CN116730873A - Synthesis method of N-Boc-L-phenylalaninol - Google Patents
Synthesis method of N-Boc-L-phenylalaninol Download PDFInfo
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- CN116730873A CN116730873A CN202210200819.7A CN202210200819A CN116730873A CN 116730873 A CN116730873 A CN 116730873A CN 202210200819 A CN202210200819 A CN 202210200819A CN 116730873 A CN116730873 A CN 116730873A
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- LDKDMDVMMCXTMO-LBPRGKRZSA-N tert-butyl n-[(2s)-1-hydroxy-3-phenylpropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](CO)CC1=CC=CC=C1 LDKDMDVMMCXTMO-LBPRGKRZSA-N 0.000 title claims abstract description 46
- 238000001308 synthesis method Methods 0.000 title claims description 4
- 238000000034 method Methods 0.000 claims abstract description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 39
- 238000007254 oxidation reaction Methods 0.000 claims description 14
- 239000005457 ice water Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 230000009467 reduction Effects 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 150000001879 copper Chemical class 0.000 claims description 6
- 230000032050 esterification Effects 0.000 claims description 5
- 238000005886 esterification reaction Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 3
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 claims description 3
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 13
- 238000001816 cooling Methods 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- 230000003647 oxidation Effects 0.000 description 12
- 238000001035 drying Methods 0.000 description 10
- 150000001299 aldehydes Chemical class 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000002386 leaching Methods 0.000 description 7
- 239000007791 liquid phase Substances 0.000 description 7
- 230000001376 precipitating effect Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 5
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 5
- 235000012141 vanillin Nutrition 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910001385 heavy metal Inorganic materials 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229960005190 phenylalanine Drugs 0.000 description 3
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 2
- 239000003810 Jones reagent Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229950009811 ubenimex Drugs 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical class [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical group CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KTMAYMHFKURUIC-UHFFFAOYSA-N tert-butyl n-(1-hydroxypropyl)carbamate Chemical compound CCC(O)NC(=O)OC(C)(C)C KTMAYMHFKURUIC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthetic method for synthesizing N-Boc-L-phenylalaninol. The synthesis of the N-Boc-L-phenylalaninol is carried out by taking N-Boc-L-phenylalanine as initial raw material, esterifying, reducing, amino protecting and reacting to obtain N-Boc-L-phenylalaninol, and oxidizing. The method has the advantages of low cost, high product content, convenient operation and less three wastes, and is suitable for industrialized amplified production.
Description
Technical field:
the invention relates to the field of pharmaceutical chemistry, in particular to a novel synthesis method of N-Boc-L-phenylalaninol.
The background technology is as follows:
the structural formula of the N-Boc-L-phenylalaninol is as follows:
N-Boc-L-phenylalaninol is an important medical intermediate, and is mainly used for synthesizing the anti-tumor drug ubenimex. Ubenimex chemical name is N- [ (2 s,3 r) -3-amino-2-hydroxy-4-phenylbutyryl ] -L-leucine; is a competitive, reversible protease inhibitor. It has the main effects of improving body immunity, and can be used for anticancer chemotherapy, adjuvant treatment of treatment, and senile immunodeficiency. Can be used for treating leukemia and multiple myeloma.
At present, the synthesis of N-Boc-L-phenylalaninol takes L-phenylalanine as a starting material, and the two main protection routes are two, wherein the first route is prepared through esterification, reduction, upper protecting group, oxidation and other reactions; the second route is to prepare the catalyst through esterification, upper protection, partial reduction of aldehyde (or reduction to alcohol and partial oxidation to aldehyde) and the like. The above method also has the following problems:
1. the first route is that L-phenylalanine is prepared through esterification, reduction, amino protection and hydroxyl oxidation. The first three steps of the route are classical reactions, the fourth step of partial oxidation of hydroxyl into aldehyde is adopted at present, the oxidation step of the method still adopts the traditional Sarrett reagent or Jones reagent (US 9371359 and the like) to oxidize N-Boc-L-phenylalaninol at present in China, and the biggest problem is that raw materials are not thoroughly reacted, side reactions are more, and the produced heavy metal wastewater is more. Of course, other oxidants, such as Dess-Martin reagent (US 20090042867 et al), are also used, and these are generally expensive and unsuitable for industrial mass production.
