CN106496263B - 六氢呋喃并呋喃醇衍生物的制备方法、其中间体及其制备方法 - Google Patents
六氢呋喃并呋喃醇衍生物的制备方法、其中间体及其制备方法 Download PDFInfo
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- CN106496263B CN106496263B CN201610726487.0A CN201610726487A CN106496263B CN 106496263 B CN106496263 B CN 106496263B CN 201610726487 A CN201610726487 A CN 201610726487A CN 106496263 B CN106496263 B CN 106496263B
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- 238000000034 method Methods 0.000 title claims description 27
- GQSAIMYKDAPIDJ-UHFFFAOYSA-N 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-5-ol Chemical class O1CCC2OC(O)CC21 GQSAIMYKDAPIDJ-UHFFFAOYSA-N 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 94
- 238000002360 preparation method Methods 0.000 claims abstract description 34
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
- -1 RLA compound Chemical class 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 238000006460 hydrolysis reaction Methods 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 238000006722 reduction reaction Methods 0.000 claims description 8
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 10
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 abstract description 9
- 229960005107 darunavir Drugs 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000001816 cooling Methods 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000003638 chemical reducing agent Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 150000007522 mineralic acids Chemical class 0.000 description 6
- 150000007524 organic acids Chemical class 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 3
- JVEGCGQXRCOAFN-UHFFFAOYSA-N C(C(C)C)[AlH]CC(C)C.[Li] Chemical compound C(C(C)C)[AlH]CC(C)C.