CN107556235B - 2 ', 6' -dimethyl tyrosine derivative and C-H activated methylation synthesis method thereof - Google Patents
2 ', 6' -dimethyl tyrosine derivative and C-H activated methylation synthesis method thereof Download PDFInfo
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Abstract
The invention provides a 2 ', 6' -dimethyltyrosine derivative and a C-H activated methylation synthesis method thereof, and particularly provides a compound shown as a formula I, wherein the definition of each group is described in the specification. The invention also provides a preparation method of the compound.
Description
Technical Field
The invention relates to the field of drug synthesis, and particularly provides a 2 ', 6' -dimethyltyrosine derivative synthesized by C-H activated methylation and a preparation method thereof.
Background
The polypeptide and protein are important physiological regulators of human body, can regulate physiological functions of human body comprehensively, enhance and exert physiological activity of human body, and have important biological functions. Peptides are important for human cellular activity, functional activities, and life existence. Introduction of non-natural amino acids into polypeptides can significantly alter the properties of the polypeptide, including bioactivity, solubility, metabolic stability. DMT (2 ', 6' -dimethyl-L-tyrosine) is a very important tailored amino acid, especially in the de novo design of diverse synthetic polypeptides. The unnatural amino acid is a component of a delta-opiate stimulant Dmt-Tic pharmacophore and is present in a plurality of polypeptide components (delta-antagonists, delta-agonists and delta-antagonists, mu-agonists) with physiological activity. Taking opioid polypeptide as an example, natural opioid receptors have poor physiological applicability and are easily decomposed in vivo due to the difficulty of blood brain barrier penetration. The non-natural amino acid DMT (2 ', 6' -dimethyl-L-tyrosine) is used for replacing tyrosine on the 1 position of a peptide chain, structure optimization is carried out on a peptide derived lead compound, various biological activities and metabolic stability are improved, the analgesic effect is obvious in vivo, and the side effect and the tolerance of opioid receptors are reduced. The intervention of DMT results in a structural conformational change of the opioid pharmacophore (N-terminal) while shifting the orientation of the NK1 pharmacophore (C-terminal), enhancing its affinity and activity in the opioid and NK1 receptors. In addition, DMT is also an intermediate in the synthesis of other drugs, such as the digestive drug Ilidoline.
Therefore, it is important to develop a method for efficiently synthesizing DMT, and various methods have been used to realize the asymmetric synthesis of DMT.
In 1992, Gary R.Beck firstly utilizes Heck reaction to synthesize hydrogenation substrate, then uses chiral rhodium catalyst to catalyze asymmetric hydrogenation reaction to implement construction of key chiral center so as to obtain the invented product with good stereoselectivity and high yield. However, the reaction needs a complex and expensive chiral rhodium catalyst, the catalyst amount is large (1 mol%), the hydrogenation condition is harsh (60psi, 60 ℃), and the deprotection condition is severe.
In 2011, the condition of the reaction is optimized by C é line F.B. Praquin, the rhodium catalyst is improved, the catalytic amount is reduced, the hydrogenation reaction condition is mild, the Boc protected DMT is obtained in a mild deprotection mode, and the yield is obviously improved. However, expensive chiral rhodium catalyst is still needed, and the hydrogenation conditions are still harsh.
In 2009, Daniele Balducci adopts chiral-methylbenzylamine as a chiral auxiliary group and a nitrogen source, and reacts with chloroacetyl chloride to generate a glycine dimeric ring compound with the chiral auxiliary group, so that chiral control of-site alkylation can be better realized, and DMT with single chirality can be synthesized de novo.
In 2000, Victor j.hruby underwent alpha-alkylation with 2 ', 6' -dimethyl-substituted benzyl bromide under alkaline conditions with the aid of a chiral nickel complex with glycine fragments to form two diastereomers, and after separation, the nickel auxiliary was removed to obtain compounds of two R and S configurations, respectively.
On the basis, in 2014, Vadim A. Solosonok designs and synthesizes chiral nickel-containing ligand, and carries out chemical resolution on the existing racemic DMT.
Despite the previous methods for synthesizing (S) -DMT, conventional methods for synthesizing DMT have significant limitations. For example, the hydrogenation asymmetric synthesis reaction needs a complex and expensive chiral rhodium catalyst, and the hydrogenation conditions are harsh; de novo synthesis is a lengthy procedure, sometimes requiring specific ligands to control chirality; chemical resolution can only obtain half of DMT with S configuration, and the method is not efficient and does not accord with the atom economy principle. In conclusion, the development of a new DMT synthesis method has important scientific significance and application value.
The invention starts from natural tyrosine, adopts palladium-catalyzed C-H activated methylation to directly obtain the optically pure 2 ', 6' -dimethyl tyrosine derivative, and has short steps and high efficiency. And the synthesized 2 ', 6' -dimethyltyrosine compound can be synthesized into 2 ', 6' -Dimethyltyrosine (DMT) by further removing the protecting group.
Disclosure of Invention
The invention aims to adopt pyridine-2-formamide as a guide group to realize direct dimethylation of a benzene ring of a tyrosine derivative under the condition of palladium catalysis, thereby efficiently synthesizing a 2 ', 6' -dimethyltyrosine compound.
In a first aspect of the present invention, there is provided a compound of formula I:
wherein the content of the first and second substances,
R1is H or C1-C10 alkyl;
R2selected from the group consisting of: H. halogen, COOR ', OR'; wherein R' is selected from the group consisting of: H. TBS, TBDPS, TIPS, TES (silane), Me, Bn (alkyl); MOM, THP (alkoxymethyl), Ac, Piv (acyl), Boc (alkoxycarbonyl), Tf (trifluoromethanesulfonyl); r' is selected from the group consisting of: C1-C4 alkyl;
R3is a substituted or unsubstituted 5-10 membered nitrogen containing heterocycle, straight or branched C1-C4 alkyl;
ra and Rb are each independently H,CF3Or C1-C4 alkyl;
and when Ra and Rb are both H, R1When is Me, R2Is not a group selected from: OH, OBn, Cl, Br, I, OMe.
