CN109704996B - Method for preparing 3-halogenated-N-protected-L-tyrosine methyl ester - Google Patents
Method for preparing 3-halogenated-N-protected-L-tyrosine methyl ester Download PDFInfo
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Abstract
The invention discloses a method for preparing 3-halogeno-N-protected-L-tyrosine methyl ester, belonging to the technical field of organic synthesis. The N-protection-L-tyrosine methyl ester reacts with chloromethyl methyl ether and NXS in sequence to obtain 3-halogen-N-protection-O-methyl ether-L-tyrosine methyl ester, and then methyl ether is demethylated under the hydrogen atmosphere under the catalysis of palladium to obtain the 3-halogen-N-protection-L-tyrosine methyl ester. The invention provides a new choice for preparing the compounds, has mild reaction conditions, high reaction selectivity in each step, simple post-treatment and potential industrial amplification value.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing 3-halogeno-N-protected-L-tyrosine methyl ester.
Background
The cyclopeptide natural product has obvious effects on the activities of resisting tumors, resisting bacteria and the like, and is a hot field of the research of new drugs at present. Tyrosine skeleton is widely existed in natural products, and has important significance for maintaining antitumor or antibacterial activity. The selective protection and deprotection of amino acids in the synthesis of such natural products is crucial to control the reaction sites and improve the reaction efficiency. At present, benzyl and methyl are mostly used for protecting tyrosine phenolic hydroxyl, the protection of amino is mainly tert-butyloxycarbonyl and benzyloxycarbonyl, and a tyrosine derivative with an iodo at the 3-position is taken as an example, and the common preparation method is as follows:
the Mark Paetzel and Floyd E.Romesberg research group react 3-iodo-L-tyrosine, starting from 3-iodo-L-tyrosine, with thionyl chloride in methanol to give 3-iodo-tyrosine methyl ester. Then with di-tert-butyl dicarbonate (Boc)2O) to obtain the tert-butyloxycarbonyl protected 3-iodo-tyrosine methyl ester. Finally reacting with benzyl bromide to obtain 3-iodo-N-tert-butoxycarbonyl-O-benzyl-tyrosine methyl ester [ J.Am.Chem.Soc.,2011,133: 17869-17877-]The reaction equation is:
when a Christopher J. Moody research group synthesizes 3-iodo-N-benzyloxycarbonyl-O-benzyl-tyrosine tert-butyl ester, 3-iodo-L-tyrosine is also taken as a raw material and reacts with benzyl chloroformate (CbzCl) and tert-butyl bromide (t-BuBr) in sequence to obtain the 3-iodo-N-benzyloxycarbonyl-tyrosine tert-butyl ester. And finally reacting with benzyl bromide to obtain the target compound. The overall yield of the reaction route is 50% [ chem.eur.j.,2016,22:1-11], and the reaction equation is as follows:
floyd E.Romesberg et al reacted tyrosine methyl ester with CbzCl and dimethyl sulfate (DMS) to give N-benzyloxycarbonyl-O-methyl-tyrosine methyl ester, which was then reacted with iodine and silver sulfate to give 3-iodo-N-benzyloxycarbonyl-O-methyl-tyrosine methyl ester in a total yield of 61% [ J.Am.chem.Soc.,2007,129: 15830-:
taking the above examples as representative examples, there are two main methods for synthesizing 3-iodo-tyrosine derivatives reported in the literature, one of which is to synthesize the target compound by using tyrosine as a raw material, protecting the tyrosine, and then iodinating the tyrosine. The other one is to take 3-iodine-tyrosine as a raw material and obtain a target compound through protection.
The first method has cheap raw materials and high overall yield, but the second method has expensive raw materials and higher overall yield than the first method. In addition, the main disadvantage of protecting phenolic hydroxyl groups with benzyl and methyl groups is the palladium-catalyzed hydrogenation which is frequently used for debenzylation, which requires that protective groups for carboxyl and amino groups in the molecule must be resistant to hydrogenation, otherwise these groups are also removed; and strong Lewis acid such as boron tribromide, boron trifluoride diethyl etherate and the like is needed during demethylation, so that other acid-proof groups are easy to react. It can be seen that the selective reaction of protecting groups plays an important role in the synthesis of amino acid derivatives.