[Li] JVEGCGQXRCOAFN-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 125000005103 alkyl silyl group Chemical group 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000004971 nitroalkyl group Chemical group 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- DBMGRFIVRJOFCS-UHFFFAOYSA-N 2-(2-iodoethoxy)-2-methylpropane Chemical compound CC(C)(C)OCCI DBMGRFIVRJOFCS-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 150000007529 inorganic bases Chemical group 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- XPLJNJGKLNJWNZ-UHFFFAOYSA-N lithium;cyclohexylazanide Chemical compound [Li+].[NH-]C1CCCCC1 XPLJNJGKLNJWNZ-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- VKNUORWMCINMRB-UHFFFAOYSA-N diethyl malate Chemical compound CCOC(=O)CC(O)C(=O)OCC VKNUORWMCINMRB-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/708—Ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
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Abstract
本发明涉及医药合成领域，具体涉及六氢呋喃并呋喃醇衍生物的制备方法、其中间体及其制备方法。该制备方法以式A1化合物或式0化合物为起始原料，
其中，R1，R2相同或不同的为烷基。这与现有专利文献中报导的起始原料不同，具体的制备方法也与现有专利文献不同，但该制备方法能产业化地生产达芦那韦关键中间体(3R,3aS,6aR)‑六氢呋喃并[2,3‑b]‑3‑醇。
Description
技术领域
本发明涉及医药合成领域，具体涉及六氢呋喃并呋喃醇衍生物的制备方法、其中间体及其制备方法。
背景技术
具有下列式Z结构的化合物为化学名称为(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇：
属于六氢呋喃并呋喃醇衍生物的一种，是抗艾滋病药物达芦那韦的中间体。
泰博特克药品有限公司的中国专利申请号为200580010400.X提供了上述(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇的制备方法，其中起始原料为如下的式(3)化合物，
日本住友化学株式会社的中国专利申请号为200380109926.4提供了上述(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇的制备方法，其中起始原料为如下的式VⅢ化合物，
考虑到(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇是制备达芦那韦药物的关键中间体，有必要开发出更多的该关键中间体的制备方法。这就要求从不同的起始原料着手研发。
发明内容
本发明的制备(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇的方法从起始原料的选择上着手，研究开发出了不同于上述已有专利申请中的起始原料制备达芦那韦关键中间体的制备方法。本发明的制备方法为该达芦那韦关键中间体的制备提供了另一条适合产业化的路线。
为实现本发明的技术目的，本发明提供了如下的技术方案：
本发明第一方面提供了如下的式1化合物，
波浪线
表示即可以为
S构型，也可以为
R构型。其中，RL为氢或羟基保护基。所述羟基保护基为烷基，硅烷基，取代苯基或芳基。
所述硅烷基为三甲基硅基，三乙基硅基，三正丁基硅基，叔丁基二甲基硅基。所述烷基优选为C1-C8的烷基。所述芳基为苯基，呋喃基，噻吩基或吲哚基。所述取代苯基为烷基取代的苯基，烷氧基烷基取代的苯基，硝基烷基取代的苯基。所述烷基取代的苯基为苄基，二苯甲基，三苯甲基；所述烷氧基烷基取代的苯基为对甲氧基苄基；所述硝基烷基取代的苯基为对硝基苄基。所述烷基取代的苯基优选为苄基。
具体地，提供了式1-1化合物或式1-2化合物，
RL与上述定义相同。优选地，为如下化合物，
