectively control
The generation of impurity 1, impurity 2, can also be avoided peculiar produced by because using during trifluoroacetic acid removing tertbutyloxycarbonyl protection group
Impurity 3, impurity 4, the more preferable Li Gelieting of purity can be obtained;
(3)Phase transfer catalysis (PTC)(R)- 3- amido piperidine hydrochlorates II and 3 direct splicing method, cost is low, simple to operate,
Products obtained therefrom purity is high.
Embodiment
It is not required to be further described, those skilled in the art can farthest utilize this by description above
Invention.Therefore, examples provided below is only that the present invention is furture elucidated and oneself, is not meant to limit in any way
The scope of the present invention.Embodiment 1-13 is(R)The derivative of -3- amino piperidine alkane(Compound I)And(R)- 3- amino piperidine salt
The example synthesis of hydrochlorate II.Embodiment 14-15 is the example synthesis of chemical compounds I and II isomers.Embodiment 16-21 is this hair
Bright compound I and(R)Li Gelieting's is another in the application of -3- amido piperidine hydrochlorates II in Li Gelieting synthesis, embodiment
One starting material 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)- 8- bromine xanthine(Chemical combination
Thing 3)Reference literature WO2006/048427(Embodiment 2)Disclosed in method prepare.
Embodiment 1:The fluoro- N- of 2,2,2- tri-(3- pyridine radicals)Acetamide
By 3- aminopyridines(60g, 0.637mol), tetrahydrofuran(THF, 300ml)Add in reaction vessel.Stirring, drop
Temperature is to 0 DEG C.By TFAA(160g, 0.764mol)It is added dropwise in reactant mixture.Room temperature reaction 3 hours.To reaction solution
In be added dropwise to saturated sodium bicarbonate aqueous solution(100ml), stir 0.5 hour.Collected organic layer, is concentrated to give 2,2,2- tri- fluoro- N-
(3- pyridine radicals)Acetamide.
Yield:118.6g(The 98% of theoretical value)
Embodiment 2::N-(3- pyridine radicals)Benzamide
By 3- aminopyridines(50g, 0.531mol), ethyl acetate(EA, 250ml)And triethylamine(64g, 0.637mol)Plus
Enter in reaction vessel.Stir, be cooled to 0 DEG C.By chlorobenzoyl chloride(78g, 0.557mol)It is added dropwise in reactant mixture.0-5℃
Reaction 5 hours.Filtering, collects filtrate.With saturated common salt water washing filtrate.Collected organic layer, is concentrated to give N-(3- pyridine radicals)Benzene
Formamide.
Yield:84.2g(The 80% of theoretical value)
Embodiment 3:1-(3- pyridine radicals)- 2,5- pyrrolidine-diones
By 3- aminopyridines(10g, 0.106mol), toluene(100ml)In the lower addition reaction vessel of nitrogen protection, stirring
Dissolved clarification.Succinic anhydride is added into reaction bulb(15.9g, 0.159mol)And triethylamine(21.4g, 0.211mol), temperature rising reflux 8
Hour separates the water in system.
Stop heating response, be naturally cooling to after room temperature to be cooled to 0 DEG C or so with ice-water bath and stir 1 hour.Filtering, filter cake
Use toluene(30ml*3)Wash three times.Filter cake is collected, drying obtains 1-(3- pyridine radicals)- 2,5- pyrrolidine-diones.
Yield:16.8g(The 90% of theoretical value)
1H-NMR(400MHz,CDCl3):δ2.93-2.94(m,4H),7.42-7.46(m,1H),7.69-7.72(m,
1H),8.61-8.64(m,2H).
Embodiment 4:2-(3- pyridine radicals)- 2H- hexahydro iso-indoles -1,3- diketone
By 3- aminopyridines(10g, 0.106mol), toluene(100ml)In the lower addition reaction vessel of nitrogen protection, stir molten
Clearly.HHPA is added into reaction bulb(24.6g, 0.159mol)And triethylamine(21.4g, 0.211mol), temperature rising reflux 8 is small
When separate water in system.
Stop heating response, be naturally cooling to after room temperature to be cooled to 0 DEG C or so with ice-water bath and stir 1 hour.Filtering, filter cake
Use toluene(30ml*3)Wash three times.Filter cake is collected, drying obtains 2-(3- pyridine radicals)- 2H- hexahydro iso-indoles -1,3- diketone.
Yield:21.5g(The 88% of theoretical value)
1H-NMR(400MHz,CDCl3):δ1.51-1.53(m,4H),1.85-1.93(m,4H),3.05-3.08(m,
2H),7.41-7.45(m,1H),7.71-7.77(m,1H),8..59-8.61(m,1H),8.64-8.67(m,1H).
Embodiment 5:The fluoro- N- of 2,2,2- tri-(3- piperidyls)Acetamide(Compound R ac- I -4)
By the fluoro- N- of 2,2,2- made from embodiment 1 tri-(3- pyridine radicals)Acetamide(40g, 0.21mol), acetic acid(200ml)
And Pd/C(10%, 10%w/w)It is added in hydrogenation container.After the air in reaction system with nitrogen, hydrogen is passed through
To 1.2MPa.84 DEG C are warming up to react 16 hours.After reaction terminates, room temperature is cooled to, is filtered.Filtrate is collected, sodium carbonate is used
Solution adjusts pH to 10.Use dichloromethane(3000ml)After extractive reaction liquid, concentration of organic layers obtains 2,2,2- tri- fluoro- N-(3- piperidines
Base)Acetamide(Compound R ac- I -4).
Yield:24.7g(The 60% of theoretical value)
1H-NMR(400MHz,DMSO-d6):δ1.31-1.41(m,2H),1.55-1.59(m,1H),1.77-1.80(m,
1H),2.33-2.38(m,2H),2.76(dd,J=12.4Hz,3.6Hz,1H),2.87(dd,J=12.0Hz,3.2Hz,1H),
3.60-3.65(m,1H).
