CN105237525A - Alpha-N-methylhistidine intermediate and preparation method thereof - Google Patents
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Abstract
The present invention relates to a kind of α-N- methylhistidin intermediates and preparation method thereof, its chemical structural formula is shown in formula I,
(Ι), in Formulas I, R is methyl, phenyl, p-methylphenyl, o-methyl-phenyl, aminomethyl phenyl, 2,4- 3,5-dimethylphenyl, 2- nitrobenzophenone, 4- nitrobenzophenone, 2,4- dinitrophenyl, p-methoxyphenyl, 2,4- Dimethoxyphenyl or benzyl; PG is blocking group. It can successfully carry out subsequent chemical reaction, can obtain the high N- methylhistidin of optical purity, and subsequent blocking group easily removes, and not will lead to product and decompose and damage optical purity; Importantly, its preparation method is simple, solves the problems, such as that previous α N methylhistidin production is difficult, can not produce in batches.
Description
Technical field
The invention belongs to organic synthesis field, relate to a kind of histidine intermediate, be specifically related to a kind of α-N-methylhistidine intermediate and preparation method thereof.
Background technology
Research shows, in the polypeptide containing α position N-methyl, introduces the conformation that N-methylamino acid residue can suppress polypeptide hydrolyzes, increase the film transparency of polypeptide or albumen, changes albumen, thus promotes polypeptide to dissolve or improve biological activity.
There is a lot of biologically active polypeptides containing α position N-methyl in nature, they are also in clinical study major part, and portioned product goes on the market.The screening of polypeptide drugs is because candidate target is many, workload can step into condition vast and hazy in a jumble greatly, even.The known listing polypeptide drug with high curative effect to be methylated or glycosylation, thus some difficult problems of encountering in the medicine practical application that is resolved and extend the range of application of this medicine, a bright working direction of can yet be regarded as like this.
Preparation is divided into two large classes containing the method for the polypeptide of α position N-methylamino acid (i.e. α-N-methylamino acid).One is when improvement on synthesis, methylates at the amine end of polypeptide fragment; The more method of current use, for first being protected by amine end alkylsulfonyl, makes acylamino hydrogen become acid, then introduces methyl by methyl iodide or Mitsunobu reaction, finally by going protecting group, then carries out follow-up polypeptide and connects; The amine end of polypeptide fragment carries out methylated problem and is that unconventional deprotection can injure polypeptide fragment, and bring unknown side reaction, affect Purity, more seriously this method can cause the halfway problem that methylates, and subsequent purification difficulty is very big.Second method, for introduce N-methylamino acid in advance when connecting peptides, finally obtains highly purified polypeptide products.If can not find very outstanding N-methylating reagent, the first-selected route that the second synthetic method will be synthesis N-methyltransferase polypeptide.
Over nearly 10 years, this field develops methods of some synthesis N-methylamino acids successively, and the method for main flow has: (1) as shown in Figure 1, first protect amido with carbamate, sodium hydride pulls out hydrogen, then adds methyl iodide and introduces methyl ((a) Coggins, J.R.; Benoiton, N.L.Can.J.Chem.1971,49,1968. (b) Cheung, S.T.; Benoiton, N.L.Can.J.Chem.1977,55,906.).(2) then the alkylsulfonyl protection of amine end introduces methyl ((a) Hlava ' cek, J. by methyl iodide, methyl-sulfate or Mitsunobu reaction; Poduska, K.; Sorm, F.; Sla ' ma, K.Collect.Czech.Commun.1976,41,2079. (b) Wisniewski, K.; Kolodziejczyk, A.S.TetrahedronLett.1997,38,483.).(3) 5-oxazolinone method, as shown in Figure 2 ((a) Ben-Ishai, D.J.Am.Chem.Soc.1957,79,5736; (b) Itoh, M.Chem.Pharm.Bull.1969,17,1679. (c) Aurelio, L.; Box, J.S.; Brownlee, R.T.C.; Hughes, A.B.; Sleebs, M.M.J.Org.Chem.2003,68,2652.).These three kinds of methods respectively have relative merits: method (1) can cause the optical purity of some N-methylamino acid not high, make to be difficult to amplify produce because needs pull out hydrogen with sodium hydride in anhydrous conditions, and the such side chain of similar Asp, Arg, Lys, Asn, Gln amino acid whose N-with functional group methylates and can not realize in this way.The applicable cases similar approach (1) of method (2).Method (3) is applicable to the amino acid of most of side chain without functional group, and some N-methylamino acid can be produced in a large number, but the amino acid whose N-that side chain has a functional group methylates and seldom realizes application.The first two kind method all can't solve the methylated difficult problem in Histidine α position at present above, and the third method had the report (AndrewB.Hughes, the etal.Org.Lett. that introduce α position methyl, Vol.4, No.21,2002), but cannot practical application be dropped into, see Fig. 3.
