CN102320920B - Method for removing benzyl protecting group of hydroxyl group - Google Patents
Method for removing benzyl protecting group of hydroxyl group Download PDFInfo
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- CN102320920B CN102320920B CN201110191238.3A CN201110191238A CN102320920B CN 102320920 B CN102320920 B CN 102320920B CN 201110191238 A CN201110191238 A CN 201110191238A CN 102320920 B CN102320920 B CN 102320920B
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- Prior art keywords
- alcohol
- benzyl
- group
- protecting group
- hydroxyl
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title claims abstract description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 34
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000001301 oxygen Substances 0.000 claims abstract description 33
- 239000000758 substrate Substances 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- -1 hydroxyl compound Chemical class 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims description 33
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 17
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 125000002723 alicyclic group Chemical group 0.000 claims description 9
- 150000002191 fatty alcohols Chemical group 0.000 claims description 9
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical group ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- KBPLFHHGFOOTCA-UHFFFAOYSA-N caprylic alcohol Natural products CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims description 8
- KEJGAYKWRDILTF-JDDHQFAOSA-N (3ar,5s,6s,6ar)-5-[(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-6-ol Chemical compound O1C(C)(C)OC[C@@H]1[C@@H]1[C@H](O)[C@H]2OC(C)(C)O[C@H]2O1 KEJGAYKWRDILTF-JDDHQFAOSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004185 ester group Chemical group 0.000 claims description 6
- 125000000524 functional group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229940051250 hexylene glycol Drugs 0.000 claims description 6
- 229940067107 phenylethyl alcohol Drugs 0.000 claims description 6
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims description 5
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 5
- 229940041616 menthol Drugs 0.000 claims description 5
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 claims description 4
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 claims description 4
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 235000013372 meat Nutrition 0.000 claims description 4
- TVMXDCGIABBOFY-UHFFFAOYSA-N n-Octanol Natural products CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 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 4
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 claims description 4
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- ZQOFBYRKKBGZLT-UHFFFAOYSA-N 6-(methoxymethoxy)hexan-1-ol Chemical compound COCOCCCCCCO ZQOFBYRKKBGZLT-UHFFFAOYSA-N 0.000 claims description 3
- ZLQBXPGETZHDHL-UHFFFAOYSA-N 6-hydroxyhexyl benzoate Chemical compound OCCCCCCOC(=O)C1=CC=CC=C1 ZLQBXPGETZHDHL-UHFFFAOYSA-N 0.000 claims description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical class O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 2
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- MQWCXKGKQLNYQG-UHFFFAOYSA-N 4-methylcyclohexan-1-ol Chemical compound CC1CCC(O)CC1 MQWCXKGKQLNYQG-UHFFFAOYSA-N 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000007800 oxidant agent Substances 0.000 abstract description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 abstract 4
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 abstract 2
- 239000012414 tert-butyl nitrite Substances 0.000 abstract 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 238000000926 separation method Methods 0.000 description 32
- 230000009466 transformation Effects 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 238000001816 cooling Methods 0.000 description 21
- 239000003480 eluent Substances 0.000 description 21
- 238000004817 gas chromatography Methods 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- 239000012074 organic phase Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 21
- 229960001866 silicon dioxide Drugs 0.000 description 21
- 238000010792 warming Methods 0.000 description 21
- 230000035484 reaction time Effects 0.000 description 8
- VTBOTOBFGSVRMA-UHFFFAOYSA-N 1-Methylcyclohexanol Chemical compound CC1(O)CCCCC1 VTBOTOBFGSVRMA-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- DGUKYCANAXQEMH-UHFFFAOYSA-N 6-hydroxyhexyl acetate Chemical compound CC(=O)OCCCCCCO DGUKYCANAXQEMH-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- AADVCYNFEREWOS-UHFFFAOYSA-N (+)-DDM Natural products C=CC=CC(C)C(OC(N)=O)C(C)C(O)C(C)CC(C)=CC(C)C(O)C(C)C=CC(O)CC1OC(=O)C(C)C(O)C1C AADVCYNFEREWOS-UHFFFAOYSA-N 0.000 description 1
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 1
- 125000006189 4-phenyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- AADVCYNFEREWOS-OBRABYBLSA-N Discodermolide Chemical compound C=C\C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C\C(C)=C/[C@H](C)[C@@H](O)[C@@H](C)\C=C/[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C AADVCYNFEREWOS-OBRABYBLSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- ODYCAZSSUVCHNU-XLAORIBOSA-N Laurencin Natural products CC[C@H]1C[C@H](CC=CC[C@@H]1Br)[C@@H](CC=CC#C)OC(=O)C ODYCAZSSUVCHNU-XLAORIBOSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- XXMIOPMDWAUFGU-UHFFFAOYSA-N hexane-1,6-diol Chemical compound OCCCCCCO XXMIOPMDWAUFGU-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000002351 wastewater Substances 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 invention discloses a method for removing a benzyl protecting group of a hydroxyl group. The method comprises the steps of: carrying out a reaction on a compound with the benzyl protecting group used as a reaction substrate in an organic solvent by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and tert-butyl nitrite (TBN) as catalysts and oxygen as an oxidant under the conditions of oxygen pressure not larger than 0.5 MPa and temperature of 100-140 DEG C to remove the benzyl protecting group of the hydroxyl group to obtain a hydroxyl compound, wherein the compound with the benzyl protecting group is obtained by introducing the benzyl protecting group to the hydroxyl compound. The method disclosed by the invention has the advantages of economy and environmental friendliness.
