CN111943893B - Synthesis method of 4, 7-diazaspiro [2,5] octane compound - Google Patents
Synthesis method of 4, 7-diazaspiro [2,5] octane compound Download PDFInfo
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- -1 4, 7-diazaspiro [2,5] octane compound Chemical class 0.000 title claims abstract description 16
- 238000001308 synthesis method Methods 0.000 title description 7
- 238000000034 method Methods 0.000 claims abstract description 32
- 125000006239 protecting group Chemical group 0.000 claims abstract description 29
- 238000005886 esterification reaction Methods 0.000 claims abstract description 15
- 238000006467 substitution reaction Methods 0.000 claims abstract description 15
- RLPYXXBIHMUZRE-UHFFFAOYSA-N 4,7-diazaspiro[2.5]octane Chemical class C1CC11NCCNC1 RLPYXXBIHMUZRE-UHFFFAOYSA-N 0.000 claims abstract description 14
- XINDIUOJBNUZMM-UHFFFAOYSA-N 7-benzyl-4,7-diazaspiro[2.5]octane Chemical compound C=1C=CC=CC=1CN(C1)CCNC21CC2 XINDIUOJBNUZMM-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 8
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 6
- 230000032050 esterification Effects 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 30
- 239000002585 base Substances 0.000 claims description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 6
- 238000010189 synthetic method Methods 0.000 claims 4
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 238000004809 thin layer chromatography Methods 0.000 description 16
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000007529 inorganic bases Chemical class 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 150000007530 organic bases Chemical class 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000007086 side reaction Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 239000012434 nucleophilic reagent Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- 150000003141 primary amines Chemical group 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- XXKCYKIJWLFVDG-UHFFFAOYSA-N tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCNC11CC1 XXKCYKIJWLFVDG-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a method for synthesizing 4, 7-diazaspiro [2,5] octane compounds, which takes derivatives of 4-methoxybenzyl (1- (hydroxymethyl) cyclopropyl) carbamate as raw materials, and obtains the 4, 7-diazaspiro [2,5] octane compounds through substitution, addition of protecting groups, esterification, re-substitution and deprotection. The final cyclization reaction of the synthetic route directly obtains 4, 7-diazaspiro [2.5] octane compounds (such as 7-benzyl-4, 7-diazaspiro [2.5] octane in the scheme), thereby avoiding the problem of reduction of carbon-oxygen double bonds in the prior literature.
Description
Technical Field
The patent relates to the field of synthesis of pharmaceutical chemistry, provides a synthesis method of 4, 7-diazaspiro [2.5] octane compounds, and more particularly relates to a synthesis method of 7-benzyl-4, 7-diazaspiro [2.5] octane.
Description of the background
4, 7-Diazaspiro [2.5] octane compound is an important pharmaceutical chemical intermediate, and the published chemical synthesis method is a method for synthesizing 4, 7-diazaspiro [2.5] octane-7-tert-butyl formate published by China patent CN 105111155A; and a synthesis method of 4, 7-diazaspiro [2.5] octane derivative series (comprising 4, 7-diazaspiro [2.5] octane-7-carboxylic acid tert-butyl ester and 7-benzyl-4, 7-diazaspiro [2.5] octane) published by Chinese patent CN 108863958A.
In both of these synthetic routes, there is a need to use boron trifluoride diethyl etherate to effect reduction of carbon-oxygen double bonds with sodium borohydride. Boron trifluoride diethyl etherate has the characteristics of corrosiveness, high toxicity, flammability and explosiveness, and limits the application of the reduction reaction in industrial mass production.
Disclosure of Invention
The patent aims to provide a novel synthesis method of 4, 7-diazaspiro [2.5] octane compounds. More particularly, the present patent provides a method for synthesizing 7-benzyl-4, 7-diazaspiro [2.5] octane.