Embodiment 6:N-(3- piperidyls)Benzamide(Compound R ac- I -5)
By N- made from embodiment 2(3- pyridine radicals)Benzamide(20g, 0.101mol), acetic acid(200ml)And Pd/C
(10%, 10%w/w)It is added in hydrogenation container.After the air in reaction system with nitrogen, hydrogen is passed through extremely
1.2MPa.84 DEG C are warming up to react 16 hours.After reaction terminates, room temperature is cooled to, is filtered.Filtrate is collected, it is water-soluble with sodium carbonate
Liquid adjusts pH to 10.Use dichloromethane(3000ml)After extractive reaction liquid, concentration of organic layers obtains N-(3- piperidyls)Benzamide(Change
Compound Rac- I -5).
Yield:17.1g(The 83% of theoretical value)
1H-NMR(400MHz,DMSO):δ1.45-1.53(m,3H),1.66-1.71(m,2H),2.53-2.58(m,2H),
2.90(d,J=12.4Hz,1H),3.05(dd,J=11.6Hz,2.8Hz,1H),3.92-3.95(m,1H),7.43-7.46(m,
2H),7.50-7.53(t,J=7.2Hz,1H),7.85(d,J=7.6Hz,2H),8.31(broad,s,1H).
Embodiment 7:1-(3- piperidyls)- 2,5- pyrrolidine-diones(Compound R ac- I -6)
By 1- made from embodiment 3(3- pyridine radicals)- 2,5- pyrrolidine-diones(20g, 0.101mol), acetic acid(200ml)
And Pd/C(10%, 10%w/w)It is added in hydrogenation container.After the air in reaction system with nitrogen, hydrogen is passed through
To 1.2MPa.84 DEG C are warming up to react 16 hours.After reaction terminates, room temperature is cooled to, is filtered.Filtrate is collected, sodium carbonate is used
Solution adjusts pH to 10.Use dichloromethane(3000ml)After extractive reaction liquid, concentration of organic layers obtains 1-(3- piperidyls)- 2,5- pyrroles
Alkane diketone(Compound R ac- I -6).
Yield:22.3g(The 91% of theoretical value)
1H-NMR(400MHz,CDCl3):δ1.71-1.78(m,2H),1.84-1.89(m,1H),2.0(broad,s,
1H),2.23-2.34(m,1H),2.67(s,4H),2.67-2.73(m,1H),3.09(dd,J=12.0Hz,4.0Hz, 1H),
3.18(d,J=12.8Hz,1H),3.43(t,J=12Hz,1H),4.24-4.30(m,1H).
Embodiment 8:2-(3- piperidyls)- 2H- hexahydro iso-indoles -1,3- diketone(Compound R ac- I -7)
By 2- made from embodiment 4(3- pyridine radicals)- 2H- hexahydro iso-indoles -1,3- diketone(20g, 0.101mol), acetic acid
(200ml)And Pd/C(10%, 10%w/w)It is added in hydrogenation container.After the air in reaction system with nitrogen, lead to
Enter hydrogen to 1.2MPa.84 DEG C are warming up to react 16 hours.After reaction terminates, room temperature is cooled to, is filtered.Filtrate is collected, carbon is used
Acid sodium aqueous solution adjusts pH to 10.Use dichloromethane(3000ml)After extractive reaction liquid, concentration of organic layers obtains 2-(3- piperidyls)-
2H- hexahydro iso-indoles -1,3- diketone(Compound R ac- I -7).
Yield:26.1g(The 87% of theoretical value)
1H-NMR(400MHz,CDCl3):δ1.34-1.47(m,4H),1.65-1.90(m,7H),2.0(s,1H),2.18-
2.28(m,1H),2.71-2.75(m,1H),2.77-2.85(m,2H),3.15-3.27(m,2H),3.49(t,J=4.0Hz,
1H),4.28-4.35(m,1H).
Embodiment 9:(R)The fluoro- N- of -2,2,2- three(3- piperidyls)Acetamide(Chemical compounds I -4)
Method 9-A:
By the fluoro- N- of 2,2,2- made from embodiment 5 tri-(3- piperidyls)Acetamide(2g, 0.01mol)And acetone(10ml)
It is added in reaction bulb, stirring and dissolving.By the D- camphorsulfonic acids configured(1.4g, 0.006mol)Acetone(5ml)Solution is added
Into reactant mixture, heating reflux reaction 0.5hr.Room temperature is cooled to, solid is slowly separated out.Filtering, collects filtration cakes torrefaction and obtains
(R)The fluoro- N- of -2,2,2- three(3- piperidyls)Acetamide camsilate(I -4 camsilate).
The above-mentioned camsilate of gained I -4 is added in 20ml dichloromethane, 50ml10% sodium bicarbonate water is added
Solution, is stirred 1 hour, collected organic layer.It is concentrated to give(R)The fluoro- N- of -2,2,2- three(3- piperidyls)Acetamide (I -4).
Yield:0.85g(The 20% of theoretical value)
Optical purity:e.e.=91.4%
Chemical compounds I -4 can also be by the following method(9-B)Prepare:
Method 9-B:
Using method same as Example 9(Method 9-A), but use D- dibenzoyl tartaric acids(2.1g, 0.006mol)
Instead of D- camphorsulfonic acids(1.4g, 0.006mol), heat temperature raising back flow reaction 0.5hr.Room temperature is cooled to, solid is slowly separated out,
Filtering, collects filtration cakes torrefaction and obtains(R)The fluoro- N- of -2,2,2- three(3- piperidyls)Acetamide-D- dibenzoyl tartaric acid salt.By institute
Obtain I -4 camsilate to be added in 20ml dichloromethane, add 50ml10% sodium bicarbonate aqueous solution, stir 1 hour,
Collected organic layer.It is concentrated to give(R)The fluoro- N- of -2,2,2- three(3- piperidyls)Acetamide (I -4).