In another preferred embodiment, when Ra and Rb are each independently H, said R is2Selected from the group consisting of: -OTBS, -OTBDPS, TIPS, TES, Bn, PMB, MOM, THP, Ac, Piv, Boc.
In another preferred embodiment, R is3Is an unsubstituted 5-10 membered nitrogen containing heterocyclic ring; preferably, R is3Selected from the group consisting of: pyridyl, pyrazinyl, quinolyl.
In another preferred embodiment, Ra and Rb are each independently H or methyl.
In another preferred embodiment, Ra and Rb are each independently methyl.
In another preferred embodiment, the compound is a compound selected from the group consisting of:
in a second aspect of the invention, there is provided a process for the preparation of a compound of formula I,
wherein the content of the first and second substances,
R1is CF3Or C1-C4 alkyl;
R2selected from the group consisting of: H. halogen, COOR ', OR'; wherein R' is selected from the group consisting of: h, TBS, TBDPS, TIPS, TES (silane); me, Bn (alkyl); MOM, THP (alkoxymethyl); ac, Piv (acyl); boc (alkoxycarbonyl); tf (trifluoromethanesulfonyl)
R3To substituteOr an unsubstituted 5-10 membered nitrogen containing heterocycle;
ra and Rb are each independently H, CF3Or C1-C4 alkyl;
the method is characterized by comprising the following steps of (2):
(2) reacting the compound of formula 2 with an alkylating agent in an inert solvent to provide a compound of formula 1'.
In another preferred embodiment, the alkylating agent is selected from the group consisting of: alkyl iodides, dialkyl sulfates, dialkyl carbonates, alkyl boranes, alkyl boronic acids, or combinations thereof; wherein the alkyl is CF3Or C1-C4 alkyl.
In another preferred embodiment, in the step (2), the reaction is carried out in the presence of a base; preferably, the base is selected from the group consisting of: NaHCO 23，KHCO3，Na2CO3，K2CO3，Cs2CO3，BaCO3，NaOAc，KOAc，CsOAc，K3PO4，K2HPO4Or a combination thereof; and/or
In the step (2), the reaction is carried out in the presence of a metal catalyst; preferably, the metal catalyst is selected from the group consisting of: pd (OAc)2、Pd(OTFA)2、Pd(TEA)2、PdCl2Preferably Pd (OAc)2(ii) a And/or
In said step (2), said reaction is carried out in the presence of an acidic additive, preferably in the presence of an additive selected from the group consisting of: pivalic acid (PivOH), dibenzyl phosphate ((BnO)2P (O) OH) or a combination thereof; and/or
In the step (2), the inert solvent is selected from the group consisting of: toluene/tert-amyl alcohol, toluene, dichloroethane, tert-amyl alcohol, dioxane, chlorobenzene, trifluorotoluene, p-xylene, o-xylene, m-xylene, (BnO)2P (O) OH/toluene, (BnO)2P (O) OH/chlorobenzene, acetonitrile, or mixtures thereofCombining; and/or
In the step (2), the methylating agent is selected from the group consisting of: methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl borane, methyl boronic acid, or combinations thereof.
In another preferred embodiment, in the step (2), the reaction is performed in a reaction atmosphere selected from the group consisting of: inert gas atmosphere, air atmosphere, oxygen atmosphere.
In another preferred embodiment, in the step (2), the ratio of the metal catalyst to the compound of formula 2 is a metal catalyst: the compound of the formula 2 is 1: 1-100, preferably the ratio is 1: 10-40.
In another preferred example, in the step (2), the ratio of the compound of formula 2 to the methylating agent is 1: 1 to 100, preferably 1: 3 to 1: 6.
In another preferred example, in the step (2), the ratio of the compound of formula 2 to the base is 1: 1 to 5, preferably 1: 1 to 3.
In another preferred embodiment, in the step (2), the reaction temperature is 50 to 150 ℃, preferably 90 to 120 ℃.
In another preferred embodiment, the compound of formula 2 is prepared by the method described below:
(1) using a compound of formula 3 and R in an inert solvent in the presence of a condensing agent and a base3-COOH reaction to give a compound of formula 2;
and when R' is TBS, said method further comprises optional steps (3) and (4):
(3) carrying out deprotection reaction by using the compound shown in the formula 2 in an inert solvent to obtain a compound shown in the formula 5;
(4) reacting the compound of formula 5 with a hydroxyl protecting reagent to obtain the compound of formula 4.
In another preferred embodiment, when Ra and Rb are both H, R1When is Me, R2Is not a group selected from: OH, OBn, C1, Br, I, OMe.
In another preferred embodiment, in the step (1), the R3-COOH is selected from the group consisting of: pyridine-2-carboxylic acid, 2-quinolinecarboxylic acid, pyrazine-2-carboxylic acid; and/or
In the step (1), the condensing agent is selected from the group consisting of: DCC, EDCI, HOBt, HOAt, HBTU, TBTU, HATU, BOP, or combinations thereof; and/or
In the step (1), the base is selected from the group consisting of: et (Et)3N, DIPEA, NMM, or a combination thereof; and/or
In the step (1), the solvent is selected from the group consisting of: DCM, THF, DMSO, DMF, or combinations thereof.
In another preferred embodiment, in the step (1), the reaction is carried out at 0 ℃ to room temperature (10 ℃ to 40 ℃).
In another preferred embodiment, in the step (3), the inert solvent is selected from the group consisting of: THF, methanol, Dioxane, or a combination thereof.
In another preferred embodiment, in the step (3), the deprotection reaction is performed in the presence of a reagent selected from the group consisting of: TBAF, lithium hydroxide, K2CO3，AcOH，HCl。
In another preferred embodiment, in the step (3), the reaction temperature is 0 ℃ to room temperature (10 ℃ to 40 ℃).