本发明第二方面提供了如下的式2化合物，
波浪线
表示即可以为
S构型，也可以为
R构型。RL与上述定义相同，R3为烷基。RL1为氢或对氯苯甲酰基。
具体地，提供了式2-1化合物或式2-2化合物，
其中R3为烷基。
优选地，为如下化合物，
本发明第三方面提供了如下的式B化合物，
特别地，如下的式B-1化合物，
其中，R1，R2为氢，相同或不同的为羧基保护基，如烷基，取代苯基如烷基取代的苯基，烷氧基烷基取代的苯基，硝基烷基取代的苯基或硅烷基；RL与上述定义相同。
所述烷基为C1-C8的烷基，如甲基，乙基，正丙基，异丙基，正丁基，叔丁基；所述烷基取代的苯基为苄基，二苯甲基，三苯甲基；所述烷氧基烷基取代的苯基为对甲氧基苄基；所述硝基烷基取代的苯基为对硝基苄基等，优选地，为甲基、异丙基，叔丁基，苄基；所述硅烷基为三甲基硅基，三乙基硅基，三正丁基硅基，叔丁基二甲基硅基；所述芳基为苯基，呋喃基，噻吩基，吲哚基。
本发明第四方面提供了式B及式B-1化合物的制备方法，其中，式B-1化合物由式A1化合物与式A2化合物反应制备得到，式B化合物与之相同，将式A1化合物调整为其外消旋物即可，
其中，R1，R2，RL与上述定义相同，所述X为离去基团。
X可以为卤素原子，优选地为碘原子，溴原子；甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基、苯磺酰氧基。
具体地，制备保护基RL为叔丁基的式B-1化合物，
其中，R1，R2，X与上述定义相同。
具体地，制备保护基RL为三甲基硅烷基的式B-1化合物，
其中，R1，R2，X与上述定义相同。
具体地，制备保护基RL为苄基的式B-1化合物，
其中，R1，R2，X与上述定义相同。
具体地，制备保护基RL为二苯甲基的式B-1化合物，
其中，R1，R2，X与上述定义相同。
其中，保护基为氢的式B-1化合物可以由保护基为烷基，苄基或烷基硅基经脱保护制备得到。如使烷基经酸水解为羟基，使苄基，二苯甲基经钯炭脱保护为羟基，使烷基硅基经酸如三氟乙酸脱保护为羟基。
所述制备式B-1化合物的反应在碱存在的条件下进行。所述碱为烷基锂或如下结构的化合物，
其中，L1，L2为烷基，环烷基，烷基硅基，M为金属原子如锂，钾，钠等。
具体地，所述碱为二异丙基氨基化锂、环己基氨基化锂、六甲基二硅氮化锂、六甲基二硅氮化钠、六甲基二硅氮化钾或正丁基锂。
优选地，所述碱为二异丙基氨基化锂。
相对于1mol的式A1化合物，碱的使用量通常为2.0～3.5mol，优选地，为2.2mol～3.0mol。
所述反应溶剂为醚类溶剂如乙醚，异丙醚，甲基叔丁基醚，四氢呋喃，甲基四氢呋喃等。
所述反应温度为-78℃-70℃，优选为-78℃-0℃。
其中，式A1化合物与式A2化合物的反应制备得到的式B-1化合物大部分地以如下构型的化合物存在，
少部分地以其非对映异构体的形式存在，
本领域技术人员可以在此通过柱层析等方法提纯得到式B-1化合物，
但较优选地是，不提纯直接用于下述反应，制备式1-2化合物。
即本发明第五方面提供了式1-2化合物的制备方法，由式B-1化合物经还原和环合反应制备。
其中，由于上述式B-1化合物大部分以如下构型存在，
那经过反应后，大部分生成式1-2化合物，
少部分以如下构型存在，
所述还原试剂可以为本领域公知的还原羰基为羟基的还原剂。如硼类还原剂或铝类还原剂。所述环合试剂可以为酸。所述酸为无机酸或有机酸。所述无机酸为盐酸或硫酸，所述有机酸为三氟乙酸。
本发明第六方面提供了式1-1化合物的制备方法。由式0化合物与式A2化合物反应制备得到。
特别地，制备RL为叔丁基二甲硅基的式1-1化合物，
所述制备式1-1化合物的反应在碱存在的条件下进行。所述碱为烷基锂或如下结构的化合物，
其中，L1，L2为烷基，环烷基，烷基硅基，M为金属原子如锂，钾，钠等。
具体地，所述碱为二异丙基氨基化锂、环己基氨基化锂、六甲基二硅氮化锂、六甲基二硅氮化钠、六甲基二硅氮化钾、六甲基二硅胺锂或正丁基锂。
优选地，所述碱为六甲基二硅胺锂或二异丙基氨基化锂。
相对于1mol的式0化合物，碱的使用量通常为2.0～3.5mol，优选地，为2.2mol～3.0mol。
所述反应溶剂为醚类溶剂如乙醚，异丙醚，甲基叔丁基醚，四氢呋喃，甲基四氢呋喃等。
所述反应温度为-78℃-70℃，优选为-78℃-0℃。
本发明第七方面提供了通式为式2化合物，具体RL1为氢的式2-1或式2-2化合物的制备方法。由式1化合物经取代和还原或式1-1化合物经还原制备或由式1-2化合物经取代和还原制备。所述反应式如下：
