CN117865969A - Preparation method of 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate - Google Patents
Preparation method of 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate Download PDFInfo
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- CN117865969A CN117865969A CN202311701496.0A CN202311701496A CN117865969A CN 117865969 A CN117865969 A CN 117865969A CN 202311701496 A CN202311701496 A CN 202311701496A CN 117865969 A CN117865969 A CN 117865969A
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- diazabicyclo
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 7
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229940126214 compound 3 Drugs 0.000 claims abstract description 15
- 229940125782 compound 2 Drugs 0.000 claims abstract description 14
- 229940125904 compound 1 Drugs 0.000 claims abstract description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 6
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 6
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- PSDAEKDIOQXLLC-UHFFFAOYSA-N tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC2CCC1N2 PSDAEKDIOQXLLC-UHFFFAOYSA-N 0.000 claims description 9
- PWAXUOGZOSVGBO-UHFFFAOYSA-N adipoyl chloride Chemical compound ClC(=O)CCCCC(Cl)=O PWAXUOGZOSVGBO-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 238000005886 esterification reaction Methods 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 239000001361 adipic acid Substances 0.000 claims description 7
- 235000011037 adipic acid Nutrition 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 230000031709 bromination Effects 0.000 claims description 6
- 238000005893 bromination reaction Methods 0.000 claims description 6
- 239000002904 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
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 238000005580 one pot reaction Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 238000007142 ring opening reaction Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- PSDAEKDIOQXLLC-DTORHVGOSA-N tert-butyl (1r,5s)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)C[C@@]2([H])CC[C@]1([H])N2 PSDAEKDIOQXLLC-DTORHVGOSA-N 0.000 claims 2
- 239000000243 solution Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- LKDJYZBKCVSODK-UHFFFAOYSA-N 3,8-diazabicyclo[3.2.1]octane Chemical compound C1NCC2CCC1N2 LKDJYZBKCVSODK-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ROVTUJRZGCDHDL-UHFFFAOYSA-N tert-butyl 2-ethylheptanoate Chemical compound CCCCCC(CC)C(=O)OC(C)(C)C ROVTUJRZGCDHDL-UHFFFAOYSA-N 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- -1 bicyclic compound Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000010779 crude oil Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 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 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 108700023159 delta Opioid Receptors Proteins 0.000 description 1
- 102000048124 delta Opioid Receptors Human genes 0.000 description 1
- 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 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000001291 vacuum drying 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
Abstract
The application discloses a preparation method of 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate, which comprises the following steps: step one: closing the ring of the compound 1 with benzyl amine under alkaline conditions, and then hydrolyzing under acidic conditions to obtain a compound 2; step two: closing the ring of the compound 2 under the condition of anhydride to form internal anhydride, then opening the ring by ammonia water to form a monoamide structure, and then closing the ring by CDI to obtain a compound 3; step three: the compound 3 is reduced, protected by Boc and Pd/C deblocked in sequence to obtain the 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate.
Description
Technical Field
The application relates to the technical field of chemical synthesis, in particular to a preparation method of 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate.
Background
3, 8-diazabicyclo [3.2.1]Octane (DBO) is a flexible limited piperazine with internal ethylenic bridges, whose 3, 8-disubstituted has high affinity and selectivity for delta-opioid receptors with potent analgesic activity. 3, 8-diazabicyclo [3.2.1]Octane-3-carboxylic acid tert-butyl ester and 3, 8-diazabicyclo [3.2.1] as an important precursor thereof]The structural formula of the octane-3-carboxylic acid tert-butyl ester is as follows:
in the prior art, the literature reports the synthesis methods mainly including the following steps:
the method comprises the following steps: document EP1178047 reports a process for the synthesis of 3, 8-diazabicyclo [3.2.1] octane, the synthetic route being as follows,
the method takes a compound I as a starting material, and prepares a bicyclic compound as a compound II through cyclizing of benzylamine, reduction of lithium aluminum hydride, chlorination of a chlorinating reagent and cyclizing of aniline. The method has the advantages of large reducing agent consumption, high cost and incapability of ensuring the yield.
The second method is as follows: the document org. Process res. Dev.,2021,25,1419-1430 reports one, the synthetic route is as follows,
the method takes 2, 5-dibromo diethyl adipate as an initial raw material, and realizes the synthesis of the compound III through the steps of cyclization, enzyme catalysis, ring closure, reduction and the like.
In addition, the literature arch.pharm.pharm.med.chem.2003,336,510-513 reports a method for preparing 3, 8-diazabicyclo [3.2.1] octane by a medium chemistry method, but this method also has disadvantages such as low ring closure yield and high cost.
Content of the application
The purpose of the application is to provide a preparation method of 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate, which is simple and efficient, and the prepared 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate has high purity and high yield.