Description
(1) technical field
The present invention relates to a kind of method of the benzyl class protecting group that removes hydroxyl.
(2) background technology
Hydroxyl is an important functional group in organic synthesis, can be transformed into multiple other functional group by reacting it.Because hydroxyl is more active, so often need to use protecting group to be protected, then slough in due course protecting group in multistep organic synthesis.In various hydroxy-protective groups, benzyl class protecting group, comprises benzyl and substituted benzyl, better for the stability of all ingredients and reaction conditions, is one of most widely used protecting group.Therefore the benzyl class blocking group that removes hydroxyl is also particularly important in organic synthesis.
The method that removes the benzyl class blocking group of hydroxyl has a variety of, and wherein one is chloro-5 with 2,3-bis-, and 6-dinitrile-Isosorbide-5-Nitrae-benzoquinones (DDQ) is oxidized deprotection for oxygenant.For example, in the complete synthesis process of natural product (+)-Laurencin, use DDQ to remove the benzyl protecting group (Org.Lett.2005,7:75-77) of hydroxyl; Document (Tetrahedron 1986,42:3021-3028) has been reported 4-methoxy-benzyl protecting group and 3, the 4-dimethoxy-benzyl protecting group that DDQ can effective elimination hydroxyl; Novartis Co.,Ltd is used the 4-methoxy-benzyl protecting group (Chem.Rev.2006,106:2943-2989) of DDQ oxidation removal hydroxyl at present for twice in the anticancer compound Discodermolide of clinical front test production process.Using DDQ to remove in the reaction of benzyl class protecting group of hydroxyl, DDQ is generally stoichiometry as the consumption of chemical oxidizing agent or exceedes stoichiometricly, and this has reduced the economy of reaction, and has increased the difficulty of product separation purifying.In order to overcome above shortcoming, document (Tetrahedron Lett.2000,41:10323-10326 and Tetrahedron Lett.2001,42:5571-5573) is taking DDQ as catalyzer, with the Mn (OAc) of three times of meterings of substrate
3for oxygenant is oxidized deprotection and has removed respectively 4-methoxy-benzyl protecting group and the 4-phenylbenzyl protecting group of hydroxyl; Document (Org.Lett.2010,12:4686-4689) is taking DDQ as catalyzer, with the Mn0 of six times of meterings of substrate
2for oxygenant is oxidized deprotection and has removed the 4-methoxy-benzyl protecting group of hydroxyl.Although these methods have reduced the consumption of DDQ, unavoidably produce a large amount of solid waste or the waste water of metal-containing salt, environment is caused to disadvantageous effect.
(3) summary of the invention
The technical problem to be solved in the present invention is to provide the method for the benzyl class protecting group of removing hydroxyl of a kind of economy, environmental protection.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
A kind of method of the benzyl class protecting group that removes hydroxyl; described method is: the compound with benzyl class protecting group obtaining taking benzyl class protecting group on the hydroxyl of oxy-compound is as reaction substrate; with 2; 3-bis-chloro-5; 6-dinitrile-1; 4-benzoquinones (DDQ) and nitrite tert-butyl (TBN) are catalyzer; taking oxygen as oxygenant; reaction substrate is in organic solvent; be not more than in oxygen pressure under the condition of 100～140 DEG C of 0.5MPa, temperature and react, the benzyl class protecting group that removes hydroxyl obtains oxy-compound.