Yield:0.94g(The 18% of theoretical value)
Optical purity:e.e.=95.2%
Chemical compounds I -4 can also be by the following method(9-C)Prepare:
Method 9-C:
Using method same as Example 9(Method 9-A), but use D- dibenzoyl tartaric acids(2.8g, 0.008mol)
Instead of D- camphorsulfonic acids(1.4g, 0.006mol), use isopropyl acetate(30ml)Instead of acetone(10ml), heat temperature raising backflow is instead
Answer 0.5hr.Room temperature is cooled to, solid is slowly separated out, filtered, filtration cakes torrefaction is collected and obtains(R)The fluoro- N- of -2,2,2- three(3- piperidines
Base)Acetamide-D- dibenzoyl tartaric acid salt.The camsilate of gained I -4 is added in 20ml dichloromethane, added
50ml10% sodium bicarbonate aqueous solution, is stirred 1 hour, collected organic layer.It is concentrated to give(R)The fluoro- N- of -2,2,2- three(3- piperidines
Base)Acetamide (I -4).
Yield:1.14g(The 21% of theoretical value)
Optical purity:e.e.=90.4%
Embodiment 10:(R)-N-(3- piperidyls)Benzamide(Chemical compounds I -5)
Method 10-A:
By N- made from embodiment 6(3- piperidyls)Benzamide(2g, 0.01mol)And ethanol(15ml)It is added to reaction
In bottle, stirring and dissolving.By the D- dibenzoyl tartaric acids configured(2.1g, 0.006mol)Acetone(5ml)Solution is added to instead
Answer in mixture, heating reflux reaction 0.5hr.Room temperature is cooled to, solid is slowly separated out.Filtering, collects filtration cakes torrefaction and obtains(R)-
N-(3- piperidyls)Benzamide-D- dibenzoyl tartaric acid salt(I -5 dibenzoyl tartaric acid salt).
The above-mentioned dibenzoyl tartaric acid salt of gained I -5 is added in 20ml dichloromethane, 50ml10% carbonic acid is added
Hydrogen sodium water solution, is stirred 1 hour, collected organic layer.It is concentrated to give R)-N-(3- piperidyls)Benzamide (I -5).
Yield:1.4g(The 25% of theoretical value)
Optical purity:e.e.=93.2%
Chemical compounds I -5 can also be by the following method(10-B)Prepare:
Method 10-B:
Using method same as in Example 10(Method 10-A), but use D- tartaric acid(0.9g, 0.006mol)Instead of D-
Dibenzoyl tartaric acid(2.1g, 0.006mol), heat temperature raising back flow reaction 0.5hr.Room temperature is cooled to, solid is slowly separated out,
Filtering, collects filtration cakes torrefaction and obtains(R)-N-(3- piperidyls)Benzamide-D- tartrates.
The above-mentioned dibenzoyl tartaric acid salt of gained I -5 is added in 20ml dichloromethane, 50ml10% carbonic acid is added
Hydrogen sodium water solution, is stirred 1 hour, collected organic layer.It is concentrated to give R)-N-(3- piperidyls)Benzamide (I -5).
Yield:0.92g(The 21% of theoretical value)
Optical purity:e.e.=90.0%
Chemical compounds I -5 can also be by the following method(10-C)Prepare:
Method 10-C:
Using method same as in Example 10(Method 10-A), but use D- tartaric acid(0.6g, 0.004mol)Instead of D-
Dibenzoyl tartaric acid(2.1g, 0.006mol), use methyl tertiary butyl ether(MTBE)(20ml)Instead of ethanol(15ml), heat temperature raising backflow
React 0.5hr.Room temperature is cooled to, solid is slowly separated out, filtered, filtration cakes torrefaction is collected and obtains(R)-N-(3- piperidyls)Benzoyl
Amine-D- tartrates.
The above-mentioned dibenzoyl tartaric acid salt of gained I -5 is added in 20ml dichloromethane, 50ml10% carbonic acid is added
Hydrogen sodium water solution, is stirred 1 hour, collected organic layer.It is concentrated to give R)-N-(3- piperidyls)Benzamide (I -5).
Yield:0.65g(The 15% of theoretical value)
Optical purity:e.e.=96.2%
Chemical compounds I -5 can also be by the following method(10-D)Prepare:
Method 10-D:
Using method same as in Example 10(Method 10-A), but use D- mandelic acids(0.9g, 0.006mol)Instead of D-
Dibenzoyl tartaric acid(2.1g, 0.006mol), heat temperature raising back flow reaction 0.5hr.Room temperature is cooled to, solid is slowly separated out,
Filtering, collects filtration cakes torrefaction and obtains(R)-N-(3- piperidyls)Benzamide-D- mandelates.
The above-mentioned dibenzoyl tartaric acid salt of gained I -5 is added in 20ml dichloromethane, 50ml10% carbonic acid is added
Hydrogen sodium water solution, is stirred 1 hour, collected organic layer.It is concentrated to give R)-N-(3- piperidyls)Benzamide (I -5).
Yield:0.82g(The 23% of theoretical value)
Optical purity:e.e.=93.6%
Embodiment 11:1-((R)- 3- piperidyls)- 2,5- pyrrolidine-diones(Chemical compounds I -6)
Method 11-A:
By 1- made from embodiment 7(3- piperidyls)- 2,5- pyrrolidine-diones(1.8g, 0.01mol)And isopropanol
(20ml)It is added in reaction bulb, stirring and dissolving.By the D- mandelic acids configured(0.9g, 0.006mol)Acetone(5ml)It is molten
Liquid is added in reactant mixture, and heating reflux reaction 0.5hr is cooled to room temperature, slowly separates out solid.Filtering, collects filter cake and does
It is dry to obtain 1-((R)- 3- piperidyls)The mandelate of -2,5- pyrrolidine-diones (I -6).
The mandelate of above-mentioned gained I -6 is added in 20ml dichloromethane, 50ml10% sodium bicarbonate water is added
Solution, is stirred 1 hour, collected organic layer.It is concentrated to give 1-((R)- 3- piperidyls)- 2,5- pyrrolidine-diones (I -6).
Yield:1.0g(The 30% of theoretical value)
Optical purity:e.e.=99.2%
Chemical compounds I -6 can also be by the following method(11-B)Prepare:
Method 11-B:
Using with the identical method of embodiment 11(Method 11-A), but use D- tartaric acid(0.9g, 0.006mol)Instead of D-
Mandelic acid(0.9g, 0.006mol), heating reflux reaction 0.5hr is cooled to room temperature, slowly separates out solid.Filtering, collects filter cake
Dry 1-((R)- 3- piperidyls)The tartrate of -2,5- pyrrolidine-diones.