其中，所述还原剂可以为本领域公知的还原羰基为羟基的还原剂。如硼类还原剂，铝类还原剂等。所述硼类还原剂可以为三氟化硼，硼氢化钠或者为三氟化硼乙醚；所述铝类还原剂可以为四氢铝锂，红铝，二异丁基氢化铝锂等。
所述反应溶剂为醇类溶剂如甲醇、乙醇。
上述还原反应中的取代可以与对氯苯甲酰氯反应，其中RL1为对氯苯甲酰基。
本发明第八方面提供了制备达芦那韦关键中间体(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇以及(3R,3aS,6aS)-六氢呋喃并[2,3-b]-3-醇的方法。由式2化合物经水解反应制备。反应式如下：
具体地，由式2-1化合物经水解反应制备，
具体地，由式2-2化合物经水解反应制备，
所述水解反应的水解试剂可以为本领域熟知的酸或碱。所述酸可以为无机酸或有机酸。所述无机酸为盐酸、硫酸；所述有机酸为三氟乙酸。
(3R,3aS,6aS)-六氢呋喃并[2,3-b]-3-醇可以通过现有文献中的方法制备达芦那韦关键中间体(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇。如期刊文献Bioorganic&Medicinal Chemistry Letters(1996),6(23),2847-2852中的方法。
其中R4为苯基，对硝基苯基，甲基，或-NH-(R)-1-(1-萘)乙基。
进一步地，(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇和(3R,3aS,6aS)-六氢呋喃并[2,3-b]-3-醇的制备，可以通过式1化合物经一锅法制备。即还原反应，水解反应在一锅中进行，不分离式2化合物。
本发明优选地一种实施方式为：
本发明优选地另一种实施方式为：
其中RL优选为叔丁基或苄基，RL1优选为对氯苯甲酰基。
本发明第九方面提供了式C化合物，
包括式C1化合物和式C2化合物，
本发明第十方面提供了式C化合物的制备方法，由式B化合物制备。
由于上述式B-1化合物大部分以如下构型存在，
那经过反应后，生成的式C化合物也是以如下构型存在，
少部分以如下构型存在，
其中，当R2为氢时，所述反应的完成可以先通过脱保护基，后环合，再水解这三个过程，也可以是先水解，后脱保护基，再环合的过程，还可以是先脱保护基，后水解，再环合的过程。即任意顺序地这三个过程。
所述脱保护试剂为酸或钯炭，所述环合试剂可以为酸，其中酸为无机酸或有机酸；所述水解试剂为无机碱。
所述无机酸为盐酸、硫酸；所述有机酸为三氟乙酸，所述无机碱为氢氧化钠，碳酸钠等。
本发明式C化合物的制备还可以由式A1化合物与式A2化合物反应后，经任意顺序地脱保护，环合和水解的一锅反应制备得到，
本发明制备达芦那韦关键中间体(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇的方法，以式A1化合物或式0化合物为起始原料，
其中，R1，R2与上述定义相同。这与现有专利文献中报导的起始原料不同，具体的制备方法也与现有专利文献不同，但该制备方法可产业化的生产达芦那韦该关键中间体。
具体实施方式
为了进一步理解本发明，下面结合实施例对本发明提供的六氢呋喃并呋喃醇衍生物的制备方法、其中间体及其制备方法进行详细说明。需要理解的是，这些实施例描述只是为进一步详细说明本发明的特征，而不是对本发明范围或本发明权利要求范围的限制。
实施例1：(3R)-二异丙基-2-(2-(叔丁氧基)-乙基)-3-羟基的制备
在一250ml配有磁力搅拌子，温度计的四口瓶中，氮气保护下，加入63ml LDA(2.1eq)和30ml THF,冷却至-60℃～-70℃，滴加苹果酸异丙酯(13.1g，60mmol)，控制温度不超过-60℃，滴毕，维持内温搅拌30min，缓慢升温至-20℃，用时半小时，再降温至-60℃～-70℃，滴加2-碘乙基叔丁基醚(27.4g，2.0eq)，滴毕保温搅拌半小时后升温至-20℃搅拌过夜。反应体系加入90ml水和40ml乙酸乙酯，搅拌5min，静置分层，水相用(40ml×3)乙酸乙酯提取，合并有机层，硫酸镁干燥，过滤，浓缩得到28.54g油状物，取部分过柱分离，确定为目标化合物，收率80％。产品谱图数据如下：
1H NMR(400.2MHz,CDCl3)δ5.10(1H,m),5.01(1H,m),4.31(1H,m)，3.54(1H,d，J＝7.2Hz),3.46(2H,m),3.06(1H,m)，2.13(1H,m),1.86(1H,m)，1.29(6H,d，J＝2.8Hz)，1.27(6H,d，J＝2.8Hz),1.18(9H,s)；