Disclosure of Invention
In order to overcome the defects, the invention adopts N-protection-L-tyrosine methyl ester to react with halogenated methyl ether and NXS in sequence to obtain 3-halogenated-N-protection-O-methyl ether-L-tyrosine methyl ester, and the 3-halogenated-N-protection-L-tyrosine methyl ester is obtained after selective deprotection under the conditions of palladium catalyst and hydrogen.
The invention provides a method for preparing 3-halogenated-N-protected-L-tyrosine methyl ester, which is characterized by comprising the following steps:
the method comprises the following steps:
the first step, reacting N-protection-L-tyrosine methyl ester with MOMX and NXS in sequence to obtain 3-halogen-N-protection-O-methyl ether-L-tyrosine methyl ester;
and secondly, deprotecting the 3-halo-N-protection-O-methyl ether-L-tyrosine methyl ester under the catalysis of palladium and in a hydrogen atmosphere to obtain the 3-halo-N-protection-L-tyrosine methyl ester.
Further, in the above technical scheme, the protecting group P is selected from tert-butoxycarbonyl, benzyloxycarbonyl, acetyl or benzoyl; x is selected from chlorine, bromine or iodine.
Further, in the above technical scheme, in the first step, the raw material of formula I reacts with halomethyl methyl ether and alkali in a chlorinated solvent, and then reacts with NXS to obtain the intermediate of formula II. The chlorinated solvent is selected from dichloromethane, chloroform or 1, 2-dichloroethane. NXS includes NCS, NBS or NIS. While the equivalent weight of NXS during halogenation is optimally no more than 1.3 equivalents of starting material I, above 1.5 equivalents, the dihalogenated product is significantly increased.
Further, in the above technical solution, in the first step, the base is selected from sodium hydride, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide.
Further, in the above technical scheme, in the second step, the intermediate of formula II is dissolved in an alcohol solution, a palladium catalyst is added, the reaction is performed under a hydrogen atmosphere, the solvent is filtered and evaporated, and the product of formula III is obtained by recrystallization. The recrystallization solvent is preferably ethyl acetate.
Further, in the above technical solution, in the second step, the palladium catalyst is selected from palladium carbon or palladium hydroxide; either 5% or 10% palladium on carbon of common commercial specifications can be used. The alcoholic solution is selected from methanol, ethanol or isopropanol. The hydrogen pressure in the reaction process is chlorine or bromine substitution at the 3-position, and the preferred pressure range is 1-5 atm; for iodine substitution at the 3 position, a pressure in the range of 1-2atm is preferred.
Further, in the above technical scheme, the molar ratio of the intermediate of the formula II to the palladium catalyst in the second step is 1000:1 to 5: 1.
Advantageous effects of the invention
According to the invention, the 3-halogenated-N-protective-O-methyl ether-L-tyrosine methyl ester is obtained by taking N-protective-L-tyrosine methyl ester as a raw material and reacting with halogenated methyl ether and NXS in sequence, the reaction yield is high, and the post-treatment is simple. Then, the 3-halogenated-N-protected-L-tyrosine methyl ester is obtained by protection under the conditions of palladium catalyst and hydrogen. The reaction is carried out under a neutral condition, the reaction condition is mild, acid-labile groups are not affected, and in the MOM removal protection process, a dehalogenation product is not detected on liquid, so that the method is very suitable for peptide synthesis. The post-treatment of the reaction only needs filtration and recrystallization, thereby improving the reaction yield, simplifying the post-treatment process and being beneficial to industrial production.