In another preferred embodiment, in the step (4), the hydroxyl protecting agent is selected from the group consisting of: acid chlorides (acetyl chloride, pivaloyl chloride, CbzCl), benzyl chloride or bromide (including p-methoxybenzyl chloride), Boc anhydride, 3, 4-dihydro-2H-pyran, MOMCl.
In another preferred embodiment, in the step (4), the reaction is carried out in the presence of a catalyst selected from the group consisting of: DMAP, PPTs.
In another preferred embodiment, in the step (4),the reaction is carried out in the presence of a base selected from the group consisting of: DIPEA, Et3N，K2CO3Or a combination thereof.
In another preferred embodiment, in the step (4), the inert solvent is selected from the group consisting of: DCM, MeCN, DMF, or combinations thereof.
In another preferred embodiment, in the step (4), the reaction temperature is 0 ℃ to room temperature (10 ℃ to 40 ℃).
In another preferred example, the method further comprises the steps of:
reacting a compound of formula 4 with R' Cl in an inert solvent in the presence of a base to provide a compound of formula 3.
In another preferred embodiment, said R' Cl is selected from the group consisting of: TBSCl, TBSOTf, TIPSCl, TBDPS, TES, TMS.
In another preferred embodiment, the base is selected from the group consisting of: DBU, imidazole, DIPEA, pyridine, or combinations thereof.
In another preferred embodiment, the inert solvent is selected from the group consisting of: DCM, acetonitrile, THF, DMF, or a combination thereof.
In another preferred embodiment, the reaction is carried out at a temperature of 0 ℃ to room temperature (10 ℃ to 40 ℃).
In another preferred example, the method further comprises the steps of:
in an inert solvent in SOCl2With L-tyrosine and R in the presence1OH to obtain the compound of the formula 4.
In another preferred embodiment, R is1OH is selected from the group consisting of: MeOH, EtOH, iPrOH, nBuOH, or combinations thereof.
In another preferred embodiment, the compound of formula 2 is prepared by the method described below:
(a) reacting a compound of formula Ia with R' OH and CO in an inert solvent in the presence of a metal catalyst, a ligand and a base to obtain a compound of formula Ib;
wherein X is selected from the group consisting of: i, Br, Cl;
preferably, in the step (a), the metal catalyst is selected from the group consisting of: pd (OAc)2、Pd(dba)3、Pd/C、PdCl2、PdCl2(Ph3P)2、PdCl2(PCy3)2(ii) a And/or
In step (a), the ligand is selected from the group consisting of: dppp, Ph3P, dippp, dppe, dppf, or a combination thereof; and/or
In step (a), the base is selected from the group consisting of: tertiary amines, NaOAc, KOAc, Na2CO3，K2CO3NaOH, or combinations thereof.
In another preferred embodiment, said R "OH is a nucleophile; preferably, the nucleophile is selected from the group consisting of: alcohols, H2O。
In another preferred embodiment, in the step (a), the inert solvent is selected from the group consisting of: toluene, DMF, DMSO, DMA, or said step (a) using the nucleophile used as a solvent.
In another preferred embodiment, in the step (a), the reaction is carried out at room temperature (10-40 ℃) to 100 ℃.
In a third aspect of the present invention, there is provided a process for preparing a 2 ', 6' -dimethyltyrosine derivative, the process comprising the steps of:
(i) in an inert solvent, carrying out deprotection by using a compound shown as a formula A to obtain a deprotection group product;
(ii) reacting the deprotected product with Boc in an inert solvent2O reaction to give N-Boc protected 2 ', 6' -dimethyltyrosine:
preferably, the method further comprises the step of: and removing the Boc protecting group of the N-Boc protected 2 ', 6' -dimethyltyrosine to obtain 2 ', 6' -dimethyltyrosine.
In another preferred embodiment, the deprotection in step (1) is performed under acidic conditions.
In another preferred embodiment, said step (2) is carried out in the presence of a base; preferably, the base is sodium hydroxide.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the invention has long and intensive research and unexpectedly found a preparation method of 2 ', 6' -dimethyltyrosine compounds, wherein pyridine-2-formamide is adopted as a guide group, and direct dimethylation of a benzene ring of a tyrosine derivative is realized under the palladium catalysis condition, so that the 2 ', 6' -dimethyltyrosine compounds are efficiently synthesized. Based on the above findings, the inventors have completed the present invention.
2 ', 6' -dimethyltyrosine compound
The invention provides a 2 ', 6' -dimethyl tyrosine compound, which has a structure shown as the following formula I:
wherein the content of the first and second substances,
R1is H or C1-C10 alkyl;
R2selected from the group consisting of: H. halogen, COOR ', OR'; wherein R' is selected from the group consisting of: h, TBS, TBDPS, TIPS, TES (silane); me, Bn (alkyl); MOM, THP (alkoxymethyl); ac, Piv (acyl); boc (alkoxycarbonyl), Tf (trifluoromethanesulfonyl); r' is selected from the group consisting of: C1-C4 alkyl
R3Is a substituted or unsubstituted 5-10 membered nitrogen containing heterocycle; straight or branched C1-C4 alkyl
Ra and Rb are each independently H or C1-C4 alkyl;
and when Ra and Rb are both H, R1When is Me, R2Is not a group selected from: OH, OBn, C1, Br, I, OMe.
In a preferred embodiment of the invention, the derivative has the structure (methylated product) shown below:
r1: h, C1-C10 alkyl
R2: h, halogen, COOR ', OR'
Wherein R': h, TBS, TBDPS, TIPS, TES (silane); me, Bn (alkyl); MOM, THP (alkoxymethyl); ac, Piv (acyl); boc (alkoxycarbonyl); tf (trifluoromethanesulfonyl).