The mandelate of above-mentioned gained I -6 is added in 20ml dichloromethane, 50ml10% sodium bicarbonate water is added
Solution, is stirred 1 hour, collected organic layer.It is concentrated to give 1-((R)- 3- piperidyls)- 2,5- pyrrolidine-diones (I -6).
Yield:0.86g(The 26% of theoretical value)
Optical purity:e.e.=98.5%
Chemical compounds I -6 can also be by the following method(11-C)Prepare:
Method 11-C:
Using with the identical method of embodiment 11(Method 11-A), but use D- tartaric acid(1.5g, 0.01mol)It is flat instead of D-
Peach acid(0.9g, 0.006mol), heating reflux reaction 0.5hr is cooled to room temperature, slowly separates out solid.Filtering, collects filter cake and does
It is dry to obtain 1-((R)- 3- piperidyls)The D- tartrates of -2,5- pyrrolidine-diones.
The mandelate of above-mentioned gained I -6 is added in 20ml dichloromethane, 50ml10% sodium bicarbonate water is added
Solution, is stirred 1 hour, collected organic layer.It is concentrated to give 1-((R)- 3- piperidyls)- 2,5- pyrrolidine-diones (I -6).
Yield:0.99g(The 30% of theoretical value)
Optical purity:e.e.=88.4%
Embodiment 12:2-((R)- 3- piperidyls)- 2H- hexahydro iso-indoles -1,3- diketone(Chemical compounds I -7)
Method 12-A:
By 2- made from embodiment 8(3- piperidyls)- 2H- hexahydro iso-indoles -1,3- diketone(2.4g, 0.01mol)With it is different
Propyl alcohol(20ml)It is added in reaction bulb, stirring and dissolving.By the D- tartaric acid configured(0.9g, 0.006mol)Acetone
(5ml)Solution is added in reactant mixture, and heating reflux reaction 1hr is cooled to room temperature, slowly separates out solid.Filtering, collects filter
Biscuit is dry to obtain 2-((R)- 3- piperidyls)The D- tartrates of -2H- hexahydro iso-indoles -1,3- diketone (I -7).
The tartrate of above-mentioned gained I -7 is added in 20ml dichloromethane, 50ml10% sodium bicarbonate water is added
Solution, is stirred 1 hour, collected organic layer.It is concentrated to give 2-((R)- 3- piperidyls)- 2H- hexahydro iso-indoles -1,3- diketone (I -7).
Yield:0.9g(The 25% of theoretical value)
Optical purity:E.e.=96.8% chemical compounds I -7 can also be by the following method(12-B)Prepare:
Method 12-B:
By 2- made from embodiment 8(3- piperidyls)- 2H- hexahydro iso-indoles -1,3- diketone(2.4g, 0.01mol)With it is different
Propyl alcohol(20ml)It is added in reaction bulb, stirring and dissolving.By the D- mandelic acids configured(0.9g, 0.006mol)Acetone
(5ml)Solution is added in reactant mixture, and heating reflux reaction 1hr is cooled to room temperature, slowly separates out solid.Filtering, collects filter
Biscuit is dry to obtain 2-((R)- 3- piperidyls)The D- mandelates of -2H- hexahydro iso-indoles -1,3- diketone.
The tartrate of above-mentioned gained I -7 is added in 20ml dichloromethane, 50ml10% sodium bicarbonate water is added
Solution, is stirred 1 hour, collected organic layer.It is concentrated to give 2-((R)- 3- piperidyls)- 2H- hexahydro iso-indoles -1,3- diketone (I -7).
Yield:0.74g(The 19% of theoretical value)
Optical purity:e.e.=97.4%
1H-NMR(400MHz,D2O):δ1.32-1.50(m,5H),1.63-1.71(m,3H),1.80-1.90(m,4H),
2.01-2.07(m,1H),2.15-2.30(m,1H),3.03-3.06(m,3H),3.34-3.41(m,2H),3.61-3.69(m,
1H),4.32-4.38(m,1H),4.99(s,1H),7.39-7.44(m,5H).
Embodiment 13:(R)- 3- amino piperidine dihydrochlorides((R) -3- amido piperidine hydrochlorates II)
By embodiment 9(Method 9-A)It is obtained(R)The fluoro- N- of -2,2,2- three(3- piperidyls)Acetamide(Ⅰ-4)Camphor sulphur
Hydrochlorate(4g, 0.009mol), potassium carbonate(6.5g, 0.045mol)And methanol(40ml)It is added in reaction bulb, is heated to backflow
Reaction 8 hours.It is down to after room temperature and filters, collects and concentrate filtrate and done near.Absolute ethyl alcohol is added into residue(10ml), use
The aqueous isopropanol of hydrogen chloride adjusts pH to 1.0-5 DEG C is stirred 2 hours, filtering, collection filter cake, dry(R)- 3- amino piperidines two
Hydrochloride.
Yield:0.95g(The 61% of theoretical value)
Specific rotation:[α]25 D=-2.4 °, C=1, H2O
1H-NMR(400MHz,DMSO):δ1.58-1.73(m,2H),1.85-2.05(m,1H),2.02-2.05(m,1H),
2.75-2.83(m,2H),3.17-3.20(m,1H),3.40-3.43(m,3H),8.61(broad,s,2H),9.67(broad,
s,2H)
(R)- 3- amido piperidine hydrochlorates II can also be prepared by the following method:
Method 13-B:
Using with the identical method of embodiment 13(Method 13-A), but use isopropanol(50ml)Instead of methanol(40ml), use
Sodium hydroxide(1.8g, 0.045mol)Instead of potassium carbonate(6.5g, 0.045mol), it is heated to 40 DEG C and reacts 2 hours.It is down to room temperature
After filter, collect and concentrate filtrate near dry.Ethanol is added into residue(10ml), adjusted with the ethyl acetate solution of hydrogen chloride
PH to 1.0-5 DEG C is stirred 2 hours, filtering, collection filter cake, dry(R)- 3- amino piperidine dihydrochlorides.