This is because on the imidazole ring of Histidine 1 and 3 atom N have alkalescence and strong nucleophilicity causes formation oxazole ring easily under attack and open loop, thus can not get α position N methylhistidine (English abbreviation is α-N-Me-His).By introducing 2,4-dinitrophenyl (DNP) in 1 atom N of imidazole ring, utilize the strong sucting electronic effect of DNP; the nucleophilicity of passivation imidazole ring; 5-oxazoline ring is formed, through reductive ring open, forms the α position N methylhistidine of DNP protection.But present method is in actual Peptide systhesis and have no usage, can remove because DNP can not find a way, even if or the condition that also will find and polypeptide can not be caused to damage can be removed.The synthesis difficulty of synthesis α position N methylhistidine is large, and also do not have other more rational preparation method to report out at present, the exploitation on polypeptide drugs of α position N methylhistidine are restricted.
Summary of the invention
The present invention seeks to provide a kind of α-N-methylhistidine intermediate to overcome the deficiencies in the prior art.
For achieving the above object, the technical solution adopted in the present invention is: a kind of α-N-methylhistidine intermediate, its chemical structural formula such as formula shown in I,
In formula I, R is methyl, phenyl, p-methylphenyl, o-methyl-phenyl-, an aminomethyl phenyl, 2,4-3,5-dimethylphenyls, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyls, p-methoxyphenyl, 2,4-Dimethoxyphenyls or benzyl; PG is blocking group.
Optimally, the chemical structural formula of described PG is
wherein, R
2for methyl, ethyl, sec.-propyl, benzyl, 2-chlorobenzyl, to methoxy-benzyl, 9-fluorene methyl, the tertiary butyl, allyl group, 2-(trimethyl silicon based) ethyl, 1,1-bis-supports band thionaphthene [b]-2-methyl, 2,2,2-trichloroethyl, 2-chloroethyl, 2-(2 '-pyridyl)-ethyl, 2-(4 '-pyridyl)-ethyl, 1-adamantyl or 2-adamantyl, R
3for methyl, trifluoromethyl or phenyl.
Another object of the present invention is the preparation method providing a kind of above-mentioned α-N-methylhistidine intermediate, and it comprises the following steps:
A () compound 1 is obtained by reacting compound 2 with sulfuryl halide in the first organic solvent under alkaline condition;
B () compound 2 generates described α-N-methylhistidine intermediate in the second organic solvent under the effect of acid catalyst with paraformaldehyde or polyformaldehyde reaction;
Optimally, in step (a), alkaline condition obtains by adding acid binding agent in described first organic solvent, and described acid binding agent is sodium carbonate, salt of wormwood, sodium hydroxide, triethylamine or nitrogen methylmorpholine.
Further, described step (a) is: compound 1 and acid binding agent are mixed in the first organic solvent, subsequently to wherein adding sulfuryl halide, is obtained by reacting compound 2 at 0 ~ 35 DEG C.
Optimally, described step (b) is: in reaction vessel, add compound 2, second organic solvent, paraformaldehyde or paraformaldehyde, acid catalyst successively, generates described α-N-methylhistidine intermediate with being placed on 40 ~ 90 DEG C of back flow reaction.
Optimally, in step (b), described acid catalyst is sulfuric acid, methylsulfonic acid, camphorsulfonic acid, tosic acid, Phenylsulfonic acid or trifluoroacetic acid, and described acid catalyst is 0.1:1 ~ 2:1 with the molar equivalent ratio of compound 2.
Optimally, the acetone-water mixing solutions of described first organic solvent to be volume ratio be 1 ~ 4:1, volume ratio are 1 ~ 4:1 tetrahydrofuran (THF)-water mixed solution or acetonitrile; Described second organic solvent is the mixture of one or more compositions in methylene dichloride, chloroform, ethyl acetate, tetrahydrofuran (THF), ethylene dibromide, Isosorbide-5-Nitrae-dioxane, Benzene and Toluene.
