CN102070526B - Method for synthesizing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with protective group - Google Patents
Method for synthesizing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with protective group Download PDFInfo
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- CN102070526B CN102070526B CN2009102018600A CN200910201860A CN102070526B CN 102070526 B CN102070526 B CN 102070526B CN 2009102018600 A CN2009102018600 A CN 2009102018600A CN 200910201860 A CN200910201860 A CN 200910201860A CN 102070526 B CN102070526 B CN 102070526B
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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
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a method for preparing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with a protective group, and mainly solves the technical problem that multi-step chromatographic purification is needed in the conventional process for preparing the 3-aza-bicyclo[4.1.0]heptane-6-formic acid. The method comprises the following steps of: performing reflux alkylation reaction on conventional and readily available ethyl isonicotinate serving as a raw material and halohydrocarbon in alcohol solution to obtain quaternary ammonium; performing cyanoborohydride reaction to obtain amino-protected 1,2,3,6-tetrahydropyridine-4-ethyl formate; not performing purification, and directly performing ring-closing reaction to obtain a three-membered ring; and performing alkaline hydrolysis reaction to obtain amino-protected 3-aza-bicyclo[4.1.0]heptane-6-formic acid. The 3-aza-bicyclo[4.1.0]heptane-6-formic acid with the protective group is an important medicinal intermediate.
Description
Technical field:
The present invention relates to the synthetic method of a kind of aza-bicyclo of the 3-with protection [4.1.0] heptane-6-formic acid.
Background technology:
3-aza-bicyclo [4.1.0] heptane-6-formic acid is a kind of useful pharmaceutical intermediate; in document, the report synthetic method obtains through polystep reaction with the 4-alanine: first esterification; the allyl group alkylated amino of then protecting obtains compound 4; α-halogenated compound 4, then at catalyst P d (PPh
3)
4under existing, with 1, two dimethylamino naphthalene (proton sponge) agent treated of 8-obtain six-ring compound 6; Triatomic ring is closed out in last alkali effect, is hydrolyzed and obtains the required aza-bicyclo of the 3-with protecting group [4.1.0] heptane-6-formic acid.
The document synthetic route:
The synthetic route that document provides, step is long, and total recovery is low, severe reaction conditions, multistep needs column chromatography purification, and the raw material costliness, has limited the possibility of amplifying.
In document, allyl group alkylated need are placed in refrigerator, and we once attempted at room temperature to carry out, and obtain more dialkyl product, and after crude product is protected post on directly, yield was less than 30%.And the halogenating reaction yield also is low to moderate 20%, need under anhydrous and oxygen-free low temperature, carries out, and must use column chromatography purification.
Summary of the invention:
The synthetic method that the purpose of this invention is to provide the aza-bicyclo of the 3-with protecting group [4.1.0] heptane that a kind of synthetic route is short, overall yield is high, processing condition are gentle-6-formic acid, mainly solve the technical problem that needs the multistep column chromatography purification in existing 3-aza-bicyclo [4.1.0] heptane-6-formic acid preparation technology.
Technical scheme of the present invention:
The present invention be take, and iso ethyl nicotinate conventional, that be easy to get is raw material; become quaternary amine through the alkylated reaction refluxed with halohydrocarbon in alcoholic solution; through sodium borohydride, reaction obtains 1 of amido protecting again; 2; 3; 6-tetrahydropyridine-4-carboxylic acid, ethyl ester, then directly carry out ring closure reaction without purifying and close out triatomic ring, finally by alkaline hydrolysis, reacts 3-aza-bicyclo [4.1.0] heptane that obtains with protecting group-6-formic acid.
Concrete synthesis technique of the present invention is as follows:
In reaction formula, R is alkyl or acyl group, and X is halogen.
In process, in alkylated reaction, halohydrocarbon can select benzyl bromine, benzyl chlorine in order to easily remove in the back benzyl, also can be with other halohydrocarbon, and methyl iodide for example, alcoholic solution is preferentially selected ethanol or methyl alcohol, and optimal reaction temperature is 60-80 ℃.In the sodium borohydride reaction, solvent is ethanol or methyl alcohol, and the optimum mole ratio of sodium borohydride and reaction substrate is (1: 0.8)～(1: 1.1), and optimal reaction temperature is room temperature (10-30 ℃).Ring closure reaction can be selected diazomethane, palladium is made catalyzer, also can heat in dimethyl sulfoxide (DMSO) (DMSO) with NaH and Trimethylsulfoxonium Iodide, by column chromatography for separation, go out 3-aza-bicyclo [4.1.0] heptane of pure N-alkyl replacement-6-ethyl formate.The alkali that hydrolysis reaction adopts can be LiOH, NaOH, KOH etc. any one, hydrolysis reaction carries out in organic solvent and water mixed solvent, the organic solvent of employing can be selected methyl alcohol, ethanol or tetrahydrofuran (THF), temperature of reaction is 0-100 ℃.