2. The second route is that L-phenylalanine is prepared by esterification, amino protection, reduction and hydroxyl oxidation, or directly reduced from ester to aldehyde after amino protection, the former two steps are similar to the first route, and in the reduction step, a weak reducing agent diisobutyl aluminum hydride substituted aluminum reducing agent (WO 20080109613 and the like) is adopted to reduce the ester to aldehyde, and the method is characterized in that the reaction is pure, no byproducts are generated, the corresponding defects are obvious, the reaction temperature is required to be at the ultralow temperature of-78 ℃, and the method is not suitable for industrial production; the reducing agent has low safety in use, storage and the like, generates violent exothermic reaction when meeting water or absorbing moisture, is inflammable and has strong corrosiveness to human bodies when being contacted. There are also processes for reduction to alcohols and then partial oxidation to aldehydes, which, depending on the overall considerations of the multi-step synthesis, may optionally be followed by costly steps to reduce costs. The upper protection step is more advanced than route one, so the cost is higher.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and provides a preparation method of N-Boc-L-phenylalaninol with high yield and environmental protection, which is mainly an improvement on an oxidation step, and the specific reaction equation is as follows:
the synthesis scheme comprises the following preferable steps:
the oxidation step is operated as follows:
adding N-Boc-L-phenylalaninol (intermediate), copper salt, potassium hydrogen persulfate, organic solvent and water into a reaction bottle under the condition of ice-water bath (5-10 ℃), stirring and reacting for about 3-5 hours until TLC or liquid phase detects that the N-Boc-L-aminopropanol disappears, stopping the reaction, concentrating under reduced pressure below 40 ℃ to remove the organic solvent, precipitating a large amount of white solid, filtering, leaching a filter cake with ice water for 2 times, and drying to obtain crude N-Boc-L-phenylalaninol.
The crude N-Boc-L-phenylalaninol and methanol are put into a reaction bottle, and the temperature is raised until the liquid in the reaction bottle is clear. Stopping heating, stirring, slowly cooling to room temperature, precipitating a large amount of white crystals, continuously cooling to-5 to-10 ℃, stirring for 1-2 hours, carrying out suction filtration, leaching a filter cake with methanol below 0 ℃ for 2 times, drying, and crushing to obtain a pure product N-Boc-L-phenylalaninol.
Wherein the copper salt comprises copper chloride, copper bromide, copper iodide, copper sulfate, copper nitrate, copper acetate, etc. Wherein the organic solvent comprises acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, etc. Wherein the molar ratio of the N-Boc-L-phenylalaninol, the copper salt and the potassium hydrogen persulfate is 1 (0.01-0.05) (1.0-1.1); the volume ratio of the N-Boc-L-phenylalaninol, the organic solvent and the water is 1 (2-2.2), wherein the reaction temperature is controlled to be 5-10 ℃.
The core of the invention is that potassium hydrogen persulfate is used as an oxidant, and the traditional method has the following advantages:
1. compared with the Sarrett reagent or Jones reagent, potassium permanganate, manganese dioxide and the like used in the oxidation step in the traditional route one, the primary problem to be solved by the invention is the conversion rate of byproducts and raw materials; secondly, heavy metal pollution is caused, and the oxidizing agents generate more byproducts or are too weak to be converted because of oxidizing property or too strong, so that the later separation and purification difficulty is increased; and the oxidation is carried out by high-price heavy metals, so the problem of heavy metal wastewater is not negligible.
2. The key point in the traditional route II is that the ester is directly partially reduced into aldehyde by a weak reducing agent, but the reaction condition is more severe, and the use and storage requirements of the reducing agent are higher. There are also processes in which the alcohol is reduced to an alcohol by reduction of the ester and then partially oxidized to an aldehyde with a weak oxidizing agent, but the cost is increased compared to route one. The invention mainly bypasses the step by selecting the route one, and greatly optimizes and improves the oxidation step of the route one.
Drawings
In the drawings of the specification: FIG. 1 is a HPLC chart of the present product (i.e., N-Boc-L-phenylalaninol) and related data.
FIG. 2 is a comparative illustration of the synthetic scheme of the present invention for N-Boc-L-phenylalaninol with a conventional scheme.
Detailed Description
The invention is further described with reference to the following detailed drawings, in order to make the technical means, authoring features, workflow, and usage method of the invention achieve the purpose and efficacy easily understood.