R3: a substituted or unsubstituted 5-10 membered nitrogen containing heterocycle; straight or branched C1-C4 alkyl
In another preferred embodiment of the present invention, the derivative has a structure shown in the following formula (which can also be used as a methylation reaction raw material).
R1: h, C1-C10 alkyl
R2: h, halogen, COOR ', OR'
Wherein R': h, TBS, TBDPS, TIPS, TES (silane); me, Bn (alkyl); MOM, THP (alkoxymethyl); ac, Piv (acyl); boc (alkoxycarbonyl); tf (trifluoromethanesulfonyl).
R3: a substituted or unsubstituted 5-10 membered nitrogen containing heterocycle; straight or branched C1-C4 alkyl
Preparation of 2 ', 6' -dimethyl tyrosine compound
The 2 ', 6' -dimethyl tyrosine compound can be prepared by the following method:
1. synthesis of Compound 1 from Compound 2 by C-H activated methylation
The reaction equation is as follows:
in the reaction, the compound of formula 2 is reacted with a methylating agent. Wherein the methylating agent is selected from the group consisting of: methyl iodide, dimethyl sulfate, dimethyl carbonate, methyl borane and methyl boric acid.
The metal catalyst used is selected from the group consisting of: pd (OAc)2、Pd(OTFA)2、Pd(TEA)2、PdCl2Preferably Pd (OAc)2
The base used is selected from the group consisting of: NaHCO 23，KHCO3，Na2CO3，K2CO3，Cs2CO3，BaCO3，NaOAc，KOAc，CsOAc，K3PO4，K2HPO4。
In the above reaction, other additives such as acid additives may be added to improve the reaction efficiency or the yield. Such other additives are for example (but not limited to) acid additives selected from the group consisting of: pivalic acid (PivOH), dibenzyl phosphate ((BnO)2P (O) OH), or a combination thereof.
The solvent used is selected from the group consisting of: toluene/tert-amyl alcohol, toluene, dichloroethane, tert-amyl alcohol, dioxane, chlorobenzene, trifluorotoluene, p-xylene, o-xylene, m-xylene, (BnO)2P (O) OH/toluene, (BnO)2P (O) OH/chlorobenzene, acetonitrile, or combinations thereof; and/or
The above reaction may be carried out in an inert atmosphere such as an inert gas atmosphere, or may be carried out in an air atmosphere or an oxygen atmosphere.
In a preferred embodiment of the invention, the charge ratio of the materials in the reaction is as follows: metal catalyst: the ratio of the compounds of formula 2: 1: 1 to 1: 100 (i.e. the ratio of the metal catalyst is from 1 mol% to 100 mol%), preferably 1: 40 to 1: 10.
The ratio of the compound of the formula 2 to the methylating agent is 1: 1-1: 100, preferably 1: 3-1: 6.
The reaction may be carried out at a suitable reaction temperature, such as reflux temperature, preferably at a reaction temperature of 50 to 150 deg.C, more preferably at a reaction temperature of 90 to 120 deg.C.
2. Synthesis of methylation reaction raw material
In the present invention, the starting compound of formula 2 for the methylation reaction can be synthesized by the following methods A to C:
the synthesis method A comprises the following steps:
starting from tyrosine, with alcohols (R) under thionyl chloride conditions1OH) is heated and refluxed for esterification, then reacts with silanization reagent (R' Cl) to obtain tyrosine phenol hydroxyl silane protective product, and finally reacts with heterocyclic carboxylic acid (R)3COOH) to obtain the raw material 2 for methylation reaction.
Equation (b)
In the first reaction step, R1OH is preferably selected from the group consisting of: MeOH, EtOH, iPrOH, nBuOH.
In a preferred embodiment of the invention, the charge ratio of the materials in the reaction is as follows: compound L-lysine with SOCl2、R1The OH ratios were L-lysine (1.0eq) and SOCl, respectively2(1.0-2.0eq, preferably 1.5eq), R1OH as a solvent (0.5-2M, preferably 1.0M);
in the second reaction step, R' Cl is preferably selected from the group consisting of: TBSCl, TBSOTf, TIPSCl, TBDPS, TES, TMS.
The base is preferably selected from the group consisting of: DBU, imidazole, DIPEA, pyridine.
The solvent is preferably selected from the group consisting of: DCM, acetonitrile, THF, DMF.
The reaction can be carried out at a suitable reaction temperature, preferably from 0 ℃ to room temperature.
In a preferred embodiment of the invention, the charge ratio of the materials in the reaction is as follows: the ratio of the compound 4 to the R 'Cl and the base is, respectively, 4(1.0eq), R' Cl (1.0-2.0eq, preferably 1.5eq), base (1.5-2.5eq, 2.0eq), solvent (0.7-1.0M)
In the third reaction step, R3-COOH is preferably selected from the group consisting of: pyridine-2-carboxylic acid, 2-quinolinecarboxylic acid, pyrazine-2-carboxylic acid.
The condensing agent is preferably selected from the group consisting of: DCC, EDCI, HOBt, HOAt, HBTU, TBTU, HATU, BOP.
The base is preferably selected from the group consisting of: et (Et)3N，DIPEA，NMM。
The solvent is preferably selected from the group consisting of: DCM, THF, DMSO, DMF.
The reaction can be carried out at a suitable reaction temperature, preferably from 0 ℃ to room temperature.
In a preferred embodiment of the invention, the charge ratio of the materials in the reaction is as follows:
the proportions of the compound 3 to the condensing agent, the base and R3-COOH were respectively compound 3(1.0eq), the condensing agent (1.0-1.5eq, preferably 1.2eq), the base (2.0-3.0eq, preferably 2.5eq), R3-COOH (1.0-1.5eq, preferably 1.2eq), and the solvent (0.1-0.5M, preferably 0.25 eq).
The synthesis method B comprises the following steps:
and (3) removing the silicon-based protecting group from the compound 2 obtained in the first synthesis method, and replacing the silicon-based protecting group with other ether protecting groups.