Yield:1.06g(The 68% of theoretical value)
Method 13-C:
By embodiment 9(Method 9-A)It is obtained(R)The fluoro- N- of -2,2,2- three(3- piperidyls)Acetamide camsilate
(4g, 0.009mol), and 12N concentrated hydrochloric acid(20ml)It is added in reaction bulb, is heated to 50 DEG C and reacts 4 hours.It is concentrated under reduced pressure
To near dry, methyl tertiary butyl ether(MTBE) 30ml and absolute ethyl alcohol 1ml is added into concentration residue.It is stirred at room temperature 2 hours, filters, receives
Collection filter cake is obtained(R)- 3- amino piperidine dihydrochlorides.
Yield:2.5g(The 77% of theoretical value)
Method 13-D:
By made from embodiment 10(R)-N-(3- piperidyls)Benzamide(Chemical compounds I -5,4g, 0.02mol)With 12N's
Concentrated hydrochloric acid(20ml)It is added in reaction bulb, heating reflux reaction 10 hours.It is concentrated under reduced pressure into and closely does, adds into concentration residue
Enter methyl tertiary butyl ether(MTBE) 30ml and absolute ethyl alcohol 2ml.It is stirred at room temperature 2 hours, filters, collects filter cake and obtain(R)- 3- amino piperidines two
Hydrochloride.
Yield:2.4g(The 72% of theoretical value)
Method 13-E:
By embodiment 11(Method 11-B)Obtained 1-((R)- 3- piperidyls)- 2,5- pyrrolidine-diones(Chemical compounds I -6)
Tartrate(3.3g, 0.01mol)With 6N concentrated hydrochloric acid(30ml)It is added in reaction bulb, heating reflux reaction 20 hours.
It is concentrated under reduced pressure near dry, the addition methyl tertiary butyl ether(MTBE) 30ml and absolute ethyl alcohol 2ml into concentration residue.It is stirred at room temperature 2 hours,
Filtering, collects filter cake and obtains(R)- 3- amino piperidine dihydrochlorides.
Yield:1.4g(The 80% of theoretical value)
Method 13-F:
By embodiment 12(Method 12-A)Obtained 2-((R)- 3- piperidyls)- 2H- hexahydro iso-indoles -1,3- diketone(Change
Compound I -7)Tartrate(3.9g, 0.01mol)With 12N concentrated hydrochloric acid(20ml)It is added in reaction bulb, is heated to reflux anti-
Answer 10 hours.It is concentrated under reduced pressure near dry, the addition methyl tertiary butyl ether(MTBE) 30ml and absolute ethyl alcohol 2ml into concentration residue.Room temperature
Stirring 2 hours, filtering is collected filter cake and obtained(R)- 3- amino piperidine dihydrochlorides.
Yield:1.2g(The 67% of theoretical value)
Embodiment 14:1-((S)- 3- piperidyls)- 2,5- pyrrolidine-diones(The S type optical isomers of chemical compounds I -6)
By 1- made from embodiment 7(3- piperidyls)- 2,5- pyrrolidine-diones(1.8g, 0.01mol)And isopropanol
(20ml)It is added in reaction bulb, stirring and dissolving.By the D- mandelic acids configured(0.9g, 0.006mol)Acetone(5ml)It is molten
Liquid is added in reactant mixture, and heating reflux reaction 0.5hr is cooled to room temperature, slowly separates out solid.Filtering, collects filtrate, dense
It is reduced to dry.Add ethyl acetate/ethanol(2:1)After mixed solution 10ml, heating dissolved clarification, cooling separates out solid.Filtering, collects filter
Cake obtains 1-((S)- 3- piperidyls)- 2,5- pyrrolidine-diones(The S type optical isomers of chemical compounds I -6).
Yield:0.5g(The 30% of theoretical value)
Embodiment 15:(S)- 3- amino piperidine dihydrochlorides(3- amido piperidine hydrochlorates II S type optical isomers)
The 1- that will be obtained in embodiment 14((S)- 3- piperidyls)- 2,5- pyrrolidine-diones(Compound I-6 S type optics
Isomers,(3.6g,0.02mol)With 12N concentrated hydrochloric acid(20ml)It is added in reaction bulb, heating reflux reaction 10 hours.Subtract
Pressure is concentrated near dry, the addition methyl tertiary butyl ether(MTBE) 30ml and absolute ethyl alcohol 2ml into concentration residue.2 hours, mistake are stirred at room temperature
Filter, collects filter cake and obtains(S)- 3- amino piperidine dihydrochlorides.
Yield:2.2g(The 63% of theoretical value)
Specific rotation:[α]25 D=+2.3 °, C=1, H2O
Embodiment 16:1-[(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)-
2,2,2- trifluoroacetyl group amino piperidine -1- bases)- xanthine(Compound III -1)
By 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)- 8- bromine xanthine(Chemical combination
Thing 3,8g, 0.018mol), embodiment 9(Method 9-A)Prepare(R)The fluoro- N- of -2,2,2- three(3- piperidyls)Acetamide(Chemical combination
Thing I -4,4.6g, 0.021mol), potassium carbonate(2.7g, 0.021mol)And ethyl acetate(80ml)It is added in reaction bulb.Heating
Back flow reaction 24 hours, is cooled to room temperature, filtering, collects filter cake.Filter cake is scattered in 100ml water, 80 DEG C of stirrings 1 are heated to
Hour.Be down to after room temperature, filter, collect filter cake obtain 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine-
1- bases)-8-(3-(R)- 2,2,2- trifluoroacetyl group amino piperidine -1- bases)- xanthine(Compound III -1).
Yield:6.6g(The 65% of theoretical value)
MS:[M+H]+=569.7
1H-NMR(400MHz,DMSO):δ1.57-1.66(m,1H),1.70-1.78(m,4H),1.82-1.86(m,1H),
1.93-1.96(m,1H),2.88(s,3H),3.02(t,J=14.0Hz,2H),3.40(s,3H),3.05-3.77(m,2H),
3.95-4.02(m,1H),4.88(s,2H),5.32(s,2H),7.67(t,J=8.0Hz,1H),7.80(d,J=8.4Hz,1H),
7.91(t,J=8.4Hz,1H),8.24(d,J=8.4Hz,1H),9.46(s,1H).