Because technique scheme is used, the present invention compared with prior art has following advantages: α-N-methylhistidine intermediate of the present invention, there is specific chemical mechanical, successfully can carry out follow-up chemical reaction, the N-methylhistidine that optical purity is high can be obtained, and follow-up blocking group is easily removed, Disassembling Products and infringement optical purity can not be caused; The more important thing is, its preparation method is simple, solves the difficult problem that α position N methylhistidine is in the past produced difficulty, cannot be produced in batches.
Accompanying drawing explanation
Accompanying drawing 1 is N-methylamino acid synthesis process flow diagram in prior art;
Accompanying drawing 2 is the synthesis process flow diagram of 5-oxazolinone in prior art;
Accompanying drawing 3 be in prior art side chain without the amino acid whose synthesis process flow diagram of functional group;
Accompanying drawing 4 is the synthesis process flow diagram of α-N-methylhistidine intermediate of the present invention.
Embodiment
α-N-methylhistidine intermediate of the present invention, its chemical structural formula such as formula shown in I,
In formula I, R is methyl, phenyl, p-methylphenyl, o-methyl-phenyl-, an aminomethyl phenyl, 2,4-3,5-dimethylphenyls, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyls, p-methoxyphenyl, 2,4-Dimethoxyphenyls or benzyl; PG is blocking group.The chemical structural formula of described PG is preferably
wherein, R
2for methyl, ethyl, sec.-propyl, benzyl, 2-chlorobenzyl, to methoxy-benzyl, 9-fluorene methyl, the tertiary butyl, allyl group, 2-(trimethyl silicon based) ethyl, 1,1-bis-supports band thionaphthene [b]-2-methyl, 2,2,2-trichloroethyl, 2-chloroethyl, 2-(2 '-pyridyl)-ethyl, 2-(4 '-pyridyl)-ethyl, 1-adamantyl or 2-adamantyl, R
3for methyl, trifluoromethyl or phenyl, namely PG can be Fmoc (fluorenes methoxy dicarbonyl chloride base, i.e. R
2situation for 9-fluorene methyl), the blocking group such as Boc (tertbutyloxycarbonyl), Cbz (carbobenzoxy-(Cbz)), Ac (ethanoyl), TFA (trifluoroacetic acid), benzoyl.
The preparation method of above-mentioned α-N-methylhistidine intermediate, it comprises the following steps:
A () compound 1 is obtained by reacting compound 2 with sulfuryl halide in the first organic solvent under alkaline condition;
B () compound 2 generates described α-N-methylhistidine intermediate in the second organic solvent under the effect of acid catalyst with paraformaldehyde or polyformaldehyde reaction;
In step (a), alkaline condition obtains by adding acid binding agent in described first organic solvent, and described acid binding agent is mineral alkali, as sodium carbonate, salt of wormwood or sodium hydroxide etc.; Or organic bases, as triethylamine, nitrogen methylmorpholine etc., its molar weight is 1 ~ 3 times of sulfuryl halide molar weight.Step (a) is preferably: compound 1 and acid binding agent are mixed in the first organic solvent, subsequently to wherein adding sulfuryl halide, compound 2 is obtained by reacting at 0 ~ 35 DEG C, and compound 1 and the mol ratio of sulfuryl halide are preferably 1:0.8 ~ 3, thus suppress the carrying out of side reaction, improve the productive rate of product 2.
Step (b) is preferably: in reaction vessel, add compound 2, second organic solvent, paraformaldehyde or paraformaldehyde, acid catalyst successively, generate compound 3 with being placed on 40 ~ 90 DEG C of back flow reaction, compound 3 i.e. α-N-methylhistidine intermediate; Compound 2 is preferably 1:1 ~ 1:10 with the mol ratio of paraformaldehyde or paraformaldehyde, makes product 2 complete reaction.In step (b), described acid catalyst is preferably sulfuric acid, methylsulfonic acid, camphorsulfonic acid, tosic acid, Phenylsulfonic acid or trifluoroacetic acid, and described acid catalyst is preferably 0.1:1 ~ 2:1 with the molar equivalent ratio of compound 2.First organic solvent is preferably acetone-water mixing solutions that volume ratio is 1 ~ 4:1, volume ratio is 1 ~ 4:1 tetrahydrofuran (THF)-water mixed solution or acetonitrile; Described second organic solvent is preferably the mixture of one or more compositions in methylene dichloride, chloroform, ethyl acetate, tetrahydrofuran (THF), ethylene dibromide, Isosorbide-5-Nitrae-dioxane, Benzene and Toluene.