Wherein the deprotecting reagent used in the desiliconizing ether protecting group step (step 1) is selected from the group consisting of: TBAF, lithium hydroxide, K2CO3，AcOH，HCl；
The reaction is carried out in a solvent selected from the group consisting of: THF, methanol, Dioxane;
the reaction temperature is preferably from 0 ℃ to room temperature.
In a preferred embodiment of the invention, the charge ratio of the materials in the reaction is as follows: the ratio of Compound 2 to deprotecting agent is Compound 2(1.0eq), deprotecting agent (1.2-3.0eq), solvent (0.3-0.7M, preferably 0.5M)
In the hydroxyl group protecting step (step 2), the hydroxyl group protecting agent used is selected from the group consisting of: acid chlorides (acetyl chloride, pivaloyl chloride, CbzCl), benzyl chloride or bromide (including p-methoxybenzyl chloride), Boc anhydride, 3, 4-dihydro-2H-pyran, MOMCl;
the base is preferably selected from the group consisting of: DIPEA, Et3N，K2CO3；
The reaction may be carried out in a catalyst selected from the group consisting of: DMAP, PPTs;
the solvent is preferably: DCM, MeCN, DMF;
the reaction can be carried out at a suitable reaction temperature, preferably from 0 ℃ to room temperature.
In a preferred embodiment of the invention, the charge ratio of the materials in the reaction is as follows:
the proportions of the compound 2, the hydroxyl-protecting group reagent, the base and the catalyst are respectively compound 2(1.0eq), the hydroxyl-protecting group reagent (1.2-3.0eq), the base (2-3eq, preferably 2.5eq), the catalyst (10-20%), and the solvent (0.3-0.5M)
The synthesis method C comprises the following steps:
equation (b)
Wherein:
x is I, Br, Cl;
the catalyst is a metal catalyst, for example a metal catalyst selected from the group consisting of: pd (OAc)2，Pd(dba)3，Pd/C，PdCl2，PdCl2(Ph3P)2，PdCl2(PCy3)2；
The ligand is preferably the following ligand: dppp, Ph3P，dippp，dppe，dppf；
The base is preferably a base selected from the group consisting of: tertiary amines, NaOAc, KOAc, Na2CO3，K2CO3，NaOH，
The nucleophilic reagent is R' -OH, and preferably: alcohol, H2O，
The reaction can be carried out in the following solvents: toluene, DMF, DMSO, DMA, the corresponding alcohol (i.e., R "-OH).
The reaction may be carried out at a suitable reaction temperature, such as reflux temperature, with a preferred reaction temperature of from room temperature to 100 ℃.
In a preferred embodiment of the invention, the charge ratio of the materials in the reaction is as follows: the proportions of the starting material to the catalyst, ligand, base and nucleophile are starting material (1.0eq), catalyst (8-12 wt%, preferably 10 wt%), ligand (8-12 wt%, preferably 10 wt%), base (1.0-5.0mmol, preferably 3.0mmol) and nucleophile (15.0-25.0eq, preferably 20eq), respectively.
3. Activating the methylated 2 ', 6' -dimethyltyrosine derivative 1 by C-H, and removing a protecting group and a guiding group by the following method to synthesize N-Boc protected 2 ', 6' -dimethyltyrosine;
the Boc protecting group can be easily removed by a conventional protecting group removal method to obtain 2 ', 6' -dimethyltyrosine.
Compared with the prior art, the invention has the main advantages that:
(1) the reaction method comprises the following steps: the existing synthesis method of 2 ', 6' -dimethyltyrosine mainly synthesizes non-amino acid raw materials from the beginning, has long synthesis route and adopts an asymmetric synthesis catalyst which is expensive; chemical resolution methods lose unwanted isomers and have low synthesis efficiency. The scheme starts from natural tyrosine, adopts palladium-catalyzed C-H activated methylation to directly obtain the optically pure 2 ', 6' -dimethyl tyrosine derivative, and has short steps and high efficiency.
(2)2 ', 6' -dimethyltyrosine derivative 1 uses: the 2 ', 6' -dimethyltyrosine can be synthesized through further removing protective groups and other reactions, and the unnatural amino acid of the 2 ', 6' -dimethyltyrosine is a very important drug intermediate and can be used for polypeptide drugs.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Abbreviations for reagents referred to in the examples:
TBS: tert-butyl dimethyl silicon base
TES: triethyl silicon base
TBDPS: tert-butyl diphenyl silicon base
MOM: methoxymethyl group
THP: tetrahydropyranyl group
Ac: acetyl group
And Piv: tert-butyryl group
Boc: tert-butyloxycarbonyl radical
DCC: dicyclohexylcarbodiimide
DBU: 1, 5-diazabicyclo [5.4.0] undecene-5
DIPEA: n, N-diisopropylethylamine
EDCI: 1-Ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride
HOBt: 1-hydroxybenzotriazoles
HATU: 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
NMM: n-methylmorpholine
Dpp: 1, 3-bis (diphenylphosphino) propane
tolumen: toluene
t-AmyloH: tert-amyl alcohol
o-xylene: ortho-xylene
p-xylene: ortho-xylene
m-xylene: ortho-xylene
1, 4-dioxane: 1, 4-dioxane
Tf: trifluoromethanesulfonic acid
DCE: 1, 2-dichloroethane
Example 1: synthesis of methylation raw Material 2a (by Synthesis method I)
Dissolving L-tyrosine (50mmol) in 50mL of dry methanol, cooling the reaction to 0 ℃, and adding SOCl dropwise2(75 mmol). After the addition, the reaction mixture was refluxed for 8 hours. Stopping the reaction, cooling the reaction to room temperature, and removing the redundant solvent to obtain a white solid compound 4a crude product. The crude compound can be directly used for the next reaction without column chromatography separation.