In order to achieve the above purpose, the present application provides the following technical solutions: a preparation method of 3, 8-diazabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester, which comprises the following steps:
step one: closing the ring of the compound 1 with benzyl amine under alkaline conditions, and then hydrolyzing under acidic conditions to obtain a compound 2;
step two: closing the ring of the compound 2 under the condition of anhydride to form internal anhydride, then opening the ring by ammonia water to form a monoamide structure, and then closing the ring by CDI to obtain a compound 3;
step three: reducing the compound 3, protecting by Boc and removing benzyl by Pd/C to obtain 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate;
the structural formulas of the compound 1, the compound 2 and the compound 3 are shown as follows:
preferably, adipic acid is reacted with thionyl chloride to prepare adipoyl chloride, and the adipoyl chloride is subjected to bromination by a bromination reagent and then esterification reaction with an esterification reagent to obtain the compound 1.
Preferably, the brominating reagent is bromine or NBS, and the esterifying reagent is an alcohol reagent.
Preferably, when preparing adipoyl chloride, the molar weight ratio of adipic acid to thionyl chloride is 1:2-4, the adipoyl chloride is subjected to bromine adding at the 2-position and the 5-position through bromine, the reaction temperature is controlled at 80-90 ℃ during bromine adding, the reaction time is 1-6 hours, and the compound 1 is obtained through esterification reaction between the adipic acid and an esterification reagent after bromine adding.
Preferably, adipic acid and thionyl chloride with the molar ratio of 1:2-3 are stirred at 50-60 ℃ for 2-3 hours, and then the reaction solution is concentrated; heating the concentrate to 85-95 ℃, dropwise adding bromine, and preserving heat for 2-3 hours after the dropwise adding is finished; dropwise adding the reaction solution into ethanol at 0-10 ℃, and stirring at 20-30 ℃ for 16-24 hours under heat preservation to obtain the compound 1.
Preferably, in the first step, the solvent used for the ring-closing reaction of the compound 1 and the benzylamine under the alkaline condition is at least one of toluene, tetrahydrofuran or ethyl acetate, the inorganic base used under the alkaline condition is at least one of sodium carbonate, potassium carbonate or potassium tert-butoxide, the acid used under the acidic condition is at least one of hydrochloric acid, sulfuric acid or trifluoroacetic acid, and the synthetic route of the first step is as follows:
preferably, the molar ratio of compound 1 to benzylamine is 1:1-2.
Preferably, the synthetic route of the second step is as follows,
in the second step, the solvent adopted in the ring opening process to form the monoamide structure is at least one of dichloromethane, chloroform or tetrahydrofuran, and the solvent adopted in the ring closing process through CDI is at least one of tetrahydrofuran, diethyl ether or toluene.
Preferably, in the third step, the reducing agent used for reducing the compound 3 is at least one of lithium aluminum tetrahydroide, borohydride or red aluminum.
Preferably, step three: the compound 3 is sequentially reduced, protected by Boc and removed by Pd/C to obtain 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate, a one-pot method is adopted, and the intermediate does not undergo a refining process, and the synthetic route is as follows:
compared with the prior art, the beneficial effects of this application are: the preparation method of the 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate synthesizes the azabicyclo under the condition of not using a biological enzyme method, has simple operation, higher reaction yield and low cost, and has important significance for industrially producing the compound with the 3, 8-diazabicyclo structure.
Detailed Description
The following description of the embodiments of the present application will be made clearly and fully, and it is apparent that the embodiments described are only some, but not all, of the embodiments of the present application. All other embodiments, which can be made by one of ordinary skill in the art without undue burden from the present disclosure, are within the scope of the present disclosure.
Example 1
Step one: compound 1 was synthesized as follows:
specifically, adipic acid (100.0 g;684mmol;1.0 eq) and SOCl were put into a reaction flask 2 (224.0 g;1883mmol;2.75 eq.) with stirring, heating to 50-60 ℃, and maintaining for 2h; after the reaction solution was completely dissolved, the reaction solution was concentrated in a 55℃water bath under reduced pressure to remove SOCl 2 The method comprises the steps of carrying out a first treatment on the surface of the Concentrating to obtain acyl chloride; heating to 85-95 ℃, slowly dripping Br into acyl chloride 2 (248.0 g;1552mmol;2.27 eq), controlling the temperature at 85-95 ℃ after dripping, preserving the temperature for 2h, sampling and controlling; after the central control reaction is finished, cooling the reaction solution to 20-30 ℃ to obtain bromide, wherein the temperature is controlled to be 0-20 ℃, and the bromide is dripped into 316g of ethanol; after the dripping is finished, heating to 20-30 ℃, and preserving heat for 20h; then controlling the temperature to be 20-30 ℃, and dropwise adding 2% NaHSO into the reaction liquid 3 The water solution (500 mL) is used for separating out a large amount of solids, the temperature is kept for 1h, the filtration is carried out, and the filter cake is rinsed with water (100 mL); subsequently, the mixture was dissolved in DCM (500 mL) and purified with 2% Na2CO 3 The organic layer was separated and concentrated in vacuo to give 209.4g of Compound 1 in 85% yield as a white solid in appearance.