Embodiment 17:1-[(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)-
Benzoyl-amido piperidin-1-yl)- xanthine(Compound III -2)
By 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)- 8- bromine xanthine(Chemical combination
Thing 3,6g, 0.013mol), prepared by embodiment 10(R)-N-(3- piperidyls)Benzamide(Chemical compounds I -5,3.0g,
0.015mol), potassium carbonate(2.7g, 0.021mol)And 1-METHYLPYRROLIDONE(NMP, 80ml)It is added in reaction bulb.Heating
Reacted 8 hours to 100 DEG C, be cooled to room temperature, 150g frozen water is added into reactant mixture.Separate out and filtered after precipitation, collect filter
Cake.Filter cake is scattered in 100ml water, 80 DEG C is heated to and stirs 1 hour.Be down to after room temperature, filter, collect filter cake obtain 1- [(4-
Methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)- benzoyl-amido piperidin-1-yl)-
Xanthine(Compound III -2).
Yield:5.5g(The 73% of theoretical value)
MS:[M+H]+=577.5
1H-NMR(400MHz,DMSO):δ1.57-1.66(m,1H),1.70-1.78(m,4H),1.82-1.86(m,1H),
1.93-1.96(m,1H),2.88(s,3H),3.02(t,J=14.0Hz,2H),3.40(s,3H),3.05-3.77(m,2H),
3.95-4.02(m,1H),4.88(s,2H),5.32(s,2H),7.43-7.46(m,2H),7.50-7.53(t,J=7.2Hz,
1H),7.67(t,J=8.0Hz,1H),7.80(d,J=8.4Hz,1H),7.85(d,J=7.6Hz,2H),7.91(t,J=8.4Hz,
1H),8.24(d,J=8.4Hz,1H),9.67(s,1H).
Embodiment 18:1-[(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)-
(2,5- dioxotetrahydro pyrroles's -1- bases)Piperidin-1-yl)- xanthine(Compound III -3)
By 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)- 8- bromine xanthine(Chemical combination
Thing 3,1g, 0.002mol), embodiment 11(Method 11-B)The 1- of preparation((R)- 3- piperidyls)- 2,5- pyrrolidine-diones winestones
Hydrochlorate(Chemical compounds I -6,1.0g, 0.003mol), N, N- diisopropyl ethyl amines(DIPEA, 0.9g, 0.006mol)With N- methyl
Pyrrolidones(NMP, 10ml)It is added in reaction bulb.It is heated to 100 DEG C to react 5 hours, room temperature is cooled to, to reactant mixture
Middle addition 15g frozen water.Separate out and filtered after precipitation, collect filter cake.Filter cake is dissolved in 20ml dichloromethane, successively with water, saturation
Salt washes dichloromethane layer.Collect and concentrate dichloromethane mutually 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -
7-(2- butine -1- bases)-8-(3-(R)-(2,5- dioxotetrahydro pyrroles's -1- bases)Piperidin-1-yl)- xanthine(Compound III-
3).
Yield:0.9g(The 82% of theoretical value)
MS:[M+H]+=556.2
1H-NMR(400MHz,DMSO):δ1.74-1.77(m,5H),1.80-1.87(m,2H),2.22-2.33(m,1H),
2.61(s,4H),2.88(s,3H),2.90-2.98(m,1H),3.39(s,3H),3.61(d,J=8.4Hz,2H),3.82(d,J=
12.4Hz,1H),4.16-4.23(m,1H),4.90(s,2H),5.31(s,2H),7.67(dd,J=8.0Hz,1.2Hz,1H),
7.81(d,J=8.0Hz,1H),7.91(dd,J=8.0Hz,1.6Hz,1H),8.24(d,J=8.0Hz,1H).
Embodiment 19:1-[(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)-
(1,3- dioxo -1H- hexahydros iso-indoles -2(3H)- base)Piperidin-1-yl)- xanthine(Compound III -4)
By 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)- 8- bromine xanthine(Chemical combination
Thing 3,1g, 0.002mol), embodiment 12(Method 12-A)The 2- of preparation((R)- 3- piperidyls)- 2H- hexahydro iso-indoles -1,3-
Diketone tartrate(Chemical compounds I -7,1.15g, 0.003mol), N, N- diisopropyl ethyl amines(DIPEA, 0.9g,
0.006mol)And 1-METHYLPYRROLIDONE(NMP, 10ml)It is added in reaction bulb.It is heated to 100 DEG C to react 5 hours, is cooled to
Room temperature, 15g frozen water is added into reactant mixture.Separate out and filtered after precipitation, collect filter cake.Filter cake is dissolved in 20ml dichloros
Methane, successively with water, saturated common salt washing dichloromethane layer.Collect and concentrate dichloromethane mutually 1- [(4- methylquinazolins-
2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)-(1,3- dioxo -1H- hexahydros iso-indoles -2(3H)-
Base)Piperidin-1-yl)- xanthine(Compound III -4).
Yield:0.9g(The 82% of theoretical value)
MS:[M+H]+=609.3
1H-NMR(400MHz,DMSO):δ1.24-1.43(m,5H),1.51-1.65(m,3H),1.69-1.78(m,7H),
1.81-1.87(m,1H),2.21-2.29(m,1H),2.88(s,3H),2.90-2.98(m,3H),3.39(s,3H),3.56-
3.64(m,2H),3.79(d,J=8.0Hz,1H),4.14-4.21(m,1H),4.89(s,2H),5.31(s,2H),7.67(dd,J
=8.4Hz,1.2Hz,1H),7.80(d,J=8.4Hz,1H),7.90(dd,J=8.4Hz,1.2Hz,1H),8.24(d,J=8.4Hz,
1H)
Embodiment 20:1-[(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)-
Amino piperidine -1- bases)- xanthine(Compound 2, Li Gelieting)
Method 20-A:
By 1- made from embodiment 16 [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-
(3-(R)- 2,2,2- trifluoroacetyl group amino piperidine -1- bases)- xanthine(Compound III -1,2g, 0.0037mol), potassium carbonate
(2.1g, 0.015mol)And methanol(20ml)It is added in reaction bulb, heating reflux reaction 3 hours.Room temperature is cooled to, is filtered,
Filtrate is collected, and is concentrated to give residue.The residue is dissolved in ethanol, and remembers in 60 DEG C methyl- tert is added dropwise in solution
Slow cooling after butyl ether, stirring 0.5 hour, less than 5 DEG C are down to after separating out solid, filtering, collection filter cake and dry 1-
[(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)- amino piperidine -1- bases)- yellow fast
Purine(Compound 2).