Compound 4a (50mmol) was dissolved in 70mL of dry acetonitrile, the reaction solution was cooled to 0 ℃ and then TBDMSCl (75mmol) and DBU (100mmol) were added to the system. After the addition, the reaction was left at room temperature for 12 hours. The reaction was complete by TLC and H was added2O (50mL) quench the reaction, BExtraction with ethyl acetate (3X 100 mL). The organic phases were combined, washed with saturated sodium chloride solution and anhydrous Na2SO4Drying and removing the redundant solvent to obtain a light yellow viscous liquid 3a crude product. The crude compound can be directly used for the next reaction without column chromatography separation.
Compound 3a (50mmol) was dissolved in 200mL of dry dichloromethane, and the reaction solution was cooled to 0 ℃ and HBTU (60mmol), DIPEA (125mmol) and pyridine-2-carboxylic acid (60mmol) were added to the reaction system. After the addition, the reaction was left at room temperature for 12 hours. The reaction was complete by TLC and H was added2The reaction was quenched with O (50mL) and extracted with dichloromethane (3X 100 mL). The organic phases were combined, washed with 1N hydrochloric acid solution and then with saturated sodium chloride solution, anhydrous Na2SO4Drying and removing excessive solvent. The crude product was isolated by silica gel column chromatography (petroleum ether: ethyl acetate: 10: 1-5: 1) to give 2a as a white solid (18.2g, 88% over three steps).1H NMR(500MHz，CDCl3)δ8.55(d，J＝4.7Hz，1H)，8.45(d，J＝8.2Hz，1H)，8.16(d，J＝7.8Hz，1H)，7.83(td，J＝7.7，1.4Hz，1H)，7.42(dd，J＝7.2，5.2Hz，1H)，7.04(d，J＝8.4Hz，2H)，6.75(d，J＝8.4Hz，2H)，4.99-5.03(m，1H)，3.71(s，3H)，3.16(d，J＝6.2Hz，2H)，0.96(s，9H)，0.16(s，6H)；
13C NMR(126MHz，CDCl3)δ172.03，164.06，154.83，149.49，148.42，137.35，130.40，128.81，126.44，122.36，120.33，53.70，52.39，37.73，25.81，18.33，-4.30.
HRMS(ESI)Calcd.for C16H17N2O4(M+H)+：301.1183，Found：301.1185.
[α]23.2 D＝66.86(c＝1，CHCl3)
Proceeding from tyrosine, using different reagents, with reference to the procedure in example 1, a series of compounds 2 were obtained as follows:
example 2: synthesis of methylation raw materials 2b and 2u (by Synthesis method II)
Compound 2a (50mmol) was dissolved in 50mL of dry tetrahydrofuran, and after cooling the reaction mixture to 0 ℃, a 1N THF solution of TBAF (60mL) was slowly added dropwise to the system. After the addition, the reaction was left at room temperature for 12 hours. The reaction was complete by TLC and H was added2The reaction was quenched with O (50mL) and extracted with ethyl acetate (3X 100 mL). The organic phases were combined, washed with saturated sodium chloride solution and anhydrous Na2SO4Drying and removing excessive solvent. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10: 1 to 2: 1) to give the desired product 2b (14.4g, 96%).1H NMR(400M Hz，CDCl3)δ8.55-8.52(m，2H)，8.13(d，J＝7.8Hz，IH)，7.82(td，J＝1.6，7.7Hz，IH)，7.42-7.39(m，1H)，7.01-6.99(m，3H)，6.73(d，J＝8.5Hz，2H)，5.05-5.00(m，1H)，3.72(s，3H)，3.21-3.07(m，2H)；13C NMR(100MHz，CDCl3)δ172.10，164.42，155.54，149.00，148.46，137.55，130.39，127.28，126.68，122.47，115.71，53.88，52.57，37.66.ESI-HRMS Calcd for C16H17N2O4[M+H+]：301.1183；Found：301.1185.
2b (10mmol), DMAP (20%) was dissolved in 30mL dry dichloromethane. After the reaction mixture was cooled to 0 ℃, triethylamine (25mmol) was added to the system, and PivCl (15mmol) was slowly added dropwise. After the addition, the reaction was left at room temperature for 12 hours.The reaction was complete by TLC and H was added2The reaction was quenched with O (30mL) and extracted with dichloromethane (3X 30 mL). The organic phases were combined, washed with saturated sodium chloride solution and anhydrous Na2SO4Drying and removing excessive solvent. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10: 1 to 1: 1) to give the title compound 2u (3.4g, 89%).1H NMR(400M Hz，CDCl3)68.56-8.52(m，2H)，8.17(dd，J＝0.9，7.8Hz，1H)，7.87-7.82(m，1H)，7.45-7.42(m，1H)，7.19(d，J＝8.4Hz，2H)，6.98(d，J＝8.5Hz，2H)，5.07-5.02(m，1H)，3.71(s，3H)，3.28-3.18(m，2H)，1.32(s，9H)；13C NMR(100MHz，CDCl3)δ177.21，171.81，164.01，150.31，149.24，148.32，137.69，137.64，133.57，130.38，126.65，122.60，122.57，121.77，77.53，77.21，76.90，53.68，52.58，39.24，37.83，27.31.ESI-HRMS Calcd for C21H25N2O5[M+H+]：385.1758；Found：385.1758.
Starting from compound 2b, the following methylated starting materials were prepared by synthesis method two, by changing the reagents and reaction conditions:
example 3: synthesis of methylation raw Material 2 (Synthesis method III)
The method comprises the following operation steps: 2m (5mmol) were placed in a Schlenk reaction flask and palladium acetate (10%) and dppp (10%) were added. After purging the reaction flask with argon, R "OH (4.0mL), DMF (8.0mL) and triethylamine (15mmol) were added in that order. The reaction flask is firstly placed at room temperature and stirred until the raw materials are completely dissolved, CO of gas is introduced into the system, and the reaction temperature is raised to 70 ℃ for reaction for 6 hours. Confirming the reaction is complete by TLC, cooling the reaction to room temperature, adding H2Quenching the reaction with O (20mL), and removing the reaction solutionR "OH of (1). Extraction with ethyl acetate (3X 30 mL). The organic phases were combined, washed with saturated sodium chloride solution and anhydrous Na2SO4Drying and removing excessive solvent. The crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate 8: 1-2: 1) to give the title compound.