Step two: compound 2 was synthesized as follows:
k is put into a reaction bottle 2 CO 3 (77.0 g;557mmol;2.0 eq), water (600 mL), stirring the solution; toluene (300 mL), compound 1 synthesized in step one (100.0 g; 274 mmol;1.0 eq.) and benzylamine (36.0 g;336mmol;1.2 eq.) were added to the solution, stirred and warmed to reflux and incubated for 20h; cooling to 20-30deg.C after the reaction is completed, and layering; the aqueous layer was extracted with toluene (300 mL), the organic layers were combined, washed twice with 3% aqueous citric acid (500 mL), the organic layer was taken, washed twice with saturated brine (500 mL), the organic layer was concentrated in vacuo to give 84.0g of a yellow crude oil, 605.0g of concentrated hydrochloric acid was added to the yellow crude oil, the mixture was warmed to reflux and kept warm for 3h, after the reaction was completed, the temperature was lowered to 20-30 ℃, stirred and crystallized for 16h, suction filtration was performed, and the filter cake was rinsed with water (100 mL). Adding water (360 mL) into the filter cake, heating to 90-95 ℃, stirring and clearing, preserving heat for half an hour, cooling to 20-30 ℃, stirring and crystallizing for 2h, filtering, and leaching the filter cake with water (100 mL); the filter cake was dried in vacuo at 50 ℃ for 16h to give 48.46g of compound 2 in a total yield of 70% in two steps as a white solid in appearance.
Step three: compound 3 was synthesized as follows:
adding a compound 2 (100.0 g;401mmol;1.0 eq.) and acetic anhydride (1000.0 g) into a reaction bottle, wherein the molar ratio of the compound 2 to the acetic anhydride is 1:10-1:40, preferably 1:20-1:25, then heating to 90-100 ℃, and preserving heat for 2 hours until the system is completely dissolved; cooling, and concentrating acetic anhydride under reduced pressure at 60-65deg.C; after the concentration is finished, cooling to 20-30 ℃, adding dichloromethane (300 mL), stirring and dissolving, and dropwise adding ammonia water (400 g) into the mixture, wherein the molar ratio of the compound 2 to the ammonia water is 1:5-1:20, preferably 1:10-1:15; after the dripping is finished, preserving the temperature for 16 hours at 20-30 ℃, and controlling the HPLC until the reaction is finished; separating, extracting dichloromethane layer with water (100 mL), collecting water layer, mixing water layers, concentrating under reduced pressure in 55-60deg.C water bath to obtain solid crude product 92.6g, adding solid crude product and toluene (1000.0 mL) at 20-30deg.C in batchesCDI (150.0 g;925mmol;2.3 eq), the molar ratio of compound 2 to CDI is 1:1.1-1:3.0, preferably 1:2.0-1:2.5, after addition, the reaction solution is kept at 20-30 ℃ for 18h until the reaction solution is clear, and the product is in an intermediate state; continuously heating to 90-100 ℃, preserving heat for 6 hours, and controlling the temperature until the reaction is completed; the temperature was lowered, and the reaction solution was concentrated to dryness under reduced pressure to give 79.4g of Compound 3 in 86% of total yield in two steps as a white solid in appearance.