Be described in detail below in conjunction with to the preferred embodiment of the invention.
Embodiment 1
The present embodiment provides a kind of preparation method of α-N-methylhistidine intermediate, and the chemical structural formula of this α-N-methylhistidine intermediate is as follows,
Specifically comprise the following steps:
A () 50gFmoc-L-His-OH and 31.6 gram anhydrous sodium carbonate is mixed in 1.2L50% acetone-water solution, then add 33g 4-Nitrobenzenesulfonyl chloride, and room temperature lucifuge reacts 2 hours, and Fmoc-L-His-OH consumes completely; 700ml water is added in reaction solution, with massfraction be 5% phosphoric acid adjust pH to about 4.0, produce pale yellow oil, drain upper strata solvent, gained crude product 200mlDCM (ethylene dichloride) dissolves, and this solution with water is washed (100ml/ time × 3 times), then anhydrous sodium sulfate drying is used, decompression is spin-dried for and obtains 67.2g white solid, this step product purity: 97.4%, yield: 80.6%.Nuclear-magnetism detects data:
1h-NMR (400Hz, DMSO-d6) δ 14.08-14.31 (s, 1H), 8.95-9.15 (m, 2H), 8.10-8.23 (m, 2H), 7.83-8.02 (m, 3H), 7.78-7.82 (d, 1H), 7.58-7.71 (m, 2H), 7.35-7.47 (m, 2H), 7.28-7.34 (m, 2H), 4.16-4.41 (m, 4H), 2.89-2.98 (d, 1H), 3.10-3.21 (d, 1H), (2.95-3.12 s, 3H) .Ms
+: 562.8 [M+1]; White solid structural formula is as shown in table 1, is called for short Fmoc-L-His (2-NBS)-OH;
B () adds 56.2gFmoc-L-His (2-NBS)-OH, 700mlDCM, 15g paraformaldehyde, 7.5g tosic acid monohydrate successively in 1L there-necked flask, be placed in 40 DEG C of backflows 4 hours, generate large-tonnage product, a small amount of raw material cannot consume completely; Being spin-dried for DCM, residue 100ml acetic acid ethyl dissolution, is then the NaHCO of 5% by mass concentration
3the aqueous solution is washed till raw material almost not to be had, then washes (20ml/ time × 3 times, namely use 20ml water washing three times), the washing of 50ml saturated sodium-chloride with water once, anhydrous sodium sulfate drying, is spin-dried for, and the paste 150mlDCM obtained dissolves, decompression is spin-dried for again, obtains crude product 22g.Crude product 50mlDCM dissolves, and is then loaded to the silica gel of 2 times of quality volumes, uses DCM wash-out, obtains 17.8g white solid, high performance liquid chromatography (HPLC) purity assay: 98.1%, yield: 31%.Nuclear-magnetism detects data:
1h-NMR (400Hz, DMSO-d6) δ 14.08-14.31 (s, 1H), 8.95-9.15 (m, 2H), 8.10-8.23 (m, 2H), 7.83-8.02 (m, 3H), 7.78-7.82 (d, 1H), 7.58-7.71 (m, 2H), 7.35-7.47 (m, 2H), 7.28-7.34 (m, 2H), 4.95-5.23 (m.2H), 4.13-4.40 (m, 4H), 2.41-2.43 (d, 1H), 2.18-2.29 (d, 1H) .Ms
+: 574.7 [M+1].