Beneficial effect of the present invention:
Reaction process of the present invention is selected rationally, and it has adopted the raw material iso ethyl nicotinate be easy to get, and yield is than the height of bibliographical information, and only needs a step column chromatography purification.All reaction times is short, and the reaction conditions gentleness can obtain the target compound needed rapidly.Employing benzyl protection amino, more easily remove.
Embodiment:
The following example contributes to understand the present invention, but is not limited to content of the present invention.
embodiment 1
1,100g iso ethyl nicotinate (0.66mol) and 115g benzyl bromine (13.2mol) are mixed in 1L methyl alcohol, stir and be heated to 65 ℃ and reflux 12 hours, the solvent steaming is dissolved in 1L ethanol except the white solid obtained, be cooled to 0 ℃ to drip 25g sodium borohydride (6.5mol) the 100mL aqueous solution, drip off and at room temperature stir 1 hour, steaming desolventizes ethanol, resistates adds 2L methylene dichloride and 1L water, stirring and segregation, twice of 1L washing for dichloromethane layer, the 250mL saturated common salt is washed once, anhydrous Na
2sO
4drying, concentrating under reduced pressure obtains weak yellow liquid N-benzyl-1,2,3,6-tetrahydropyridine-4-ethyl formate (compound 10, R=Bn).Yield 98%.
28g sodium hydrogen (0.7mol) is suspended in the DMSO of 1.3L, in nitrogen protection, stirs and adds 153g (0.7mol) Trimethylsulfoxonium Iodide in batches, and the mixed solution of gained at room temperature stirs 1h.Drip 125g N-benzyl-1,2,3, the 500mL DMSO solution of 6-tetrahydropyridine-4-ethyl formate (0.51mol), drip off and be rapidly heated 110 ℃, and stir 3 hours at this temperature, (normal hexane: the volume percent of ethyl acetate=4: 1) detection reaction finishes TLC.Reaction solution is cooled to 30 ℃, is poured into the NH of 3L
4in the frozen water solution of Cl, stir, extract by ethyl acetate (1Lx3), extraction liquid merges washes secondary with 1L, and the 1L saturated common salt is washed once, anhydrous Na
2sO
4drying, concentrating under reduced pressure, residual oily matter with column chromatography purification obtain the faint yellow oily matter N-benzyl of 5.2g-3-aza-bicyclo [4.1.0] heptane-6-ethyl formate (compound 11, R=Bn), yield 3.9%.
2, in alkylated reaction, halohydrocarbon is methyl iodide, and solvent is ethanol, and in the sodium borohydride reaction, solvent is methyl alcohol, and all the other are identical with 1.
embodiment 2
By N-methyl isophthalic acid, 2,3,6-tetrahydropyridine-4-ethyl formate (10g, 59mmol) is dissolved in the 100mL ether, adds the 0.2g palladium, be cooled to 0 ℃, drip the dry diazomethane diethyl ether solution (250mL) of the approximately 0.5mol/L of fresh preparation, temperature is controlled at 0-2 ℃.Drip off under 25 ℃ and stir 12 hours.The unnecessary diazomethane with the acetic acid cancellation, reaction solution is mixed diatomite filtration, filtrate is concentrated into dry, mix purification by silica gel column chromatography obtain the required N-methyl of 500mg-3-aza-bicyclo [4.1.0] heptane-6-ethyl formate (compound 11, R=Me), yield 4.9%
embodiment 3
1,4.5g N-benzyl-3-aza-bicyclo [4.1.0] heptane-6-ethyl formate (compound 11, R=Bn, 17.4mmol) is dissolved in 100ml ethanol, adds 3.9g Boc
2o (17.8mmol) and 0.5g10%Pd (OH)
2/ C, mixed solution, at 45psi hydrogen, stirs hydrogenation 5 hours under room temperature, and (normal hexane: the volume percent of ethyl acetate=4: 1) detection reaction is complete for TLC.Reacting liquid filtering, concentrated obtain 4.3g white solid N-Boc-3-aza-bicyclo [4.1.0] heptane-6-ethyl formate (compound 11, R=Boc), yield 92%.