Yield:1.4g(The 80% of theoretical value)
Chemical purity:99.65%;Impurity 1,0.03%;Impurity 2,0.01%;Other single impurity are respectively less than 0.1%.
Optical purity:99.9%.
Specific rotation [α]25 D=-20.1 °, C=1, DMF
MS:[M+H]+=473.3
1H-NMR(400MHz,DMSO):δ1.19-1.31(m,1H),1.57-1.69(m,1H),1.77(t,J=2.0Hz,
3H),1.75-1.83(m,1H),1.84-1.92(m,1H),2.75-2.88(m,2H),2.89(s, 3H),2.97-3.06(m,
1H),3.36(broad,s,2H),3.41(s,3H),3.58-3.88(m,2H),4.90(s,2H),5.32(s,2H),7.68
(dd,J=8.4,6.8Hz,1H),7.81(d,J=8.3Hz,1H),7.92(dd,J=8.2Hz,1H),8.25(d,J=8.1Hz,
1H).
Compound 2 can also be prepared by following several method:
Method 20-B:
By 1- made from embodiment 18 [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-
(3-(R)-(2,5- dioxotetrahydro pyrroles's -1- bases)Piperidin-1-yl)- xanthine(Compound III -3,0.5g, 1mmol), ethanol
Amine(0.6g, 1mmol)It is added to toluene 5ml in reaction bulb, is heated to 80-85 DEG C and reacts 8 hours.In 80 DEG C with hot water
Washing reaction mixture twice, collects toluene solution, and the residue after toluene is concentrated is heated to reflux with ethanol after dissolving, dissolved clarification
Slow cooling is separated out after solid to room temperature~25 DEG C, adds methyl tertiary butyl ether(MTBE), continues to stir 2 hours.Suspension is cooled to low
In 5 DEG C, continue stir 2 hours, filtering, collect filter cake obtain 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- fourths
Alkynes -1- bases)-8-(3-(R)- amino piperidine -1- bases)- xanthine(Compound 2).
Yield:0.3g(The 70% of theoretical value)
Chemical purity:99.68%;Impurity 1,0.02%;Impurity 2,0.01%;Other single impurity are respectively less than 0.1%.
Optical purity:99.9%.
Method 20-C:
By 1- made from embodiment 19 [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-
(3-(R)-(1,3- dioxo -1H- hexahydros iso-indoles -2(3H)- base)Piperidin-1-yl)- xanthine(Compound III -4,0.6g,
1mmol)80-85 DEG C is heated in 18ml toluene.Then, in 75-80 DEG C by monoethanolamine(3g, 5mmol)It is added to mixture
In.Make reaction complete within 6 hours in 80-85 DEG C of stirring in mixture.Add 80 DEG C of hot water 10ml and wash mixture 2 times, separation, receipts
Collect toluene solution, be concentrated to give 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)-
Amino piperidine -1- bases)- xanthine(Compound 2).
Yield:0.25g(The 55% of theoretical value)
Chemical purity:99.57%;Impurity 1,0.02%;Impurity 2,0.02%;Other single impurity are respectively less than 0.1%.
Optical purity:99.9%
Method 20-D:
By 1- made from embodiment 17 [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-
(3-(R)- benzoyl-amido piperidin-1-yl)- xanthine(Compound III -2,0.57g, 1mmol), cesium carbonate(0.65g,
2mmol)And sodium hydroxide(0.04g, 1mmol)It is added in ethanol 20ml, heating reflux reaction 24 hours.Filtering, collects filter
Liquid, is concentrated to give residue.Residue is added in 20ml dichloromethane, dichloromethane layer is washed with water 15ml, is collected organic
Layer.Be concentrated to give 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)- amino piperazine
Pyridine -1- bases)- xanthine(Compound 2).
Yield:0.23g(The 50% of theoretical value)
Method 20-E:
By 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)- 8- bromine xanthine(Chemical combination
Thing 3,3g, 0.006mol)、(R)- 3- amino piperidine dihydrochlorides(Compound II, 1.7g, 0.01mol), sodium acid carbonate(2.8g,
0.03mol)And ethanol(30ml)It is added in reaction bulb, is heated to back flow reaction 18 hours.It is down to after room temperature and filters, collects filter
Liquid, concentration is steamed after 1/3 solvent, adds 30ml methyl tertiary butyl ether(MTBE)s, separates out solid.Filtering, collect filter cake obtain 1- [(4- methyl
Quinazoline -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)- amino piperidine -1- bases)- xanthine(Chemical combination
Thing 2).
Yield:1.3g(The 47% of theoretical value)
Embodiment 21:(R)- 3- amido piperidine hydrochlorates II and compound 3 under PTC effects synthesis 1- [(4- methyl quinoline azoles
Quinoline -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-(R)- amino piperidine -1- bases)- xanthine(Li Gelieting,
Compound 2)
Method 21-A:
By 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)- 8- bromine xanthine(Chemical combination
Thing 3,3g, 0.006mol)、(R)- 3- amino piperidine dihydrochlorides(Compound II, 1.7g, 0.01mol), sodium acid carbonate(2.8g,
0.03mol), TBAB(PTC, TBAB, 0.97g, 0.003mol), water(10ml)And tetrahydrofuran(30ml)It is added to
In reaction bulb, back flow reaction is heated to 24 hours.It is down to after room temperature, add water 20ml, collected organic layer after stirring uses tetrahydrofuran
Wash aqueous phase, merge organic phase and be concentrated to give 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1-
Base)-8-(3-(R)- amino piperidine -1- bases)- xanthine(Compound 2).