Starting from compound 2m, the following methylated starting materials were prepared by synthesis method three, by changing the reagents and reaction conditions:
example 4: synthesis of Compound 2h
The method comprises the following operation steps: dissolve 2a (10mmol) in 50mL dry methanol. To the system was added LiOH monohydrate (30 mmol). After the addition, the reaction was left at room temperature for 12 hours. The reaction was complete by TLC, the pH of the system was adjusted to 2 by addition of 1N HCl and extracted with ethyl acetate (3X 30 mL). The organic phases were combined, washed with saturated sodium chloride solution and anhydrous Na2SO4Drying and removing excessive solvent. A white solid was obtained. The hydrolyzed crude product was directly subjected to the next reaction without separation.
The crude product obtained in the previous step was dissolved in 20mL of dry DMF, and after cooling the reaction mixture to 0 ℃ imidazole (37mmol) and TBSCl (25mmol) were added to the system. After the addition, the reaction was left at room temperature for 12 hours. The reaction was complete by TLC and H was added2The reaction was quenched with O (20mL) and extracted with ethyl acetate (3X 30 mL). The organic phases were combined, washed with saturated sodium chloride solution and anhydrous Na2SO4Drying and removing excessive solvent. The crude product was separated by silica gel column chromatography (5: 1-1: 1 petroleum ether: ethyl acetate) to give the title compound 2h (3.4g, 85% over two steps).1H NMR(400M Hz，DMSO-d6)δ8.67(d，J＝8.2Hz，1H)，8.63(d，J＝4.24Hz，1H)，7.99-7.98(m，2H)，7.61-7.58(m，1H)，7.09(d，J＝8.3Hz，2H)，6.71(d，J＝8.3Hz，2H)，4.73-4.67(m，1H)，3.18-3.08(m，2H)，0.89(s，9H)，0.11(s，6H)；13C NMR(100M Hz，DMSO-d6)δ172.66，163.42，153.74，149.21，148.55，137.93，130.31，130.10，126.83，121.88，119.59，53.42，35.71，25.57，17.93，-4.53.ESI-HRMS Calcd for C21H29N2O4Si[M+H+]：401.1891；Found：401.1893.
Example 5: synthesis of Compound 1a
In a 10ml reaction tube, 83mg of compound 2a (MW. 414.57, 0.2mmol), 2.2mg pd (oac)2(MW＝224.51，0.01mmol)，55mgK2CO3(MW-138.21, 0.4mmol) and then 62. mu.l of MeI (MW-141.94, 1mmol), 1ml of tol/t-AmyloH (9: 1) as solvent, in a 110 ℃ oil bath for 24 hours, cooled to room temperature, filtered through celite, filtered off the excess metal, spun dry and separated on a silica gel column (eluent petroleum ether: ethyl acetate 10: 1-5: 1) to give 388mg of product 1a in 92% yield and 100% ee.
1H NMR(400MHz，CDCl3)δ8.64-8.46(m，1H)，8.09(d，J＝7.8Hz，1H)，7.79(td，J＝7.7，1.4Hz，1H)，7.40(dd，J＝6.5，4.9Hz，1H)，6.49(s，1H)，4.94(q，J＝8.1Hz，1H)，3.64(s，3H)，3.17(d，J＝7.9Hz，3H)，2.33(s，6H)，0.95(s，9H)，0.15(s，6H).
13C NMR(101MHz，CDCl3)δ172.81，163.92，153.90，149.29，148.27，138.35，137.31，126.38，126.03，122.26，119.88，52.33，52.10，32.44，25.75，20.33，18.23，-4.33.ESI-HRMS Calcd for C24H35N2O4Si(M+H)+：443.2361，found：443.2358.
[α]23.5 D＝-43.498(c＝1，CHCl3).
Example 6: synthesis of Compound 1a
The reaction was carried out as in example 5, using a solvent toluene/t-AmylOH ═ 9: 1, the dosage of the alkali is 3 equivalents, the conditions of the catalyst, the dosage of the catalyst, the alkali and the like are changed under the condition of 24-hour reaction, and the experimental results are shown in the following table:
a. the reaction time is 36h, the amount of the base is 5equiv,
example 7: synthesis of Compound 1a
The reaction was carried out as in example 5, with K as base2CO3(3equiv), under the air reaction atmosphere condition, changing the conditions of the catalyst, the catalyst dosage, the solvent and the like of the reaction, and the experimental results are shown in the following table:
example 8: synthesis of Compound 1b-1x
The reaction was carried out as in example 5, using different tyrosine derivatives 2b-2x, and the results are shown in the following table:
example 9: synthesis of N-Boc protected 2 ', 6' -dimethyltyrosine
1a (5g, 12mol, 100% ee) was placed in a 100ml reaction flask, 17ml of water was added, and HCl (36.5% w/w; 16.6ml, 19mol) was added slowly dropwise to the cold bath to form a suspension. After the dropwise addition, the mixture is moved into an oil bath at 90 ℃ for reflux and reacted for 12 hours. Cooling to room temperature, adding NaOH (40%) to adjust pH to 10, and adding Boc2And O (2.9g, 13.27mol), stirring at room temperature for 4 hours, continuously supplementing 40% NaOH in the reaction process, and keeping the pH value at 8-10. After the reaction was completed, the pH was adjusted to about 2.3 with HCl (36.5%, w/w), ethyl acetate (10 ml. times.3) was added for extraction, the organic phases were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, and passed through a column to obtain N-Boc protected 2 ', 6' -dimethyltyrosine (2g, 57%) as a white product.