Embodiment 2
The present embodiment provides a kind of preparation method of α-N-methylhistidine intermediate, and the chemical structural formula of this α-N-methylhistidine intermediate is as follows,
Specifically comprise the following steps:
A () 50gFmoc-L-His-OH and 33g anhydrous sodium carbonate is mixed in 500ml tetrahydrofuran (THF), add 500ml water, then adds 21g methylsulfonyl chloride, room temperature reaction 2 hours, and Fmoc-L-His-OH consumes completely; In reaction solution, add 1000ml water, then adjust pH to about 4.0 with 5% phosphoric acid that mass content is, produce white precipitate, continue stirring 0.5 hour; Filter, get filter cake washing with acetone, dry and obtain 52.4g white solid.Gai Walk product purity: 98.9%, yield: 77.6%.Detect data:
1h-NMR (400Hz, DMSO-d6) δ 14.06-14.27 (s, 1H), 7.83-8.02 (m, 3H), 7.69-7.81 (m, 3H), 7.38-7.45 (m, 2H), 7.28-7.36 (m, 3H), 4.13-4.40 (m, 4H), 2.80-2.85 (s, 3H), 2.42-2.44 (d, 1H), 2.17-2.28 (d, 1H) .Ms
+: 456.7 [M+1]; White solid structural formula is as shown in table 1, is called for short Fmoc-L-His (Ms)-OH;
B () adds 46gFmoc-L-His (Ms)-OH, 500ml toluene, 13g paraformaldehyde, 9g tosic acid monohydrate successively in 1L there-necked flask.This mixture was 60 DEG C of backflows 3 hours, and a small amount of Fmoc-L-His (Ms)-OH cannot consume completely, reaction solution cool to room temperature, was then the NaHCO of 5% by mass concentration
3the aqueous solution is washed till raw material almost not to be had, then washes with water (20ml/ time × 3 times), and 50ml saturated sodium-chloride washs once, anhydrous sodium sulfate drying, and decompression is spin-dried for, and obtains paste 19g; Crude product 40mlDCM dissolves, and is then loaded to the silica gel of 2 times of quality volumes, uses DCM wash-out, obtains 11.1g white solid, HPLC purity: 98.7%, yield: 23.7%.Detect data:
1h-NMR (400Hz, DMSO-d6) δ 7.80-8.01 (m, 3H), 7.67-7.79 (m, 2H), 7.35-7.41 (m, 2H), 7.24-7.32 (m, 3H), 5.03-5.29 (m.2H), 4.10-4.37 (m, 4H), 2.76-2.82 (s, 3H), 2.35-2.41 (d, 1H), 2.14-2.23 (d, 1H) .Ms
+: 468.8 [M+1].
Embodiment 3
The present embodiment provides a kind of preparation method of α-N-methylhistidine intermediate, and the chemical structural formula of this α-N-methylhistidine intermediate is as follows,
A () 182gFmoc-L-His-OH and 76 gram anhydrous sodium carbonate is mixed in 1.5L50% acetone-water solution, then add 111g Tosyl chloride, room temperature reaction 4 hours, and Fmoc-L-His-OH consumes completely; In reaction solution, add 1000ml water, gained mixed solution 5% phosphoric acid adjusts pH to about 4.0, produces white precipitate, then stirs 0.5 hour; Filter, filter cake washing with acetone, dries and obtains 206.6g white solid.Gai Walk product purity: 98.3%, yield: 81%.Detect data:
1h-NMR (400Hz, DMSO-d6) δ 8.29-8.35 (s, 1H), 7.81-9.02 (t, 4H), 7.58-7.71 (t, 3H), 7.48-7.52 (m, 1H), 7.32-7.52 (m, 4H), 7.22-7.31 (m, 2H), 4.09-4.31 (m, 4H), 2.89-2.98 (d, 1H), 2.75-2.87 (d, 1H), 2.24-2.32 (s, 3H) .Ms
+: 532.1 [M+1]; White solid structural formula is as shown in table 1, is called for short Fmoc-L-His (Tos)-OH;
B () adds 50gFmoc-L-His (Tos)-OH, 600mlDCM, 12g paraformaldehyde, 6g tosic acid monohydrate successively in 1L there-necked flask.This mixture was 40 DEG C of backflows 6 hours, and generate large-tonnage product, a small amount of raw material cannot consume completely; Be spin-dried for DCM, residue 100ml acetic acid ethyl dissolution, then gained ethyl acetate solution is the NaHCO of 5% by mass concentration
3the aqueous solution is washed till raw material almost not to be had, then washes with water (20ml/ time × 3 times), and once, anhydrous sodium sulfate drying, is spin-dried for the washing of 30ml saturated sodium-chloride, and the paste 100mlDCM obtained dissolves, then decompression is spin-dried for, and obtains crude product 29g.Crude product 50mlDCM dissolves, and is then loaded to the silica gel of 2 times of quality volumes, uses DCM wash-out, obtains 21g white solid, HPLC purity: 98.6%, yield: 43%.Nuclear-magnetism detects data:
1h-NMR (400Hz, DMSO-d6) δ 8.29-8.35 (s, 1H), 7.81-9.02 (t, 4H), 7.58-7.71 (t, 3H), 7.48-7.52 (m, 1H), 7.32-7.52 (m, 4H), 7.22-7.31 (m, 2H), 5.05-5.29 (m.2H), 4.21-4.69 (m, 4H), 2.39-2.42 (d, 1H), 2.30-2.36 (d, 1H), 2.19-2.24 (s, 3H) .Ms
+: 544.2 [M+1].