The patent relates to the field of synthesis of pharmaceutical chemistry, and provides a synthesis method of 4, 7-diazaspiro [2.5] octane compounds, wherein the chemical structural formula of the compounds is shown as follows:
Wherein R 1,R2 may be any protecting group that facilitates removal in subsequent production syntheses, including but not limited to protecting groups such as esters, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, and the like. In the synthetic route of the invention, the R 1 protecting group is benzyl, C 1-C6 ester group, tert-butoxycarbonyl, benzyl or benzyloxycarbonyl, and the R 2 position is free of protecting group, specifically H; in the specific synthetic route of the patent, the R 1 protecting group is benzyl, the R 2 position is not provided with the protecting group, and the chemical name of the specific substance is 7-benzyl-4, 7-diazaspiro [2.5] octane.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
the invention provides a method for synthesizing 4, 7-diazaspiro [2.5] octane compounds, which takes derivatives of 4-methoxybenzyl (1- (hydroxymethyl) cyclopropyl) carbamate as raw materials, and obtains the 4, 7-diazaspiro [2.5] octane compounds shown in a formula V through substitution, addition of protecting groups, esterification and deprotection, wherein the reaction route is as follows:
Wherein R 1 is benzyl, C 1-C6 ester group, tert-butyloxycarbonyl, benzyl or benzyloxycarbonyl, X is halogen; r 1 is more preferably benzyl, and X is more preferably bromine.
The reaction route described in the present invention can be applied to the preparation of chemical substances represented by the general formula V.
In a specific embodiment, the invention also provides a method for synthesizing 7-benzyl-4, 7-diazaspiro [2.5] octane, which takes (1- (((4-methoxybenzyl) oxy) carbonyl) amino) cyclopropyl) methyl methanesulfonate (compound I) as a raw material, and obtains 7-benzyl-4, 7-diazaspiro [2.5] octane shown in a formula V-1 through substitution, addition of a protecting group, esterification and deprotection, wherein the reaction route is as follows:
Starting materials: in the embodiments described in this patent, we have chosen derivatives of 4-methoxybenzyl (1- (hydroxymethyl) cyclopropyl) carbamate as starting materials. More specifically, in the specific synthetic route of the present patent, (1- ((((4-methoxybenzyl) oxy) carbonyl) amino) cyclopropyl) methyl methanesulfonate (compound I) is preferable as a starting material.
Formation of Compound II:
The derivatives of 4-methoxybenzyl (1- (hydroxymethyl) cyclopropyl) carbamate of the present invention undergo substitution to form compound II, in one embodiment, the substitution reaction of the present invention is specifically: dissolving the compound I and a nucleophilic reagent in an organic solvent according to a certain proportion, adding alkali, and stirring to react to generate the compound II.
The mesylate (MsO-) in the starting material compound I is an excellent leaving group, and in the specific experimental scheme, the nucleophilic reagent used in the invention is ethanolamine with relatively stable chemical property and low price, and under the attack of ethanolamine as nucleophilic reagent, the mesylate (MsO-) is easy to leave and undergo substitution reaction.
The nucleophile used in the substitution reaction according to the invention is added in excess, calculated on the molar amount of the reactant compound I, and the nucleophile may be added in any amount greater than 1 time the molar amount of the compound I, for example in a molar amount of from 2 to 6 times. The molar amount is preferably 2 times in this particular protocol.
The substitution reaction of the invention requires a base as an acid-binding agent for absorbing the methanesulfonic acid produced by the reaction, the base may be an inorganic base or an organic base, for example, the inorganic base may be sodium carbonate, potassium carbonate or sodium acetate, and the organic base may be pyridine, N-diisopropylethylamine or triethylamine, etc. The preferred base in this particular protocol is an inorganic base, more preferably potassium carbonate.
The base used in the substitution reaction of the present invention needs to be added in excess, and the amount of the base to be added may be any amount larger than 1 time the molar amount of the compound I, for example, 2 to 6 times the molar amount, based on the molar amount of the reactant compound I. The molar amount is preferably 3 times in this particular protocol.
The organic solvent used in the substitution reaction of the present invention may optionally be selected from organic solvents which have a certain solubility to inorganic bases and do not have any side reaction with the added reagents, including but not limited to organic solvents such as ethanol, isopropanol, acetonitrile, acetone, ethyl acetate, etc. In this particular embodiment, the organic solvent is preferably acetonitrile.
In a particular protocol of the present experiment, starting compound I, nucleophile, base are fed in a preferred molar ratio of 1:2:3 and stirred at room temperature until TLC thin layer chromatography shows complete starting reaction.