Yield:2.3g(The 83% of theoretical value)
Method 21-B:
By 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)- 8- bromine xanthine(Chemical combination
Thing 3,3g, 0.006mol)、(R)- 3- amino piperidine dihydrochlorides(Compound II, 1.7g, 0.01mol), sodium hydroxide(1.2g,
0.03mol), benzyltrimethylammonium chloride(PTC,0.56g,0.003mol), water(10ml)And isopropyl acetate(40ml)Add
Into reaction bulb, back flow reaction is heated to 24 hours.It is down to after room temperature, add water 20ml, collected organic layer after stirring is different with acetic acid
Propyl ester wash aqueous phase, merge organic phase and be concentrated to give 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine-
1- bases)-8-(3-(R)- amino piperidine -1- bases)- xanthine(Compound 2).
Yield:2.5g(The 90% of theoretical value)
Method 21-C:
By 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)- 8- bromine xanthine(Chemical combination
Thing 3,3g, 0.006mol)、(R)- 3- amino piperidine dihydrochlorides(Compound II, 1.7g, 0.01mol), triethylamine(3.0g,
0.03mol), benzyltrimethylammonium chloride(PTC,0.56g,0.003mol), water(10ml)And toluene(40ml)It is added to reaction
In bottle, back flow reaction is heated to 24 hours.It is down to after room temperature, add water 20ml, collected organic layer after stirring uses toluene washings
Phase, merge organic phase and be concentrated to give 1- [(4- methylquinazolin -2- bases)Methyl] -3- methyl -7-(2- butine -1- bases)-8-(3-
(R)- amino piperidine -1- bases)- xanthine(Compound 2).
Yield:1.8g(The 64.8% of theoretical value).
Claims (12)
1. a kind of preparation method with optically active compound I, it is technically characterized in that:Using 3- aminopyridines as raw material,
Split by the protection of 3- bit aminos, catalytic hydrogen reduction pyridine ring, chiral reagent and obtain chemical compounds I;
Its reaction scheme is as follows:
Wherein,
(a) first step substitution reaction, used initiation material is 3- aminopyridines, uses R1And R2Group is protected to N,
The reaction reagent of the substitution reaction is to include R1And R2Acyl chlorides or acid anhydrides;
R1And R2Cyclization, collectively forms hexahydro phthalyl;
(b) second step catalytic hydrogenation, used catalyst is Pd/C, Pt/C, PtO2Or Rh/C;Need Hydrogen Vapor Pressure for 1~
20bar;Solvent for use is one or more mixed solvents in acetic acid, methanol, ethanol, propyl alcohol;Reaction temperature is 25~140
℃;
(c) the 3rd step resolution reaction, resolving agent used is D- tartaric acid, D- mandelic acids, D- dibenzoyl tartaric acids, D- camphor sulphurs
One or more mixtures in acid and their optical isomer;Solvent for use be water, acetone, butanone, methanol, ethanol,
Isopropanol, ethyl acetate, isopropyl acetate, acetic acid, tetrahydrofuran, 2- methyltetrahydrofurans, methyl tertiary butyl ether(MTBE), toluene, two
One or more mixtures in toluene.
2. preparation method as claimed in claim 1, it is characterised in that:3rd step resolution reaction, it is flat that resolving agent used is selected from D-
Peach acid and D- dibenzoyl tartaric acids.
3. preparation method as claimed in claim 1, it is characterised in that:3rd step resolution reaction, solvent for use is acetone, ethanol
Or isopropanol.
4. preparation method as claimed in claim 1, it is characterised in that:First step substitution reaction solvent for use be tetrahydrofuran,
One kind in 2- methyltetrahydrofurans, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, toluene, dimethylbenzene;It is described
The temperature range of substitution reaction is -10 DEG C of reflux temperatures to solvent for use.
5. preparation method as claimed in claim 4, it is characterised in that:The solvent is tetrahydrofuran or toluene.
6. preparation method as claimed in claim 1, it is characterised in that:3rd step resolution reaction, reaction temperature is 30 DEG C to institute
With the reflux temperature of solvent;The equivalent of resolving agent used is 0.4-1.0 equivalents.
7. preparation method as claimed in claim 6, it is characterised in that:The equivalent of the resolving agent is 0.4-0.6 equivalents.
(8. R) -3- amido piperidine hydrochlorates II preparation method, it is characterised in that comprise the following steps:
(1) according to claim 1 methods described prepare compound I;
(2) compound I is deprotected, has optically active (R) -3- amino piperidine dihydrochlorides II into salt is obtained;
The reaction equation of the step (2) is:
9. a kind of Li Gelieting preparation method, it is characterised in that comprise the following steps:
(1) according to preparation method prepare compound I described in claim 1;
(2) compound I obtains Li Gelieting midbody compounds III by being reacted with compound 3;
(3) Li Gelieting midbody compounds III obtain Li Gelieting by deprotection again;
Wherein,
The structural formula of the compound 3 is:
The structural formula of the Li Gelieting intermediate compound IIIs is:
The step (2), the reaction equation of (3) are:
10. a kind of Li Gelieting preparation method, it is characterised in that comprise the following steps:
(1) (R) -3- amido piperidine hydrochlorates II is prepared according to according to preparation method described in claim 8;
(2) (R) -3- amido piperidine hydrochlorates II generates Li Gelieting in the presence of phase transfer catalyst with the reaction of compound 3;
Wherein,
The structural formula of the compound 3 is:
The reaction equation of the step (2) is:
11. preparation method according to claim 10, it is characterised in that:The phase transfer catalyst is with following structure
Compound:R1’R2’R3’R4’N+X4 -,
Wherein, R1’、R2’、R3' and R4' it is each independently C1-C18 alkyl or C6-C18 aryl, X4For fluorine, chlorine, bromine, hydrogen sulfate
Root or hydroxyl.
12. preparation method according to claim 11, it is characterised in that:The phase transfer catalyst is tetrabutyl phosphonium bromide
Ammonium.
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