1H NMR(400MHz，CDCl3)δ8.93(s，1H)，7.10(d，J＝8.5Hz，1H)，6.37(s，2H)，4.00-3.93(m，1H)，2.96-2.89(m，1H)，2.77(dd，J＝14.2，8.4Hz，1H)，2.17(s，6H)，1.32(s，9H).
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (8)
1. A process for the preparation of a 2 ', 6' -dimethyltyrosine derivative comprising the steps of:
(i) in an inert solvent, carrying out deprotection by using a compound shown as a formula A to obtain a deprotection group product;
(ii) reacting the deprotected product with Boc in an inert solvent2O reaction to give N-Boc protected 2 ', 6' -dimethyltyrosine:
and the method further comprises the following steps:
(2) reacting a compound of formula 2 with methyl iodide in an inert solvent in the presence of a base and a metal catalyst to obtain a compound' of formula 1;
wherein R is1Is CH3、R2Is OTBS, Ra and Rb are each independently methyl, R3Is pyridin-2-yl;
and in the step (2), the inert solvent is selected from the following group: 9: 1 of toluene/tert-amyl alcohol, toluene, dichloroethane, trifluorotoluene, p-xylene, o-xylene, m-xylene;
the alkali is potassium carbonate or potassium bicarbonate, and the metal catalyst is Pd (OAc)2。
2. The method of claim 1, wherein the method further comprises the steps of: and removing the Boc protecting group of the N-Boc protected 2 ', 6' -dimethyltyrosine to obtain 2 ', 6' -dimethyltyrosine.
3. The method of claim 2, wherein in step (2), the reaction is carried out in the presence of an acidic additive, and wherein the reaction is carried out in the presence of an acidic additiveThe acidic additive of (A) is selected from pivalic acid (PivOH), or dibenzyl phosphate ((BnO)2P(O)OH)。
4. The process of claim 1, wherein the compound of formula 2 is prepared by the process of:
(1) using a compound of formula 3 and R in an inert solvent in the presence of a condensing agent and a base3-COOH reaction to give a compound of formula 2; wherein R' is TBS, R1Is CH3、R3-COOH is pyridine-2-carboxylic acid.
5. The method of claim 4, wherein in step (1), the condensing agent is selected from the group consisting of: DCC, EDCI, HOBt, HOAt, HBTU, TBTU, HATU, BOP, or combinations thereof; and/or
In the step (1), the base is selected from the group consisting of: et (Et)3N, DIPEA, NMM, or a combination thereof; and/or
In the step (1), the solvent is selected from the group consisting of: DCM, THF, DMSO, DMF, or combinations thereof.
6. A process for the preparation of a compound of the formula I,
wherein the content of the first and second substances,
the method is characterized by comprising the following steps of (2):
(2) reacting a compound of formula 2 with an alkylating agent in an inert solvent in the presence of a base and a metal catalyst to obtain a compound of formula I;
and the compound of formula I is selected from the group consisting of:
the alkali is potassium carbonate; the metal catalyst is Pd (OAc)2(ii) a The inert solvent is 9: 1 toluene/tert-amyl alcohol; the alkylating agent is methyl iodide.
7. The method of claim 6, wherein the compound of formula 2 is prepared by the method of:
(1) using a compound of formula 3 and R in an inert solvent in the presence of a condensing agent and a base3-COOH reaction to give a compound of formula 2 a; wherein R' is TBS, R3-COOH is pyridine-2-carboxylic acid;
and in the reaction formula 1, R1Is selected from the group consisting of: et, Me, i-Pr, n-Bu, Bn;
and the process further comprises optional steps (3) and (4):
(3) carrying out deprotection reaction by using a compound shown as a formula 2a in an inert solvent to obtain a product;
(4) reacting the product of step (3) with a hydroxyl protecting reagent to obtain a compound of formula 2 b;
wherein in the reaction formula 2, R3Is pyridin-2-yl; and R1Is selected from the group consisting of:
i.R1is Bn, and R is Bn;
ii.R1is Me, and R is Me;
iii.R1me, and R is Bn;
iv.R1me, and R is TBDPS;
v.R1is Me, and R is CH3OCH2-；
vi.R1Me, and R is TIPS.
8. The method of claim 7, wherein in step (1), the condensing agent is selected from the group consisting of: DCC, EDCI, HOBt, HOAt, HBTU, TBTU, HATU, BOP, or combinations thereof; and/or
In the step (1), the base is selected from the group consisting of: et (Et)3N, DIPEA, NMM, or a combination thereof; and/or
In the step (1), the solvent is selected from the group consisting of: DCM, THF, DMSO, DMF, or combinations thereof.
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Non-Patent Citations (6)
| Title |
|---|
| "A Modified Method for the Synthesis of Tetradentate Ligand Involving Peptide Bond";Pulimamidi Rabindra Reddy等;《International Journal of Organic Chemistry》;20140630(第4期);第122-134页 * |
| "Coordinating activation strategy for C(sp3)-H/C(sp3)–H cross-coupling to access β -aromatic a-amino acids";Kaizhi Li等;《Nature Communications》;20150929(第6期);第1-9页 * |
| "Development of an Asymmetric Hydrogenation Route to （S)-N-Boc-2,6-dimethyltyrosine";Celine F. B. Praquin等;《Organic Process Research & Development》;20110526;第15卷;第1124-1129页 * |
| "Palladium-Catalyzed Alkylation of ortho-C(sp 2 )-H Bonds of Benzylamide Substrates with Alkyl Halides";Yingsheng Zhao等;《Org. Lett.》;20110819;第13卷(第18期);第4850-4853页 * |
| 125470-95-3;REGISTRY;《ACS on STN》;19900216 * |
| Celine F. B. Praquin等."Development of an Asymmetric Hydrogenation Route to （S)-N-Boc-2,6-dimethyltyrosine".《Organic Process Research & Development》.2011,第15卷第1124-1129页. * |
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