Example 1
Under the condition of ice-water bath (5-10 ℃), 251g (1 mol) of N-Boc-L-phenylalaninol, 6.73g (0.05 mol) of copper chloride, 307g (1 mol) of potassium hydrogen persulfate, 500ml of acetonitrile and 500ml of water are added into a reaction bottle, stirred and reacted for about 3-5 hours until TLC or liquid phase detects that vanillin disappears, the reaction is stopped, the reaction is reduced pressure and concentrated under 40 ℃ to remove the organic solvent, a large amount of white solid is separated out, the white solid is filtered, and a filter cake is leached for 2 times by 250ml of ice water and dried, thus obtaining 261.7g of crude N-Boc-L-phenylalaninol.
1000ml of the crude N-Boc-L-phenylalaninol and methanol are put into a reaction bottle, and the temperature is raised until the liquid in the reaction bottle is clear. Stopping heating, stirring, slowly cooling to room temperature, precipitating a large amount of white crystals, continuously cooling to-5 to-10 ℃, stirring for 1-2 hours, carrying out suction filtration, leaching a filter cake with 200ml of methanol below 0 ℃ for 2 times, drying, and crushing to obtain 227.3g of pure N-Boc-L-phenylalanyl aldehyde with the yield of 91.3%. The results of liquid phase and nuclear magnetism detection of the product are shown in figure 1.
Example 2
Under the condition of ice-water bath (5-10 ℃), 251g (1 mol) of N-Boc-L-phenylalaninol, 11.75g (0.05 mol) of copper bromide, 307g (1 mol) of potassium hydrogen persulfate, 500ml of methanol and 500ml of water are added into a reaction bottle, stirred and reacted for about 3-5 hours until TLC or liquid phase detects that vanillin disappears, the reaction is stopped, the reduced pressure concentration is carried out below 40 ℃ to remove the organic solvent, a large amount of white solid is separated out, the filtration is carried out, the filter cake is leached with 250ml of ice water for 2 times, and the crude product N-Boc-L-phenylalaninol is obtained after drying is carried out for 265.3g.
1000ml of crude N-Boc-L-phenylalaninol and methanol are put into a reaction bottle, and the temperature is raised to reflux until the liquid in the reaction bottle is clear. Stopping heating, stirring, slowly cooling to room temperature, precipitating a large amount of white crystals, continuously cooling to-5 to-10 ℃, stirring for 1-2 hours, carrying out suction filtration, leaching a filter cake with 200ml of methanol below 0 ℃ for 2 times, drying, and crushing to obtain 229.3g of pure N-Boc-L-phenylalanyl aldehyde with a yield of 92.1%. HPLC content detection of the obtained product 1 The H-NMR nuclear magnetic hydrogen spectrum results were similar to those of example 1.
Example 3
Under the condition of ice-water bath (5-10 ℃), 251g (1 mol) of N-Boc-L-phenylalaninol, 14.78g (0.05 mol) of copper nitrate, 307g (1 mol) of potassium hydrogen persulfate, 500ml of ethanol and 500ml of water are added into a reaction bottle, stirred and reacted for about 3-5 hours until TLC or liquid phase detects that vanillin disappears, the reaction is stopped, the reduced pressure concentration is carried out below 40 ℃ to remove the organic solvent, a large amount of white solid is separated out, the filtration is carried out, the filter cake is leached with 250ml of ice water for 2 times, and the crude product N-Boc-L-phenylalaninol 263.8g is obtained after drying.
1000ml of crude N-Boc-L-phenylalaninol and methanol are put into a reaction bottle, and the temperature is raised to reflux until the liquid in the reaction bottle is clear. Stopping heating, stirring, slowly cooling to room temperature, precipitating a large amount of white crystals, continuously cooling to-5 to-10 ℃, stirring for 1-2 hours, carrying out suction filtration, leaching a filter cake with 200ml of methanol below 0 ℃ for 2 times, drying, and crushing to obtain 228.6g of pure N-Boc-L-phenylalanyl aldehyde with the yield of 91.8%. HPLC content detection of the obtained product 1 The H-NMR nuclear magnetic hydrogen spectrum results were similar to those of example 1.