In one embodiment, the reaction equation is:
formation of Compound III or III-1:
The compounds II according to the invention are reacted with a halide of a protecting group in the presence of a base to give the compounds III or III-1.
In the product compound II obtained by the substitution reaction, the ethanolamine molecule replaces a hydrogen atom on the amine NH of the amine which is generated after the methanesulfonate group, and the amine is protected by adding a proper protecting group so as to avoid side reactions in the subsequent operation. These possible protecting groups include, but are not limited to, C 1-C6 ester groups, t-butoxycarbonyl groups, benzyl groups, benzyloxycarbonyl groups, and the like. In this particular embodiment, benzyl is preferred as protecting group. In one embodiment, the halide of the protecting group is benzyl bromide.
In the reaction of adding the protecting group in this patent, the halide of the protecting group needs to be added in excess, and the amount of benzyl bromide added may be any amount greater than 1 time the molar amount of compound II, for example, 2 to 6 times the molar amount, calculated on the molar amount of compound II. The molar amount is preferably 3 times in this particular protocol.
In the reaction of adding the protecting group, a base is added as an acid-binding agent to absorb hydrogen bromide acidic gas generated in the reaction, wherein the base can be inorganic base or organic base, for example, the inorganic base can be sodium carbonate, potassium carbonate or sodium acetate, and the organic base can be pyridine, N-diisopropylethylamine or triethylamine, and the like. In the specific experimental scheme of the experiment, for the purpose of saving cost, the same alkali as the previous reaction can be directly selected as the acid binding agent.
The base in the reaction of adding the protecting group of this patent needs to be added in excess, and the amount of the base to be added may be any amount larger than 1 time the molar amount of the compound II, for example, 2 to 6 times the molar amount, based on the molar amount of the compound II. The molar amount is preferably 3 times in this particular protocol.
The organic solvent used in the reaction of adding a protecting group according to the present invention may optionally be selected from organic solvents which have a certain solubility to inorganic bases and do not have any side reaction with the added reagents, including but not limited to organic solvents such as ethanol, isopropanol, acetonitrile, acetone, ethyl acetate, etc. In this particular embodiment, the organic solvent is preferably acetonitrile.
In a specific protocol of this experiment, the starting compound II, benzyl bromide, potassium carbonate are fed in the preferred molar ratio of 1:3:3 in an appropriate amount of organic solvent and stirred at room temperature until TLC thin layer chromatography shows complete reaction of the starting materials.
In one embodiment, the reaction equation is:
Formation of Compound IV or IV-1:
The compound III or III-1 of the invention undergoes esterification reaction to produce the compound IV or IV-1.
The free hydroxyl groups in the compounds III or III-1 according to the invention can be converted under suitable conditions into methanesulfonates.
In one embodiment, compound III or III-1 is esterified with methanesulfonyl chloride in the presence of a base to form compound IV or IV-1.
The methanesulfonyl chloride was added in excess in the particular protocol of this experiment. The methanesulfonyl chloride may be added in any amount greater than 1-fold molar amount, for example 2-4-fold molar amount, calculated on the molar amount of compound III. The molar amount of 1.5 times is preferred in this particular protocol.
The esterification reaction of the invention uses a base as an acid binding agent to absorb hydrogen chloride gas generated in the reaction, wherein the base can be inorganic base or organic base, for example, the inorganic base can be sodium carbonate, potassium carbonate or sodium acetate, and the organic base can be pyridine, N-diisopropylethylamine or triethylamine. In this experimental scheme, the organic base triethylamine is preferred as the acid-binding agent.
The addition of the base for the esterification reaction of the present invention requires an excess, calculated as the molar amount of compound III, and the base addition amount may be any amount greater than 1 time the molar amount, for example, 2 to 6 times the molar amount. The preferred molar amount in this particular protocol is 3-fold.
The esterification reaction of the present invention is preferably carried out at a reaction temperature of 0 to 20 degrees celsius, more preferably 0 to 10 degrees celsius.