The chemical structural formula of table 1 chemistry abbreviation and correspondence
Above-described embodiment, only for technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (8)
1. a α-N-methylhistidine intermediate, is characterized in that: its chemical structural formula such as formula shown in I,
（Ι），
In formula I, R is methyl, phenyl, p-methylphenyl, o-methyl-phenyl-, an aminomethyl phenyl, 2,4-3,5-dimethylphenyls, 2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyls, p-methoxyphenyl, 2,4-Dimethoxyphenyls or benzyl; PG is blocking group.
2. α-N-methylhistidine intermediate according to claim 1, is characterized in that: the chemical structural formula of described PG is
or
, wherein, R
2for methyl, ethyl, sec.-propyl, benzyl, 2-chlorobenzyl, to methoxy-benzyl, 9-fluorene methyl, the tertiary butyl, allyl group, 2-(trimethyl silicon based) ethyl, 1,1-bis-supports band thionaphthene [b]-2-methyl, 2,2,2-trichloroethyl, 2-chloroethyl, 2-(2 '-pyridyl)-ethyl, 2-(4 '-pyridyl)-ethyl, 1-adamantyl or 2-adamantyl, R
3for methyl, trifluoromethyl or phenyl.
3. the preparation method of arbitrary described α-N-methylhistidine intermediate in claim 1 to 2, it is characterized in that, it comprises the following steps:
A () compound 1 is obtained by reacting compound 2 with sulfuryl halide in the first organic solvent under alkaline condition;
；
B () compound 2 generates described α-N-methylhistidine intermediate in the second organic solvent under the effect of acid catalyst with paraformaldehyde or polyformaldehyde reaction;
。
4. the preparation method of α-N-methylhistidine intermediate according to claim 3, it is characterized in that: in step (a), alkaline condition obtains by adding acid binding agent in described first organic solvent, and described acid binding agent is sodium carbonate, salt of wormwood, sodium hydroxide, triethylamine or nitrogen methylmorpholine.
5. the preparation method of α-N-methylhistidine intermediate according to claim 4, it is characterized in that: described step (a) is: compound 1 and acid binding agent are mixed in the first organic solvent, subsequently to wherein adding sulfuryl halide, be obtained by reacting compound 2 at 0 ~ 35 DEG C.
6. the preparation method of α-N-methylhistidine intermediate according to claim 3, it is characterized in that: described step (b) is: in reaction vessel, add compound 2, second organic solvent, paraformaldehyde or paraformaldehyde, acid catalyst successively, generating described α-N-methylhistidine intermediate with being placed on 40 ~ 90 DEG C of back flow reaction.
7. the preparation method of α-N-methylhistidine intermediate according to claim 3, it is characterized in that: in step (b), described acid catalyst is sulfuric acid, methylsulfonic acid, camphorsulfonic acid, tosic acid, Phenylsulfonic acid or trifluoroacetic acid, and described acid catalyst is 0.1:1 ~ 2:1 with the molar equivalent ratio of compound 2.
8. the preparation method of α-N-methylhistidine intermediate according to claim 3, is characterized in that: acetone-water mixing solutions, the volume ratio of described first organic solvent to be volume ratio be 1 ~ 4:1 are 1 ~ 4:1 tetrahydrofuran (THF)-water mixed solution or acetonitrile; Described second organic solvent is the mixture of one or more compositions in methylene dichloride, chloroform, ethyl acetate, tetrahydrofuran (THF), ethylene dibromide, Isosorbide-5-Nitrae-dioxane, Benzene and Toluene.
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| CN1089604A (en) * | 1992-07-02 | 1994-07-20 | 藤泽药品工业株式会社 | The synthetic intermediate and the method for the novelty of preparation amino acid derivative |
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