Example 4
Under the condition of ice-water bath (5-10 ℃), 251g (1 mol) of N-Boc-L-phenylalaninol, 12.5g (0.05 mol) of copper sulfate, 307g (1 mol) of potassium hydrogen persulfate, 500ml of tetrahydrofuran and 500ml of water are added into a reaction bottle, the reaction is stirred for about 3-5 hours until TLC or liquid phase detects that vanillin disappears, the reaction is stopped, the reaction is reduced pressure and concentrated below 40 ℃ to remove the organic solvent, a large amount of white solid is separated out, the filtration is carried out, the filter cake is leached for 2 times by 250ml of ice water, and the crude product N-Boc-L-phenylalaninol 270.1g is obtained after drying.
1000ml of crude N-Boc-L-phenylalaninol and methanol are put into a reaction bottle, and the temperature is raised to reflux until the liquid in the reaction bottle is clear. Stopping heating, stirring, slowly cooling to room temperature, precipitating a large amount of white crystals, continuously cooling to-5 to-10 ℃, stirring for 1-2 hours, carrying out suction filtration, leaching a filter cake with 200ml of methanol below 0 ℃ for 2 times, drying, and crushing to obtain 230.5g of pure N-Boc-L-phenylalanyl aldehyde with the yield of 92.6%. HPLC content detection of the obtained product 1 The H-NMR nuclear magnetic hydrogen spectrum results were similar to those of example 1.
Example 5
Under the condition of ice-water bath (5-10 ℃), 251g (1 mol) of N-Boc-L-phenylalaninol, 9.98g (0.05 mol) of copper acetate, 307g (1 mol) of potassium hydrogen persulfate, 500ml of acetonitrile and 500ml of water are added into a reaction bottle, stirred and reacted for about 3-5 hours until TLC or liquid phase detects that vanillin disappears, the reaction is stopped, the reaction is reduced pressure and concentrated under 40 ℃ to remove the organic solvent, a large amount of white solid is separated out, the white solid is filtered, and a filter cake is leached for 2 times by 250ml of ice water and dried, thus obtaining 272.5g of crude N-Boc-L-phenylalaninol.
1000ml of crude N-Boc-L-phenylalaninol and methanol are put into a reaction bottle, and the temperature is raised to reflux until the liquid in the reaction bottle is clear. Stopping heating, stirring, slowly cooling to room temperature, precipitating a large amount of white crystals, continuously cooling to-5 to-10 ℃, stirring for 1-2 hours, carrying out suction filtration, leaching a filter cake with 200ml of methanol below 0 ℃ for 2 times, drying, and crushing to obtain 231.6g of pure N-Boc-L-phenylalanyl aldehyde with the yield of 93.0%. HPLC content detection of the obtained product 1 The H-NMR nuclear magnetic hydrogen spectrum results were similar to those of example 1.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (6)
1. The synthesis method of the N-Boc-L-phenylalaninol is characterized in that the N-Boc-L-phenylalaninol is prepared by taking N-Boc-L-phenylalanine as a starting raw material, sequentially carrying out esterification, reduction, amino protection and other reactions to obtain the N-Boc-L-phenylalaninol, and carrying out oxidation reaction again:
wherein, the N-Boc-L-phenylalaninol is mixed with copper salt, potassium hydrogen persulfate, organic solvent and water in ice water bath for the oxidation reaction to obtain the product N-Boc-L-phenylalaninol.
2. The method for producing N-Boc-L-phenylalaninol according to claim 1, wherein the copper salt comprises copper chloride, copper bromide, copper iodide, copper sulfate, copper nitrate, copper acetate, etc.
3. The method for producing N-Boc-L-phenylalaninol according to claim 1, wherein the organic solvent comprises acetonitrile, methanol, ethanol, isopropanol, tetrahydrofuran, etc.
4. The process for producing N-Boc-L-phenylalaninol according to claim 1, wherein the molar ratio of N-Boc-L-phenylalaninol, copper salt and potassium hydrogen persulfate is 1 (0.01 to 0.05): 1.0 to 1.1.
5. The method for preparing N-Boc-L-phenylalaninol according to claim 1, wherein the volume ratio of N-Boc-L-phenylalaninol, organic solvent and water is 1 (2-2.2).
6. The process for producing N-Boc-L-phenylalaninol according to claim 1, wherein the reaction temperatures are controlled to be 5 to 10 ℃.
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