Benzyl class protecting group of the present invention can be benzyl, 4-methoxy-benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl or 3,4-dimethoxy-benzyl, preferably 4-methoxy-benzyl.
In the present invention, described oxy-compound is fatty alcohol (fatty alcohol of for example C1～C20), alicyclic ring alcohol (for example alicyclic ring alcohol of 3～8 ring structures), saturated or unsaturated heterocycle alcohol or the alcohol with other functional group, and can be monohydroxy-alcohol or polyvalent alcohol.Described saturated or unsaturated heterocycle alcohol for example can be, containing heteroatomic saturated or unsaturated heterocycle alcohol such as N, O,
deng.The described alcohol with other functional groups can be fatty alcohol, the alicyclic ring alcohol of replacement or the saturated or unsaturated heterocycle alcohol of replacement replacing, the fatty alcohol of described replacement refers to that the alkyl of fatty alcohol is replaced by one or more substituting groups, it is one of following that described substituting group is independently selected from separately: the alkoxyl group of halogen, C1-C4, ester group, phenyl, saturated heterocyclic group, described saturated heterocyclic group can be containing heteroatomic saturated heterocyclic groups such as N, O, as
deng; The alicyclic ring alcohol of described replacement refers on the ring of alicyclic ring alcohol and replaced by one or more substituting groups, and it is one of following that described substituting group is independently selected from separately: the alkyl of C1-C4, halogen, the alkoxyl group of C1-C4, ester group, tertbutyloxycarbonyl; Saturated or the unsaturated heterocycle alcohol of described replacement refers on the heterocycle of saturated or unsaturated heterocycle alcohol and replaced by one or more substituting groups, and it is one of following that described substituting group is independently selected from separately: the alkyl of C1-C4, halogen, the alkoxyl group of C1-C4, ester group, tertbutyloxycarbonyl, acetal radical.
Further, one of described oxy-compound is preferred following: n-Octanol, sec-n-octyl alcohol, phenylethyl alcohol, hexalin, methyl-cyclohexanol, hexylene glycol, N-Boc-L-dried meat ammonia alcohol, MENTHOL, tetrahydrofurfuryl alcohol, 2-chloro-5,6,7,8-tetrahydrochysene-oxine, diacetoneglucose, 6-methoxyl group-1-hexanol, 6-(methoxymethoxy)-1-hexanol, 1,6-hexylene glycol monoacetate or 1,6-hexylene glycol mono benzoate.
The preferred orthodichlorobenzene of organic solvent of the present invention, Meta Dichlorobenzene or ethylene glycol diethyl ether, preferably ethylene glycol diethyl ether.
The molar ratio of catalyzer DDQ of the present invention and reaction substrate is 3～15: 100, preferably 5～10: 100.
The molar ratio of catalyzer TBN of the present invention and reaction substrate is 3～15: 100, preferably 5～10: 100.
In the present invention, the quality consumption of described organic solvent is recommended as 3～15 times of reaction substrate.
In the present invention, the pressure of described oxygen is preferably 0.1～0.5MPa, more preferably 0.2～0.3MPa.
In the present invention, described temperature of reaction is 100～140 DEG C, is preferably 120～125 DEG C.
In the present invention, the described reaction times is generally 30～240min, is preferably 50～120min.
The method that removes the benzyl class protecting group of hydroxyl described in the concrete recommendation of the present invention is carried out according to following steps: reaction substrate is dissolved in organic solvent, add 2,3-bis-chloro-5,6-dinitrile-1,4-benzoquinones and nitrite tert-butyl taking the oxygen of 0.2～0.3MPa as oxygenant, react 50～120min at 120～125 DEG C, remove benzyl class protecting group, obtain oxy-compound; Described organic solvent is orthodichlorobenzene, Meta Dichlorobenzene or ethylene glycol diethyl ether; Described 2,3-bis-is chloro-5, and the molar ratio of 6-dinitrile-Isosorbide-5-Nitrae-benzoquinones, nitrite tert-butyl and reaction substrate is 5～10: 5～10: 100.
Remove after the reacting completely of benzyl class protecting group above-mentioned, can adopt the conventional post of crossing to separate and obtain oxy-compound.
The present invention is easy to operate and safe, and its beneficial effect is mainly:
A) compared with defending the doctrine with the traditional stoichiometric DDQ oxidation of use remove-insurance, in the present invention, the consumption of DDQ greatly reduces, and has reduced reaction cost.