Drawings
FIG. 1 is a drawing showing the preparation of 3-iodo-N-benzyloxycarbonyl-L-tyrosine methyl ester in example 11H-NMR；
FIG. 2 is the preparation of methyl 3-iodo-N-benzyloxycarbonyl-L-tyrosine in example 113C-NMR；
FIG. 3 is the preparation of methyl 3-bromo-N-tert-butoxycarbonyl-L-tyrosine in example 21H-NMR；
FIG. 4 shows the preparation of methyl 3-bromo-N-tert-butoxycarbonyl-L-tyrosine in example 213C-NMR。
Detailed Description
Example 1
Preparation of 3-iodo-N-benzyloxycarbonyl-L-tyrosine methyl ester
1) Weighing 2.0mmol of N-benzyloxycarbonyl-L-tyrosine methyl ester, placing the N-benzyloxycarbonyl-L-tyrosine methyl ester into a round-bottomed flask, adding 40mL of dichloromethane, then adding 6.0mmol of triethylamine and 2.0mmol of chloromethyl methyl ether (MOMCl), then reacting for 5 hours, evaporating the solvent under reduced pressure, adding 20mL of water, extracting with 3 × 50mL of ethyl acetate, washing the separated organic phase with 20mL of water and saturated saline water once respectively, then drying with anhydrous sodium sulfate, evaporating the organic solvent under reduced pressure, dissolving with 20mL of methanol, adding 2.0mmol of NIS (N-iodosuccinimide), reacting for 6 hours at normal temperature, evaporating the solvent under reduced pressure, adding 15mL of water, extracting with 3 × 50mL of ethyl acetate, evaporating the organic solvent under reduced pressure to obtain a crude product of 0.97g, recrystallizing with 80mL of ethyl acetate to obtain 0.88g of 3-iodo-N-benzyloxycarbonyl-O-methyl ether-L-tyrosine methyl ester, the yield thereof was found to be 88%.1H-NMR(300MHz,CDCl3):δ(ppm)7.52(1H,d),7.38-7.29(5H,m),7.01-6.92(2H,m),5.32-5.27(1H,m),5.20(2H,s),5.14-5.04(2H,m),4.63-4.57(1H,m),3.72(3H,s),3.49(3H,s),3.05-2.94(2H,m).13C-NMR(75MHz,CDCl3):δ(ppm)171.82,155.69,155.37,140.22,136.29,131.25,130.40,128.66,128.30,128.17,114.85,95.09,87.30,67.14,56.52,54.91,52.51,36.93.
2) Weighing 1mmol of 3-iodine-N-benzyloxycarbonyl-O-methyl ether-L-tyrosine methyl ester, putting the 3-iodine-N-benzyloxycarbonyl-O-methyl ether-L-tyrosine methyl ester into a round-bottomed flask, dissolving the 3-iodine-N-benzyloxycarbonyl-L-tyrosine methyl ester in 10mL of methanol, adding 0.008mmol of 5% palladium carbon, reacting the mixture at room temperature for 1 hour under a hydrogen atmosphere (1atm), and detecting the completion of the reaction until no iodine product or other impurities are found (HPLC and liquid mass analysis). Filtering to remove solid, evaporating organic solvent under reduced pressure, recrystallizing with ethyl acetate to obtain 0.4g of 3-iodo-N-benzyloxycarbonyl-L-tyrosine methyl ester with yield of 88%;1H-NMR(300MHz,CDCl3):δ(ppm)7.23(5H,s),6.83(1H,d),6.69(1H,d),6.61(1H,d),5.37(1H,dd),4.99(2H,s),4.52-4.48(1H,m),3.60(3H,s),2.93-2.84(2H,m).13C-NMR(75MHz,CDCl3):δ(ppm)172.38,172.03,156.00,155.47,154.58,139.21,136.08,130.72,130.34,129.49,128.58,128.54,128.23,128.05,126.96,115.65,115.16,85.02,67.22,55.10,52.43,37.39,36.88.
