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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- bicyclo
- heptane
- formic acid
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- 125000006239 protecting group Chemical group 0.000 title claims abstract description 11
- DIITVVANFKGDNX-UHFFFAOYSA-N 3-azabicyclo[4.1.0]heptane-6-carboxylic acid Chemical compound C1NCCC2(C(=O)O)C1C2 DIITVVANFKGDNX-UHFFFAOYSA-N 0.000 title abstract description 6
- 238000000034 method Methods 0.000 title abstract description 5
- 230000002194 synthesizing effect Effects 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 9
- 239000012279 sodium borohydride Substances 0.000 claims description 9
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 claims description 8
- 238000010189 synthetic method Methods 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- 229940064982 ethylnicotinate Drugs 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- MZFQJBMXUXJUHF-UHFFFAOYSA-N 4-azabicyclo[4.1.0]heptane Chemical compound C1CNCC2CC21 MZFQJBMXUXJUHF-UHFFFAOYSA-N 0.000 claims description 3
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 claims description 3
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 3
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical group 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- PKAUVIXBZJUYRV-UHFFFAOYSA-N methane;hydroiodide Chemical compound C.I PKAUVIXBZJUYRV-UHFFFAOYSA-N 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 7
- 150000005826 halohydrocarbons Chemical class 0.000 abstract description 5
- -1 cyanoborohydride Chemical compound 0.000 abstract description 3
- 238000010992 reflux Methods 0.000 abstract description 3
- 238000005804 alkylation reaction Methods 0.000 abstract 1
- 238000011097 chromatography purification Methods 0.000 abstract 1
- MCRPKBUFXAKDKI-UHFFFAOYSA-N ethyl pyridine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NC=C1 MCRPKBUFXAKDKI-UHFFFAOYSA-N 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 125000001453 quaternary ammonium group Chemical group 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- RMTDJEYZSNNPNM-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonyl]-3-azabicyclo[4.1.0]heptane-6-carboxylic acid Chemical compound C1N(C(=O)OC(C)(C)C)CCC2(C(O)=O)CC21 RMTDJEYZSNNPNM-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- KPUNOVLMCQQCSK-UHFFFAOYSA-N diazomethane;ethoxyethane Chemical compound C=[N+]=[N-].CCOCC KPUNOVLMCQQCSK-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- AJUXDFHPVZQOGF-UHFFFAOYSA-N n,n-dimethyl-1-naphthylamine Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1 AJUXDFHPVZQOGF-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102018600A CN102070526B (en) | 2009-11-24 | 2009-11-24 | Method for synthesizing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with protective group |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102018600A CN102070526B (en) | 2009-11-24 | 2009-11-24 | Method for synthesizing 3-aza-bicyclo[4.1.0]heptane-6-formic acid with protective group |
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| Publication Number | Publication Date |
|---|---|
| CN102070526A CN102070526A (en) | 2011-05-25 |
| CN102070526B true CN102070526B (en) | 2013-12-25 |
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| CN104860870A (en) * | 2014-02-26 | 2015-08-26 | 欧美嘉股份有限公司 | Preparation method of piperidines 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 | A kind of preparation method of synthesizing 3-azabicyclo[4.1.0]heptane-2-carboxylic acid and its hydrochloride |
| 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 |
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| CN1198156A (en) * | 1995-09-28 | 1998-11-04 | 科研制药株式会社 | The preparation method of 4-methylene piperidine |
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| CN1198156A (en) * | 1995-09-28 | 1998-11-04 | 科研制药株式会社 | The preparation method of 4-methylene piperidine |
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