13C NMR(100.6MHz,CDCl3)δ172.8(d,J＝8.8Hz),171.45(d,J＝36.8Hz),72.83(d,J＝5.9Hz),71.18(d,J＝37.3Hz),69.48(t,J＝8.2Hz),68.1(d,J＝8.2Hz),58.88(s),45.67ppm(s)，28.59(s),27.34ppm(s)，21.58ppm(s)；质谱(ESI方法)C16H30O6(M)+,计算值318.20.测量值319.2
实施例2：(3R)-二乙基-2-(2-(叔丁氧基)-乙基)-3-羟基的制备
在一250ml配有磁力搅拌子，温度计的四口瓶中，氮气保护下，加入42ml LDA(2.1eq)和20ml THF,冷却至-60℃～-70℃，滴加苹果酸乙酯(7.5g，40mmol)，控制温度不超过-60℃，滴毕，维持内温搅拌30min，缓慢升温至-20℃，用时半小时，再降温至-60℃～-70℃，滴加2-碘乙基叔丁基醚(9.58g，2.0eq)，滴毕保温搅拌半小时后升温至-20℃搅拌过夜。反应体系加入90ml水和40ml乙酸乙酯，搅拌5min，静置分层，水相用(40ml×3)乙酸乙酯提取，合并有机层，硫酸镁干燥，过滤，浓缩得到7.49g油状物，取部分过柱分离，确定为目标化合物，收率60％。产品谱图数据如下：
1H NMR(400.2MHz,CDCl3)δ4.30(1H,m),4.20(2H,m),4.11(2H,m)，3.52(1H,m),3.49(2H,m),3.10(1H,m)，2.12(1H,m),1.88(1H,m)，1.31(6H,d，J＝2.8Hz)，1.27(6H,d，J＝2.8Hz),1.15(9H,s)。
实施例3：(3R)-二异丙基甲基-2-(2-(三甲基硅氧基)-乙基)-3-羟基的制备
保护基为三甲基硅基的式B-1化合物可以按照实施例1或2制备。
实施例4：
保护基为苄基的的式B-1化合物可以按照实施例1或2制备。
实施例5：
保护基为氢的式B-1化合物可以经脱保护制备，产品谱图数据如下：
1H NMR(400.2MHz,CDCl3)δ5.14(1H,m),5.04(1H,m),4.53(2H,m)，4.28(1H,s),3.22(1H,m),3.02(1H,m)，2.60(1H,m),2.35(1H,m)，1.29(6H,m)，1.25(6H,m)；
质谱(ESI方法)C12H22O6(M)+,计算值262.29.测量值263.2。
实施例6：式C化合物的制备
在一50ml的两口瓶中加入300mg(3R)-二异丙基-2-(2-(叔丁氧基)-乙基)-3-羟基和1ml三氟乙酸，冷却至-10℃～-5℃搅拌过夜，低温蒸掉三氟乙酸，加入氢氧化钠水溶液和四氢呋喃于室温下搅拌6小时，后稀盐酸调pH＝2,乙酸乙酯萃取，蒸干溶剂，加入甲苯，常压蒸干，此操作重复2次，得到127mg白色固体，收率为80％，核磁鉴定为目标化合物。产品谱图数据如下：
1H NMR(400.2MHz,DMSO-d6)δ4.25(3H,m),3.13(1H,m),2.33(1H,m)，2.13(1H,m)。
质谱(ESI方法)C6H8O5(M)-,计算值160.1测量值159.1。
实施例7：
在反应瓶中投入硼氢化钠，THF，氮气保护下冷却至-10—15℃搅拌，并在氮气保护下滴加RL为叔丁基的式B化合物/THF溶液，控温-10--5℃。滴加完毕，保温，并开始滴加醋酸，控温-10--5℃，升温至20-25℃保温。保温完毕，冷却至-10--5℃滴加水，控温-10--5℃，加毕搅拌至TLC原料反应完毕，升温至0-5℃加入二氯甲烷提取，分层，并50-55℃减压浓缩有机层，得16.5g油状物,将上述所得油状物投入反应瓶中，加入THF，对甲苯磺酸，搅拌，并升温至75-80℃回流16-18h，TLC至原料反应完毕。冷却，并55-60℃减压浓缩至不滴馏液，冷却反应液至0-5℃，加入水和DCM搅拌，分层，收集有机层50-55℃减压浓缩至不滴馏液，得油状物11.7g收率80％。
实施例8：
在反应瓶中投入实施例7中的油状物，DCM，对氯苯甲酰氯，搅拌，并滴加三乙胺，控温20-25℃，TLC至原料反应完毕。冷却，加入100ml水，静止，分层。得有机层并55-60℃减压浓缩去除溶剂，再用EA和己烷结晶得产物20g，收率90％。在反应瓶中投入该结晶产物，THF氮气保护下搅拌冷却至-65--70℃滴加二异丁基氢化铝锂，TLC至原料反应完毕。冷却，加入100ml甲醇，三氟化硼乙醚10g，20-25℃搅拌16-18h，并50-55℃减压浓缩至不滴馏液，得产物28g，可以不经分离，直接制备(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇。