The solvent for the esterification reaction of the present invention is an organic solvent which has good solubility for the reactants and does not have any side reaction with the added reagent, and includes, but is not limited to, methylene chloride, dioxane, tetrahydrofuran, etc. In this particular embodiment, the organic solvent is preferably methylene chloride. In one embodiment, the reaction equation is:
formation of Compound V or V-1:
The p-methoxybenzyloxycarbonyl protecting group of the compound IV or IV-1 is unstable under a strong acid condition, and under a proper acid condition, the protecting group can be removed to expose a free primary amine group (-NH 2), and then the free primary amine group and the excellent leaving group methanesulfonic acid group in the molecule undergo intramolecular nucleophilic substitution reaction to conduct ring closure, so that the compound V or V-1, such as a hexacyclic compound 7-benzyl-4, 7-diazaspiro [2.5] octane, is formed.
The acidic conditions of the deprotection of the present invention may be common inorganic strong acids such as hydrochloric acid or common organic strong acids such as trifluoroacetic acid. In the experimental scheme, organic strong acid trifluoroacetic acid is preferable, and the trifluoroacetic acid can be directly used or can be dissolved in a proper organic solvent according to a certain proportion for use. In a particular protocol of this experiment, a 5% solution of trifluoroacetic acid in dichloromethane was used.
In one specific example, compound V was directly dissolved in an appropriate amount of 5% trifluoroacetic acid in dichloromethane and stirred at room temperature to effect reaction until TLC showed complete reaction of the starting materials.
In one specific embodiment, the reaction equation is:
this patent is relative prior art's advantage:
In both the patent CN105111155A and the patent CN108863958a mentioned in the introduction, there is finally a one-step reduction of the carbon-oxygen double bonds in the amide molecules with a reducing agent to give the product. And both of them use boron trifluoride diethyl etherate which is inflammable and explosive and has corrosive toxicity to cooperate with sodium borohydride for reduction reaction.
The final cyclization reaction in the synthetic route directly obtains 4, 7-diazaspiro [2.5] octane compounds (such as 7-benzyl-4, 7-diazaspiro [2.5] octane in the scheme), thereby avoiding the problem of reduction of carbon-oxygen double bonds in the literature. Abbreviations and nouns of the invention are explained below, unless otherwise indicated:
Tlc=thin-layer chromatography =thin layer chromatography.
Rf value: in thin layer chromatography, the ratio of the distance between the movement of the substance to be measured from the starting point to the final stop position to the maximum distance of movement of the developing agent.
G=gram=gram; mg= milligram =mg.
Mol = moles; mmol= millimole =mmol.
L=lite=liter; ml= milliliter =ml.
Detailed Description
The invention is further illustrated below with reference to examples. It should be understood that the following examples are presented merely to provide a more clear illustration of the experimental procedure and are not intended to limit other possible experimental methods of operation. It is easy for a person skilled in the art to modify the experimental procedure to a different extent to obtain similar experimental results. Because of the limited article space, it is not possible to enumerate all the possibilities one by one. Such simple but obvious variations or modifications remain within the scope of this patent.
Example 1 preparation of compound II:
In a 50mL round bottom flask was added Compound I (509 mg,1.5 mmol), ethanolamine (188 mg,3.0 mmol), potassium carbonate (640 mg,4.6 mmol) and acetonitrile (20 mL.) the resulting mixture was reacted at room temperature until TLC thin layer chromatography showed complete reaction of starting compound I and the formation of a more polar new product, typically in the range of 2 to 3 hours.
The resulting suspension was filtered, the filter cake was rinsed with dichloromethane and the filtrates were combined. The filtrate was concentrated, evaporated to dryness, dissolved again in an appropriate amount of dichloromethane and washed with water and saturated brine in this order, and the organic phase was dried over anhydrous sodium sulfate solid and concentrated to give the product (389 mg,1.3 mmol) as an oil in 87% yield.
Experimental data:
rf value: 0.1 (developer-dichloromethane: methanol=9:1).
ESI-MS：[M+H]+＝295.0
Example 2
Preparation of Compound III-1:
to a25 mL round bottom flask was added the product compound II from example 1 (190 mg,0.65 mmol), benzyl bromide (331 mg,1.95 mmol), potassium carbonate (270 mg,1.95 mmol) and acetonitrile (5 mL). The reaction is carried out at room temperature after the completion of the addition until TLC thin layer chromatography shows complete reaction of starting compound II, which reaction takes typically 1 to 2 hours.