B) with taking DDQ as catalyzer, metal oxide or metal-salt compared with the oxidation remove-insurance of oxygenant is defended the doctrine, in the present invention, used clean oxygen for oxygenant, greatly reduce Environmental costs.
(4) embodiment
Below by embodiment, the invention will be further described, but protection scope of the present invention is not limited to this.
The structural formula of the following embodiment reaction substrate with benzyl class protecting group used is respectively suc as formula shown in (1)～(20):
Embodiment 1:
In 300mL teflon-lined autoclave pressure; add the n-Octanol (formula (1)) of 8mmol 4-methoxy-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 120min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of n-Octanol is 93%.
Embodiment 2:
In 300mL teflon-lined autoclave pressure; add the phenylethyl alcohol (formula (2)) of 8mmol 4-methoxy-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 120min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of phenylethyl alcohol is 95%.
Embodiment 3:
Reactions steps is with embodiment 2, and difference is that ethylene glycol diethyl ether changes orthodichlorobenzene into, and transformation efficiency is 100%, and selectivity of product is 99%.The separation yield of phenylethyl alcohol is 95%.
Embodiment 4:
Reactions steps is with embodiment 2, difference be fill oxygen to tensimeter be 0.3MPa, the reaction times is 105min, transformation efficiency is 98%, selectivity of product is 99%.The separation yield of phenylethyl alcohol is 94%.
Embodiment 5:
In 300mL teflon-lined autoclave pressure; add the sec-n-octyl alcohol (formula (3)) of 8mmol 4-methoxy-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 90min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of sec-n-octyl alcohol is 94%.
Embodiment 6:
Reactions steps is with embodiment 5, and difference is that DDQ consumption is 0.24mmol, and the reaction times is 160min, and transformation efficiency is 100%, and selectivity of product is 98%.The separation yield of sec-n-octyl alcohol is 93%.
Embodiment 7:
Reactions steps is with embodiment 5, and difference is that TBN consumption is 0.24mmol, and the reaction times is 155min, and transformation efficiency is 98%, and selectivity of product is 98%.The separation yield of sec-n-octyl alcohol is 92%.
Embodiment 8:
In 300mL teflon-lined autoclave pressure; add the hexalin (formula (4)) of 8mmol 4-methoxy-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 90min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of hexalin is 93%.
Embodiment 9:
Reactions steps is with embodiment 8, and difference is that ethylene glycol diethyl ether changes Meta Dichlorobenzene into, and transformation efficiency is 100%, and selectivity of product is 99%.The separation yield of hexalin is 93%.
Embodiment 10:
In 300mL teflon-lined autoclave pressure; add the 1 methyl cyclohexanol (formula (5)) of 8mmol 4-methoxy-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 90min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of 1 methyl cyclohexanol is 94%.
Embodiment 11:
Reactions steps is with embodiment 10, difference be fill oxygen to tensimeter be 0.5MPa, the reaction times is 60min, transformation efficiency is 100%, selectivity of product is 98%.The separation yield of 1 methyl cyclohexanol is 94%.
Embodiment 12:
Reactions steps is with embodiment 10, difference be fill oxygen to tensimeter be 0.1MPa, the reaction times is 140min, transformation efficiency is 97%, selectivity of product is 99%.The separation yield of 1 methyl cyclohexanol is 92%.
Embodiment 13:
In 300mL teflon-lined autoclave pressure; add the N-Boc-L-dried meat ammonia alcohol (formula (6)) of 8mmol 4-methoxy-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 105min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of N-Boc-L-dried meat ammonia alcohol is 93%.
Embodiment 14:
In 300mL teflon-lined autoclave pressure; add the diacetoneglucose (formula (7)) of 8mmol 4-methoxy-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.96mmol; the TBN of 0.96mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 35min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 91%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of diacetoneglucose is 84%.
Embodiment 15:
Reactions steps is with embodiment 14, and difference is that DDQ consumption is 1.2mmol, and the consumption of TBN is 1.2mmol, and the reaction times is 30min, and transformation efficiency is 100%, and selectivity of product is 95%.The separation yield of diacetoneglucose is 89%.
Embodiment 16:
Reactions steps is with embodiment 14, and difference is that the consumption of ethylene glycol diethyl ether is 50mL, and transformation efficiency is 98%, and selectivity of product is 91%.The separation yield of diacetoneglucose is 83%.
Embodiment 17:
In 300mL teflon-lined autoclave pressure; add the MENTHOL (formula (8)) of 8mmol 4-methoxy-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 105min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of MENTHOL is 95%.