实施例9：
实施例10：
四口瓶中投入式0化合物15g，DMPU18.8g，THF10ml。N2保护，降温-78～-80℃，滴HMDSLi 407ml。控温-70～-65℃，滴毕保温1h。滴加式A化合物2-碘乙基叔丁基二甲硅基醚15.4g，控温-65～-60℃。滴毕保温4h，TLC原料反应完，用NaCl30ml饱和水溶液淬灭，分层20ml乙酸乙酯提取水层。合并有机层，浓缩至干得目标产物，收率75％，纯度98％。
DMPU为1,3-二甲基-3,4,5,6-四氢-2-嘧啶酮，HMDSLi：六甲基二硅胺锂
实施例11：
在反应瓶中投入式1-1化合物(RL为叔丁基二甲硅基)，THF，氮气保护下冷却至-65--70℃，滴加二异丁基氢化铝锂，TLC至原料反应完毕，加入100ml甲醇，三氟化硼乙醚10g，20-25℃搅拌16-18h，再50-55℃减压浓缩去除溶剂，在用DCM提出得产物21.4g，收率85％。
DCM：二氯甲烷
实施例12：
在250ml四口瓶中加入2-1化合物(RL为叔丁基二甲硅基)，THF，冷却至0-5℃加入30％盐酸10g，于0-5℃反应至原料消失，加入碳酸氢钠中和至pH＝7-8，过滤除去固体，加入DCM提取然后再去除溶剂得到(3R,3aS,6aS)-六氢呋喃并[2,3-b]-3-醇7.99g，收率85％。
Claims (10)
1.一种如下式1所示的化合物：
其中波浪线
表示为
S构型或
R构型，RL为羟基保护基；所述羟基保护基为烷基，硅烷基，取代苯基、苄基或芳基。
2.一种式1-1化合物或式1-2化合物：
RL与权利要求1中的定义相同。
3.根据权利要求2所述的化合物，其特征在于，RL为叔丁基二甲硅基的式1-1化合物，RL为叔丁基或苄基的式1-2化合物，
4.一种式1-2化合物的制备方法，其特征在于，由式B-1化合物经还原和环合反应制备，
其中R1，R2为氢，相同或不同的为羧基保护基，所述羧基保护基为烷基，硅烷基或取代苯基；RL与权利要求1中定义相同。
5.一种式1-1化合物的制备方法，其特征在于，由式0化合物与式A2化合物反应制备得到，
其中，RL与权利要求1中定义相同；所述X为离去基团，所述离去基团为卤素原子，甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基、苯磺酰氧基。
6.一种式2化合物的制备方法，其特征在于，由式1化合物经还原反应或取代和还原反应制备，
其中RL与权利要求1中定义相同；R3为烷基；RL1为氢或对氯苯甲酰基。
7.一种(3R,3aS)-六氢呋喃并[2,3-b]-3-醇的制备方法，其特征在于，由式1化合物经还原反应或取代和还原反应制备式2化合物，
式2化合物经水解反应制备得到，
其中RL与权利要求1中定义相同，RL1，R3与权利要求6中的定义相同；波浪线表示为R或S构型。
8.根据权利要求7所述的(3R,3aS)-六氢呋喃并[2,3-b]-3-醇的制备方法，其特征在于，所述(3R,3aS)-六氢呋喃并[2,3-b]-3-醇为(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇；由式2-2化合物经水解反应制备得到，
其中RL与权利要求1中定义相同，RL1与权利要求6中的定义相同；波浪线表示为R或S构型。
9.根据权利要求7所述的(3R,3aS)-六氢呋喃并[2,3-b]-3-醇的制备方法，其特征在于，所述(3R,3aS)-六氢呋喃并[2,3-b]-3-醇为(3R,3aS,6aS)-六氢呋喃并[2,3-b]-3-醇；由式2-1化合物经水解反应制备得到，
其中RL与权利要求1中的定义相同，波浪线表示为R或S构型。
10.(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇的制备方法，其特征在于，根据权利要求9中的方法制备(3R,3aS,6aS)-六氢呋喃并[2,3-b]-3-醇,由(3R,3aS,6aS)-六氢呋喃并[2,3-b]-3-醇进一步制备(3R,3aS,6aR)-六氢呋喃并[2,3-b]-3-醇，
其中R4为苯基，对硝基苯基，甲基，或-NH-(R)-1-(1-萘)乙基。
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