The obtained reaction solution is filtered to remove solids, and the filter cake is rinsed with a proper amount of acetonitrile and the filtrates are combined. After acetonitrile in the filtrate was removed by rotary evaporation, the filtrate was dissolved in an appropriate amount of methylene chloride, and the solution was washed with an appropriate amount of water and saturated brine in this order, and dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation again, the product was purified by silica gel column chromatography to give a pure product (97 mg,0.25 mmol) of compound III in 54% yield.
Experimental data:
rf value: 0.15 (developer-hexane: ethyl acetate=1:1).
ESI-MS：[M+H]+＝385.2
Example 3
Preparation of Compound IV-1:
To a 25mL round bottom flask was added the product compound III from example 2 (20 mg,0.05 mmol), triethylamine (15 mg,0.15 mmol) and dichloromethane (5 mL). After the obtained solution was cooled to 0 to 10℃in an ice-water bath, methanesulfonyl chloride (12 mg,0.10 mmol) was slowly added dropwise. After the addition was complete, the reaction was continued in an ice water bath at 0-10 ℃ for about 30min until TLC thin layer chromatography showed complete reaction of starting compound III.
Rf value: 0.45 (developer-dichloromethane: methanol=19:1).
ESI-MS：[M+H]+＝463.2
Example 4
Preparation of Compound V-1:
A25 mL round bottom flask was charged with the product compound IV-1 from example 3 (33 mg,0.067 mmol) and a solution of 5% trifluoroacetic acid in dichloromethane (1.5 mL). The resulting solution was stirred at room temperature for two hours until TLC thin layer chromatography showed complete reaction of starting compound IV-1 and the formation of a new product.
The obtained reaction solution is filtered to remove solids, and the filter cake is rinsed with a proper amount of acetonitrile and the filtrates are combined. After acetonitrile in the filtrate was removed by rotary evaporation, it was dissolved in an appropriate amount of methylene chloride, and the solution was washed with an appropriate amount of water and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was removed by rotary evaporation again, the product was purified by silica gel column chromatography to give a pure product (9.5 mg,0.047 mmol) of compound VI in 70% yield.
Rf value: 0.15 (developer-dichloromethane: methanol=9:1).
ESI-MS：[M+H]+＝203.2
Claims (31)
- The method for synthesizing 1.4,7-diazaspiro [2.5] octane compounds is characterized in that 4, 7-diazaspiro [2.5] octane compounds shown in formula V are obtained by taking derivatives of 4-methoxybenzyl (1- (hydroxymethyl) cyclopropyl) carbamate as raw materials, and carrying out substitution, addition of protecting groups, esterification and deprotection, wherein the reaction route is as follows:Wherein R 1 is benzyl, C 1-C6 ester group, tert-butyloxycarbonyl, benzyl or benzyloxycarbonyl, and X is halogen.
- 2. The method for synthesizing 4, 7-diazaspiro [2.5] octane-based compound according to claim 1, wherein R 1 is benzyl.
- 3. The method for synthesizing 4, 7-diazaspiro [2.5] octane-based compound according to claim 1, wherein X is bromine.
- 4. A synthetic method of 7-benzyl-4, 7-diazaspiro [2.5] octane is characterized in that (1- ((((4-methoxybenzyl) oxy) carbonyl) amino) cyclopropyl) methyl mesylate is used as a raw material, and 7-benzyl-4, 7-diazaspiro [2.5] octane shown in a formula V-1 is obtained through substitution, addition of a protecting group, esterification and deprotection, and the reaction route is as follows:
- 5. The synthetic method according to any one of claims 1 to 4, wherein the substitution reaction is specifically: dissolving the compound I and ethanolamine in an organic solvent according to a certain proportion, adding alkali, and stirring to react to generate the compound II.
- 6. The method according to claim 5, wherein the molar amount of ethanolamine added is greater than 1 time the molar amount of compound I.
- 7. The method according to claim 6, wherein the molar amount of ethanolamine added is 2 to 6 times the molar amount of compound I.