Embodiment 18:
Reactions steps is with embodiment 17, and difference is that the temperature of oil bath is 125 DEG C, and the reaction times is 95min, and transformation efficiency is 100%, and selectivity of product is 99%.The separation yield of MENTHOL is 95%.
Embodiment 19:
In 300mL teflon-lined autoclave pressure; add the tetrahydrofurfuryl alcohol (formula (9)) of 8mmol 4-methoxy-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 100min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of tetrahydrofurfuryl alcohol is 94%.
Embodiment 20:
In 300mL teflon-lined autoclave pressure; add the 2-chloro-5,6,7 of 8mmol 4-methoxy-benzyl protection; 8-tetrahydrochysene-oxine (formula (10)); 10mL ethylene glycol diethyl ether, the DDQ of 0.4mmol, the TBN of 0.4mmol; seal-off pressure still; fill oxygen to tensimeter be 0.2MPa, autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C, reaction 58min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 97%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, 2-is chloro-5,6,7, the separation yield of 8-tetrahydrochysene-oxine is 90%.
Embodiment 21:
In 300mL teflon-lined autoclave pressure; add 6-methoxyl group-1-hexanol (formula (11)) of 8mmol 4-methoxy-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 120min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of 6-methoxyl group-1-hexanol is 93%.
Embodiment 22:
In 300mL teflon-lined autoclave pressure; add 1 of 8mmol 4-methoxy-benzyl protection; 6-hexylene glycol monoacetate (formula (12)); 10mL ethylene glycol diethyl ether, the DDQ of 0.4mmol, the TBN of 0.4mmol; seal-off pressure still; fill oxygen to tensimeter be 0.2MPa, autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C, reaction 90min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of 1,6-hexylene glycol monoacetate is 94%.
Embodiment 23:
In 300mL teflon-lined autoclave pressure; add 1 of 8mmol 4-methoxy-benzyl protection; 6-hexylene glycol mono benzoate (formula (13)); 10mL ethylene glycol diethyl ether, the DDQ of 0.4mmol, the TBN of 0.4mmol; seal-off pressure still; fill oxygen to tensimeter be 0.2MPa, autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C, reaction 100min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of 1,6-hexylene glycol mono benzoate is 95%.
Embodiment 24:
In 300mL teflon-lined autoclave pressure; add 6-(the methoxymethoxy)-1-hexanol (formula (14)) of 8mmol 4-methoxy-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 100min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 98%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of 6-(methoxymethoxy)-1-hexanol is 93%.
Embodiment 25:
In 300mL teflon-lined autoclave pressure; add two hydroxyls of 8mmol by 1 of 4-methoxy-benzyl protection; 6-hexylene glycol (formula (15)); 10mL ethylene glycol diethyl ether, the DDQ of 0.4mmol, the TBN of 0.4mmol; seal-off pressure still; fill oxygen to tensimeter be 0.2MPa, autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C, reaction 120min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of 1,6-hexylene glycol is 96%.
Embodiment 26:
In 300mL teflon-lined autoclave pressure; add the hexalin (formula (16)) of 8mmol benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 200min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 98%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of hexalin is 92%.
Embodiment 27:
In 300mL teflon-lined autoclave pressure; add 8mmol 3; the hexalin (formula (17)) of 4-dimethoxy-benzyl protection; 10mL ethylene glycol diethyl ether, the DDQ of 0.4mmol, the TBN of 0.4mmol; seal-off pressure still; fill oxygen to tensimeter be 0.2MPa, autoclave pressure is put in the oil bath that is warming up in advance 140 DEG C, reaction 60min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of hexalin is 93%.
Embodiment 28:
In 300mL teflon-lined autoclave pressure; add 8mmol 3; the hexalin (formula (17)) of 4-dimethoxy-benzyl protection; 10mL ethylene glycol diethyl ether, the DDQ of 0.4mmol, the TBN of 0.4mmol; seal-off pressure still; fill oxygen to tensimeter be 0.2MPa, autoclave pressure is put in the oil bath that is warming up in advance 100 DEG C, reaction 240min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of hexalin is 93%.
Embodiment 29:
In 300mL teflon-lined autoclave pressure; add the hexalin (formula (18)) of 8mmol 4-methyl-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 110min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 99%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of hexalin is 93%.
Embodiment 30:
In 300mL teflon-lined autoclave pressure; add the hexalin (formula (19)) of 8mmol 3-methyl-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 150min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 100%, and selectivity of product is 97%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of hexalin is 91%.