example 2
Preparation of 3-bromo-N-tert-butoxycarbonyl-L-tyrosine methyl ester
1) Weighing1.0mmol of N-tert-butoxycarbonyl-L-tyrosine methyl ester is put into a round-bottom flask, 25mL of dichloromethane is added, 2.0mmol of sodium hydride and 1.0mmol of MOMCl are added, the mixture is reacted for 1 hour, the solvent is evaporated to dryness under reduced pressure, 15mL of water is added, the mixture is extracted by 3 multiplied by 25mL of ethyl acetate, the separated organic phase is washed by 15mL of water and saturated saline solution respectively, the mixture is dried by anhydrous sodium sulfate, the organic solvent is evaporated to dryness under reduced pressure, the mixture is dissolved by 15mL of methanol, 1.0mmol of NBS (N-bromosuccinimide) is added, the solvent is evaporated to dryness under reduced pressure after the reaction for 4 hours at room temperature, 15mL of water is added, the mixture is extracted by 3 multiplied by 25mL of ethyl acetate, the crude product is obtained after the organic solvent is evaporated to dryness under reduced pressure, 20mL of ethyl acetate is recrystallized, 0.35g of 3-bromo-, the yield thereof was found to be 83%.1H-NMR(300MHz,CDCl3):δ(ppm)7.20(1H,s),6.93-6.82(2H,m),5.21(2H,s),5.18(1H,d),4.53(1H,d),3.73(3H,s),3.50(3H,s),3.07-2.91(2H,m),1.43(9H,s).13C-NMR(75MHz,CDCl3):δ(ppm)172.25,155.30,154.98,134.82,131.57,130.06,115.53,110.85,80.51,56.66,54.50,52.39,36.92,28.28.
2) Weighing 0.6mmol of 3-bromo-N-tert-butoxycarbonyl-O-methyl ether-L-tyrosine methyl ester, placing into a round-bottom flask, dissolving with 10mL of methanol, adding 0.010mmol of 5% palladium carbon, reacting at room temperature under hydrogen atmosphere (2.2atm) for 1 hour, and detecting the completion of the reaction without finding bromine products and other impurities (HPLC and liquid mass analysis). Filtering to remove solid, evaporating the organic solvent under reduced pressure, and recrystallizing with ethyl acetate to obtain 0.37g of 3-bromo-N-tert-butoxycarbonyl-L-tyrosine methyl ester with yield of 85%;1H-NMR(300MHz,CDCl3):δ(ppm)7.24(1H,s),6.94(1H,d),6.87(1H,d),6.67(1H,s),5.19(1H,d),4.53(1H,d),3.75(3H,s),3.07-2.92(2H,m),1.43(9H,s).13C-NMR(75MHz,CDCl3):δ(ppm)172.28,155.25,151.84,133.01,129.71,129.26,116.25,109.97,80.27,54.51,52.36,37.10,28.27.
example 3
Preparation of 3-chloro-N-tert-butoxycarbonyl-L-tyrosine methyl ester
1) 0.5mmol of N-tert-butoxycarbonyl-L-tyrosine methyl ester was weighed into a round-bottom flask, 10mL of dichloromethane was added, then 1mmol of diisopropylethylamine and 0.5mmol of chloromethyl methyl ether (MO) were addedMCl), then reacting for 1.5 hours, evaporating the solvent under reduced pressure, adding 5mL of water, extracting with 3 × 15mL of ethyl acetate, washing the separated organic phase with 5mL of water and saturated saline solution once respectively, then drying with anhydrous sodium sulfate, evaporating the organic solvent under reduced pressure, dissolving with 5mL of methanol, adding 0.5mmol of NCS (N-chlorosuccinimide), evaporating the solvent under reduced pressure after reacting for 5 hours, adding 5mL of water, extracting with 3 × 15mL of ethyl acetate, evaporating the organic solvent under reduced pressure to obtain a crude product, recrystallizing with 10mL of ethyl acetate to obtain 0.13g of 3-chloro-N-tert-butoxycarbonyl-O-methyl ether-L-tyrosine methyl ester with a yield of 71%;1H-NMR(300MHz,CDCl3):δ(ppm)7.35(1H,s),7.05-6.96(2H,m),5.20(2H,s),5.04(1H,d),4.53(1H,d),3.73(3H,s),3.51(3H,s),3.06-2.98(2H,m),1.43(9H,s).13C-NMR(75MHz,CDCl3):δ(ppm)172.15,156.28,151.86,133.01,129.74,129.27,116.26,109.99,81.04,56.60,54.54,52.38,37.32,28.33.