- 8. The method according to claim 5, wherein the base is sodium carbonate, potassium carbonate, sodium acetate, pyridine, N-diisopropylethylamine or triethylamine.
- 9. The method of synthesis according to claim 5, wherein the base is added in a molar amount greater than 1 time the molar amount of compound I.
- 10. The synthesis according to claim 9, wherein the molar addition of the base is 2 to 6 times the molar amount of compound I.
- 11. The method according to claim 5, wherein the organic solvent is ethanol, isopropanol, acetonitrile, acetone or ethyl acetate.
- 12. The method according to any one of claims 1 to 4, wherein the addition of the protecting group is specifically: the compound II reacts with halogenide of the protecting group in the presence of alkali to generate a compound III or III-1.
- 13. The method of claim 12, wherein the protecting group is selected from the group consisting of C 1-C6 ester group, t-butoxycarbonyl group, benzyl group and benzyloxycarbonyl group.
- 14. The method of claim 13, wherein the protecting group is benzyl.
- 15. The method of claim 12, wherein the molar addition of the halide of the protecting group is greater than 1 molar amount of compound II.
- 16. The method of claim 15, wherein the molar addition of the halide of the protecting group is 2 to 6 times the molar amount of compound II.
- 17. The method of claim 12, wherein the base is sodium carbonate, potassium carbonate, sodium acetate, pyridine, N-diisopropylethylamine or triethylamine.
- 18. The method of claim 12, wherein the base is added in a molar amount greater than 1 time the molar amount of compound II.
- 19. The synthetic method of claim 18 wherein the base is added in a molar amount of 2 to 6 times the molar amount of compound II.
- 20. The method according to claim 12, wherein the organic solvent used for the addition of the protecting group is ethanol, isopropanol, acetonitrile, acetone or ethyl acetate.
- 21. The method according to any one of claims 1 to 4, wherein the esterification reaction is specifically: the compound III or III-1 and methanesulfonyl chloride are subjected to esterification reaction in the presence of alkali to generate the compound IV or IV-1.
- 22. The method of claim 21, wherein the methanesulfonyl chloride is added in a molar amount greater than 1-fold molar amount of compound III.
- 23. The method of synthesis according to claim 22, wherein the molar amount of methanesulfonyl chloride added is 2 to 4 times the molar amount of compound III.
- 24. The method of claim 21, wherein the base is sodium carbonate, potassium carbonate, sodium acetate, pyridine, N-diisopropylethylamine or triethylamine.
- 25. The method of claim 21, wherein the base is added in a molar amount greater than 1 time the molar amount of compound III.
- 26. The synthetic method of claim 25 wherein the base is added in a molar amount of 2 to 6 times the molar amount of compound III.
- 27. The method of claim 21, wherein the esterification reaction is carried out at a reaction temperature of 0 to 20 ℃.
- 28. The method of claim 27, wherein the esterification reaction is carried out at a temperature of 0 to 10 ℃.
- 29. The method of claim 21, wherein the solvent for the esterification reaction is methylene chloride, dioxane or tetrahydrofuran.
- 30. The method according to any one of claims 1 to 4, wherein the deprotecting group is specifically: under proper acidic condition, the compound IV or IV-1 is subjected to ring closure by removing the p-methoxybenzyloxycarbonyl protecting group and the excellent leaving group methanesulfonic acid group in the molecule to generate intramolecular nucleophilic substitution reaction, so that the compound V or V-1 is formed.
- 31. The method of claim 30, wherein the acid used in the acidic condition is hydrochloric acid or trifluoroacetic acid.
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| CN105111155A (en) * | 2015-08-31 | 2015-12-02 | 武汉工程大学 | Synthesis method of tert-butyl 4,7-diazaspiro[2.5]octyl-7-formate |
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| CN106749233B (en) * | 2016-11-24 | 2020-04-21 | 中山大学 | Sulfonamide derivatives and application thereof |
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| CN105111155A (en) * | 2015-08-31 | 2015-12-02 | 武汉工程大学 | Synthesis method of tert-butyl 4,7-diazaspiro[2.5]octyl-7-formate |
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