Embodiment 31:
In 300mL teflon-lined autoclave pressure; add the hexalin (formula (20)) of 8mmol 3-methyl-benzyl protection; 10mL ethylene glycol diethyl ether; the DDQ of 0.4mmol; the TBN of 0.4mmol, seal-off pressure still, fill oxygen to tensimeter be 0.2MPa; autoclave pressure is put in the oil bath that is warming up in advance 120 DEG C to reaction 160min.After cooling careful release, gas-chromatography for organic phase (GC) is analyzed, and transformation efficiency is 93%, and selectivity of product is 96%.Cross silicagel column, taking volume ratio as the ethyl acetate of 1: 3 and the mixture of sherwood oil as eluent, the separation yield of hexalin is 82%.
Claims (7)
1. one kind removes the method for the benzyl class protecting group of hydroxyl; it is characterized in that described method is: the compound with benzyl class protecting group obtaining taking benzyl class protecting group on the hydroxyl of oxy-compound is as reaction substrate; with 2; 3-bis-chloro-5; 6-dinitrile-1; 4-benzoquinones and nitrite tert-butyl are catalyzer; taking oxygen as oxygenant; reaction substrate is in organic solvent; under the condition of 100～140 DEG C of oxygen pressure 0.1～0.2MPa, temperature, react, remove benzyl class protecting group and obtain oxy-compound.
2. the method for the benzyl class protecting group that removes hydroxyl as claimed in claim 1, is characterized in that described benzyl class protecting group is benzyl, 4-methoxy-benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl or 3,4-dimethoxy-benzyl.
3. the method for the benzyl class protecting group that removes hydroxyl as claimed in claim 1, is characterized in that described oxy-compound is fatty alcohol, alicyclic ring alcohol, saturated or unsaturated heterocycle alcohol or the alcohol with other functional groups; The described alcohol with other functional groups is fatty alcohol, the alicyclic ring alcohol of replacement or the saturated or unsaturated heterocycle alcohol of replacement replacing; The fatty alcohol of described replacement refers to that the alkyl of fatty alcohol is replaced by one or more substituting groups, it is one of following that described substituting group is independently selected from separately: the alkoxyl group of halogen, C1-C4, ester group, phenyl, saturated heterocyclic group, and described saturated heterocyclic group is containing N or the heteroatomic saturated heterocyclic group of O; The alicyclic ring alcohol of described replacement refers on the ring of alicyclic ring alcohol and replaced by one or more substituting groups, and it is one of following that described substituting group is independently selected from separately: the alkyl of C1-C4, halogen, the alkoxyl group of C1-C4, ester group, tertbutyloxycarbonyl; Saturated or the unsaturated heterocycle alcohol of described replacement refers on the heterocycle of saturated or unsaturated heterocycle alcohol and replaced by one or more substituting groups, and it is one of following that described substituting group is independently selected from separately: the alkyl of C1-C4, halogen, the alkoxyl group of C1-C4, ester group, tertbutyloxycarbonyl, acetal radical.
4. the method for the benzyl class protecting group that removes hydroxyl as claimed in claim 1; it is characterized in that described oxy-compound is selected from one of following: n-Octanol, sec-n-octyl alcohol, phenylethyl alcohol, hexalin, methyl-cyclohexanol, hexylene glycol, N-Boc-L-dried meat ammonia alcohol, MENTHOL, tetrahydrofurfuryl alcohol, 2-chloro-5; 6; 7; 8-tetrahydrochysene-oxine, diacetoneglucose, 6-methoxyl group-1-hexanol, 6-(methoxymethoxy)-1-hexanol, 1; 6-hexylene glycol monoacetate or 1,6-hexylene glycol mono benzoate.
5. the method for the benzyl class protecting group that removes hydroxyl as described in one of claim 1～4, is characterized in that described organic solvent is orthodichlorobenzene, Meta Dichlorobenzene or ethylene glycol diethyl ether.
6. the method for the benzyl class protecting group that removes hydroxyl as described in one of claim 1～4, is characterized in that described catalyzer 2, and 3-bis-is chloro-5, and the molar ratio of 6-dinitrile-Isosorbide-5-Nitrae-benzoquinones and reaction substrate is 3～15:100; The molar ratio of described catalyzer nitrite tert-butyl and reaction substrate is 3～15:100.
7. the method for the benzyl class protecting group that removes hydroxyl as described in one of claim 1～4, is characterized in that temperature of reaction is 120～125 DEG C.
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