2) 0.2mmol of 3-chloro-N-tert-butoxycarbonyl-O-methyl ether-L-tyrosine methyl ester is weighed and put into a round-bottom flask, dissolved by 5mL of methanol, added with 0.015mmol of 5% palladium carbon and reacted for 1 hour at room temperature under hydrogen atmosphere (3.5atm), and after the reaction is detected to be finished, no chlorine product and other impurities are found (HPLC and liquid mass analysis). Filtering to remove solid, evaporating organic solvent under reduced pressure, and recrystallizing with ethyl acetate to obtain 0.05g of 3-chloro-N-tert-butoxycarbonyl-L-tyrosine methyl ester with yield of 80%;1H-NMR(300MHz,CDCl3):δ(ppm)7.08(1H,s),6.93(1H,d),6.89(1H,d),5.04(1H,d),4.52(1H,d),3.72(3H,s),3.02-2.94(2H,m),1.42(9H,s).13C-NMR(75MHz,CDCl3):δ(ppm)172.28,155.25,151.84,133.01,129.71,129.26,116.25,109.97,80.27,54.51,52.36,37.10,28.27.
example 4:
the reaction was carried out analogously as in example 3, with the following results for the other reaction substrates:
the foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (7)
1. A process for preparing 3-halo-N-protected-L-tyrosine methyl ester, characterized by the reaction equation:
the method comprises the following steps:
the first step, reacting N-protection-L-tyrosine methyl ester with MOMX and NXS in sequence to obtain 3-halogen-N-protection-O-methyl ether-L-tyrosine methyl ester;
secondly, deprotecting the 3-halo-N-protection-O-methyl ether-L-tyrosine methyl ester under the catalysis of palladium in a hydrogen atmosphere to obtain 3-halo-N-protection-L-tyrosine methyl ester; in the reaction process, the hydrogen pressure is replaced by chlorine or bromine at the 3-position, and the pressure range is 1-5 atm; for iodine substitution at position 3, pressure range 1-2 atm;
wherein the protecting group P is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, acetyl or benzoyl; x is selected from chlorine, bromine or iodine; NXS comprises NCS, NBS or NIS, and the NXS equivalent weight does not exceed 1.3 equivalent weight of the starting material I.
2. A process for the synthesis of 3-halo-N-protected-L-tyrosine methyl ester according to claim 1, characterized in that: in the first step, the starting material of formula I is reacted with halomethylether and base in a chlorinated solvent, followed by reaction with NXS to give the intermediate of formula II.
3. A process for the synthesis of 3-halo-N-protected-L-tyrosine methyl ester according to claim 2, characterized in that: the chlorinated solvent is selected from dichloromethane, chloroform or 1, 2-dichloroethane.
4. A process for the synthesis of 3-halo-N-protected-L-tyrosine methyl ester according to claim 3, characterized in that: in the first step, the base is selected from sodium hydride, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide.
5. A process for the synthesis of 3-halo-N-protected-L-tyrosine methyl ester according to claim 1, characterized in that: and in the second step, dissolving the intermediate in the formula II in an alcohol solution, adding a palladium catalyst, reacting under a hydrogen atmosphere, filtering and evaporating the solvent, and recrystallizing to obtain the product in the formula III.
6. The method of synthesizing 3-halo-N-protected-L-tyrosine methyl ester according to claim 5, wherein: in the second step, the palladium catalyst is selected from palladium carbon or palladium hydroxide; the alcoholic solution is selected from methanol, ethanol or isopropanol.
7. The method of synthesizing 3-halo-N-protected-L-tyrosine methyl ester according to claim 5, wherein: in the second step, the molar ratio of the intermediate of formula II to the palladium catalyst is 1000:1 to 5: 1.
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| Platinum-Catalyzed α,β –Unsaturated Carbene Formation in the Formal Syntheses of Frondosin B and Liphagal;Khoi Q. Huynh et al.;《Organic Letters》;20161220;第19卷;第294-297页 * |
| Synthesis of F-18 labeled fluoroalkyltyrosine derivatives and their biological evaluation in rat bearing 9L tumor;Byung Seok Moon et al.;《Bioorganic & Medicinal Chemistry Letters》;20061010;第17卷;第200-204页 * |
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