4.3g N-Boc-3-aza-bicyclo [4.1.0] heptane-6-ethyl formate (compound 11, R=Boc, 16mmol) be dissolved in 50mL methyl alcohol, drip the 50mL aqueous solution of 6.8g Lithium Hydroxide Monohydrate (160mmol), dripping off stirring heating refluxes 3 hours, cool to room temperature, most of methyl alcohol is removed in decompression, with the ether washing, removes neutral impurity.It is 2,30mL ethyl acetate extraction 3 times that the aqueous solution neutralizes the pH value with 5N dilute hydrochloric acid, and extracting solution merges with the washing of 30mL saturated common salt once, anhydrous Na
2sO
4drying, concentrating under reduced pressure obtain 3.7g white solid N-Boc-3-aza-bicyclo [4.1.0] heptane-6-formic acid (compound 1, R=Boc).Yield 96%.
2, the alkali that hydrolysis reaction adopts is sodium hydroxide, and organic solvent is tetrahydrofuran (THF), and all the other are identical with 1.
3, the hydrolysis reaction raw material is N-methyl-3-aza-bicyclo [4.1.0] heptane-6-ethyl formate, and the alkali of employing is NaOH, and organic solvent is methyl alcohol, 25 ℃ of reactions of room temperature 12 hours, and all the other are identical with 1.
Claims (4)
1. the synthetic method of the aza-bicyclo of the 3-with protecting group [4.1.0] heptane-6-formic acid, it is characterized in that, take iso ethyl nicotinate as raw material, become quaternary amine through the alkylated reaction refluxed with benzyl bromine or iodine methane in ethanol or methanol solution, through sodium borohydride, reaction obtains 1 of amido protecting again, 2,3,6-tetrahydropyridine-4-carboxylic acid, ethyl ester, then directly carry out ring closure reaction without purifying and close out triatomic ring, finally by alkaline hydrolysis, react 3-aza-bicyclo [4.1.0] heptane that obtains with protecting group-6-formic acid; Described protecting group is alkyl or acyl group; The sodium borohydride reaction is carried out in ethanol or methanol solvate, and the mol ratio of sodium borohydride and reaction substrate is (1:0.8)～(1:1.1); Ring closure reaction is one of following reaction: select diazomethane, palladium is made catalyzer, or heats in dimethyl sulfoxide (DMSO) with NaH and Trimethylsulfoxonium Iodide, by column chromatography for separation, goes out pure N-alkyl-3-aza-bicyclo [4.1.0] heptane-6-ethyl formate; The described alkali of hydrolysis reaction is a kind of in LiOH, NaOH or KOH, and hydrolysis reaction carries out in organic solvent and water mixed solvent, and organic solvent is selected from a kind of in methyl alcohol, ethanol or tetrahydrofuran (THF).
2. the aza-bicyclo of the 3-with protecting group according to claim 1 [4.1.0] heptane-6-formic acid synthetic method, is characterized in that, the alkylated reaction temperature is 60-80
0c.
3. a kind of aza-bicyclo of the 3-with protecting group according to claim 1 [4.1.0] heptane-6-formic acid synthetic method, is characterized in that, the sodium borohydride temperature of reaction is 0
oc-30
oc.
4. a kind of aza-bicyclo of the 3-with protecting group according to claim 1 [4.1.0] heptane-6-formic acid synthetic method, is characterized in that, hydrolysising reacting temperature is 0-100
oc.
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| CN104860870A (en) * | 2014-02-26 | 2015-08-26 | 欧美嘉股份有限公司 | Preparation method of piperidine with different substituents |
| CN104628644A (en) * | 2015-01-23 | 2015-05-20 | 常州大学 | 3-azabicyclo [4,1,0] heptyl aldehydes and preparation method thereof |
| CN110092753B (en) * | 2018-01-31 | 2022-04-26 | 南京药石科技股份有限公司 | Preparation method for synthesizing 3-azabicyclo [4.1.0] heptane-2-formic acid and hydrochloride thereof |
| CN109879797A (en) * | 2019-01-10 | 2019-06-14 | 安徽昊帆生物有限公司 | N- benzyl-tetrahydropyridines and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1198156A (en) * | 1995-09-28 | 1998-11-04 | 科研制药株式会社 | Process for preparation of 4-methylenepiperidines |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1198156A (en) * | 1995-09-28 | 1998-11-04 | 科研制药株式会社 | Process for preparation of 4-methylenepiperidines |
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Effective date of registration: 20170220 Address after: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Patentee after: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Patentee after: Yaomingkangde New Medicine Development Co., Ltd., Wuxi Patentee after: Shanghai SynTheAll Pharmaceutical Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Patentee before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Patentee before: Yaomingkangde New Medicine Development Co., Ltd., Wuxi |
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Address after: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Co-patentee after: Wuxi pharmatechs Limited by Share Ltd Patentee after: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Co-patentee after: Shanghai SynTheAll Pharmaceutical Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Co-patentee before: Yaomingkangde New Medicine Development Co., Ltd., Wuxi Patentee before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Co-patentee before: Shanghai SynTheAll Pharmaceutical Co., Ltd. |