Step four: the synthetic 3, 8-diazabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester has the following reaction route:
adding a compound 3 (100.0 g;434mmol;1.0 eq) and toluene (800 mL) into a reaction bottle, stirring, controlling the temperature to be 20-30 ℃, dropwise adding a 70% red aluminum solution (550 g;1904mmol;4.4 eq), after the dropwise adding is finished, preserving the temperature at 20-30 ℃ for 18h, and controlling the temperature until the reaction is finished; dropwise adding the reaction solution into water (300 mL) at the temperature of 20-30 ℃, quenching the reaction, dropwise adding Boc anhydride (123.0 g;564mmol;4.1 eq) into the reaction solution for later use at the temperature of 20-30 ℃, preserving the heat at the temperature of 20-30 ℃ for 16 hours after the dropwise adding is finished, centrally controlling the reaction solution until the reaction is complete, then dropwise adding 25% concentrated ammonia water (120.0 g; 1760 mmol;4.1 eq) into the reaction solution at the temperature of 20-30 ℃, and preserving the heat at the temperature of 20-30 ℃ for 16 hours after the dropwise adding is finished; filtering, eluting the filter cake with toluene (200 mL), separating filtrate, extracting the water layer with toluene (200 mL), mixing toluene layers, concentrating under reduced pressure to obtain a yellow oily crude product, adding the yellow oily crude product, methanol (500 mL) and 5% palladium-carbon (5.0 g) into an autoclave, heating to 60-70 ℃, preserving heat for 4h under the hydrogen atmosphere of 0.1MPa, and sampling and controlling until the reaction is completed; the reaction solution is cooled to room temperature, filtered by suction, and rinsed with methanol (200 mL), and the filtrate is concentrated to dryness under reduced pressure to obtain 3, 8-diazabicyclo [3.2.1]]Crude product of tert-butyl octane-3-carboxylate. Adding n-heptane (300 mL) into the crude product, pulping at-5-0deg.C for 2h, suction filtering, eluting the filter cake with ice n-heptane (100 mL), and vacuum drying the filter cake at 50deg.C for 16h to obtain 3, 8-diazabicyclo [3.2.1]]82.9g of tert-butyl octane-3-carboxylate, the total yield of three steps is 90 percent, the appearance is white solid, and the purity is 98.8 percent.
The methods used in the present invention are conventional in the art unless otherwise specified.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and any simple modification, variation and equivalent transformation of the above embodiment according to the technical substance of the present invention still fall within the scope of the technical solution of the present invention.
Claims (8)
1. A method for preparing 3, 8-diazabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester, which is characterized by comprising the following steps:
step one: closing the ring of the compound 1 with benzyl amine under alkaline conditions, and then hydrolyzing under acidic conditions to obtain a compound 2;
step two: closing the ring of the compound 2 under the condition of anhydride to form internal anhydride, then opening the ring by ammonia water to form a monoamide structure, and then closing the ring by CDI to obtain a compound 3;
step three: reducing the compound 3, protecting by Boc and removing benzyl by Pd/C to obtain 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate;
the structural formulas of the compound 1, the compound 2 and the compound 3 are shown as follows:
2. the process for preparing 3, 8-diazabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester according to claim 1, characterized in that the process for preparing compound 1 comprises: adipic acid and thionyl chloride are reacted to prepare adipoyl chloride, and the adipoyl chloride is subjected to bromination by a bromination reagent and then is subjected to esterification reaction with an esterification reagent to obtain the compound 1.
3. The method for preparing 3, 8-diazabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester according to claim 2, wherein the brominating reagent is bromine or NBS, and the esterifying reagent is an alcohol reagent.
4. The process for preparing 3, 8-diazabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester according to any one of claims 1-3, characterized in that, when adipoyl chloride is prepared, the molar ratio of adipic acid to thionyl chloride is 1:2-4, adipoyl chloride is brominated to positions 2 and 5 by bromine, the reaction temperature is controlled at 80-90 ℃ during the bromination, the reaction time is 1-6 hours, and the esterification reaction is carried out with an esterification reagent after the bromination to obtain the compound 1.
5. The process for producing t-butyl 3, 8-diazabicyclo [3.2.1] octane-3-carboxylate according to claim 1, wherein in the first step, the solvent used for the ring-closure reaction of the compound 1 with benzylamine under alkaline conditions is at least one of toluene, tetrahydrofuran or ethyl acetate, the inorganic base used under alkaline conditions is at least one of sodium carbonate, potassium carbonate or potassium t-butoxide, and the acid used under acidic conditions is at least one of hydrochloric acid, sulfuric acid or trifluoroacetic acid.
6. The process for producing t-butyl 3, 8-diazabicyclo [3.2.1] octane-3-carboxylate according to claim 1, wherein in the second step, the solvent used for ring opening to form the monoamide structure is at least one of dichloromethane, chloroform or tetrahydrofuran, and the solvent used for ring closing by CDI is at least one of tetrahydrofuran, diethyl ether or toluene.
7. The process for preparing tert-butyl 3, 8-diazabicyclo [3.2.1] octane-3-carboxylate according to claim 1, wherein in step three, the reducing agent used for reducing the compound 3 is at least one of lithium aluminum tetrahydroide, borohydride or red aluminum.
8. The process for preparing tert-butyl 3, 8-diazabicyclo [3.2.1] octane-3-carboxylate according to claim 1 or 2 or 3 or 5 or 6 or 7, characterized by the step three: and (3) reducing the compound 3, protecting the compound by Boc and removing benzyl from Pd/C to obtain the 3, 8-diazabicyclo [3.2.1] octane-3-tert-butyl formate, wherein a one-pot method is adopted, and the intermediate does not undergo a refining process.
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