CN101084192B - Manufacture of vitamin B6 - Google Patents

Manufacture of vitamin B6 Download PDF

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CN101084192B
CN101084192B CN2005800437544A CN200580043754A CN101084192B CN 101084192 B CN101084192 B CN 101084192B CN 2005800437544 A CN2005800437544 A CN 2005800437544A CN 200580043754 A CN200580043754 A CN 200580043754A CN 101084192 B CN101084192 B CN 101084192B
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CN101084192A (en
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安德鲁·乔治·谷姆
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
    • C07D213/67—2-Methyl-3-hydroxy-4,5-bis(hydroxy-methyl)pyridine, i.e. pyridoxine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles

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Abstract

The present invention relates to a process for the manufacture of pyridoxamine, pyridoxine and further clodely related 3-hydroxy-pyridine derivatives and of acid salts thereof. Pyridoxamine and pyridoxine belong to the vitamin B6 group. This new multistep process is represented schematically in the following Reaction Scheme .

Description

Vitamins B 6Preparation
The present invention relates to the preparation technology of Pyridoxylamine, pyridoxol and closely-related 3-hydroxyl-pyridine derivate and acid salt thereof.Pyridoxylamine and pyridoxol belong to vitamins B 6Family.Pyridoxylamine has vital role in a large amount of Biochemical processes, and is that (usually, pyridoxol itself or especially its hydrochloride are known as " vitamins B for the useful presoma of pyridoxol 6").
Nearly all vitamins B 6Industry is synthetic all to start from L-Ala cheap, that be easy to get, and L-Ala experiences several chemical steps and is converted into 5-oxyethyl group-4-methyl-oxazoles (EMO), and it is the most expensive intermediate in the chemical production processes for this reason.EMO is used as diene, and with protected 2-butylene-1, the 4-glycol carries out the Diels-Alder reaction.The acid catalyzed rearrangement and the hydrolysis in aqueous hydrochloric acid of Diels-Alder adducts subsequently can obtain pyridoxine hydrochloride, i.e. the vitamins B of business form 6This can be schematically shown by following reaction scheme 1, and wherein Et represents ethyl, and R represents 2-butylene-1, the integral part of the protecting group of 4-glycol:
Figure G200580043754420070622D000011
Reaction scheme 1:Diels-Alder reaction and acid rearrangement the---known vitamins B 6Crucial production stage during industry is synthetic
From EMO and protected 2-butylene-1, the 4-glycol is to vitamins B about this 6The document of the route of the finished product comprises United States Patent (USP) 3,250,778,3,296,275 and 3,822,274 and indian patent 175,617.Shown in the practice that the Diels-Alder reaction obtains mixing prod unfriendly.
Because several chemical steps of synthetic needs that Cong oxazole EMO begins also produce a large amount of waste streams products, therefore avoid the synthetic route of these shortcomings and above mentioned inefficient Diels-Alder reaction is the target of a lot of chemical research always.Now have surprisingly been found that, can prepare Pyridoxylamine (hydrochloride) or other closely-related 3-hydroxyl-pyridine derivate by the rapid technology of a kind of new multistep, described technology starts from L-Ala or other amino acid (as required) that cheaply is easy to get equally, but has avoided 5-alkoxyl group-oxazoles that EMO or relevant 4-replace and the participation of Diels-Alder reaction simultaneously.In addition, compare with route previously discussed, for from L-Ala or other amino acid to Pyridoxylamine, pyridoxol or its salt or relevant 3-hydroxyl-pyridine derivate, this new rapid technology of multistep comprises chemical step still less.
The rapid technology of this new multistep can be schematically shown by following reaction scheme 2, described scheme be start from L-Ala ( 1) reduction procedure, and comprise the Michael acceptor 5Acyl group (that is acylated gamma-hydroxycrotononitril NC-CH=CHCH, 2OAc), the simplest this group is ethanoyl (Ac):
Reaction scheme 2: the example of the route of final preparation pyridoxol of the present invention or its closely related derivative
In reaction scheme 2,4-methyl-5 (4H)-azolactones 4In bracket, provide, represent this compound at it by N-formyl radical L-Ala 3Generation does not need separated afterwards, but, the Michael acceptor of post reaction mixture and interpolation 5Can direct reaction, this is via following two bracketed compounds 6With 7, first in three 3-Tetrahydrothienopyriderivatives derivatives that obtain in this route, forming, i.e. compound 8, wherein said compound 6With 7Be that imagination forms, need not separated (also can be separated) if form really.
Technology of the present invention is mainly reflected in 5 (4H) ,-azolactones that 4-replaces (4-methyl-5 (4H)-azolactones in the reaction scheme 2 for example 4) with acylated gamma-hydroxycrotononitril (γ-acetoxyl group-propenyl cyanide in the reaction scheme 2 for example 5) reaction in, this reaction generates 3-hydroxyl-4-cyano group-5-acyl-oxygen methyl-pyridinium salt that suitable 2-replaces (pyridine derivate with acetyl-o-methyl that methyl that 2-replaces and 5-replace in the reaction scheme 2 for example 8).This technology can be included in preceding step alternatively: the a-amino acid that the N-formyl radical is replaced (N-formyl radical-L-Ala in the reaction scheme 2 for example 3) be converted into 5 (4H) ,-azolactones, particularly Dang Suo Shu azolactone that 4-replaces with acylated gamma-hydroxyl-propenyl cyanide reaction before not from above-mentioned post reaction mixture under the isolating situation.And, technology of the present invention can also comprise follow-up reduction and hydrolysing step alternatively, 3-hydroxyl-4-cyano group-5-acyl-oxygen methyl-pyridinium salt (the salt of Pyridoxylamine or its closely related derivative that needs this step that aforementioned 2-is replaced, the 2-methyl compound in the reaction scheme 2 for example, be Pyridoxylamine itself, as its dihydrochloride 9Illustrate), technology of the present invention also can comprise the 3-hydroxyl-4 that the last-mentioned compound in front is converted into corresponding 2-replacement by diazotization and hydrolysis alternatively, 5-two (methylol)-pyridinium salt (salt of pyridoxol or its closely related derivative, the 2-methyl compound in the reaction scheme 2 for example, be pyridoxol itself, as its dihydrochloride 10Illustrate) final step.
Therefore, main aspect of the present invention provides the technology of the 3-hydroxyl-4-cyano group-5-acyl-oxygen methyl-pyridine of the 2-replacement for preparing general formula I,
Figure G200580043754420070622D000041
In the formula, R 1Expression methyl, sec.-propyl, isobutyl-, 2-butyl or phenmethyl, or be the methylol protected by hydroxyl protection or thiohydroxy, 1-hydroxyethyl, thiohydroxy methyl or to the oxybenzene methyl as the case may be, or the methyl thio-ethyl; R 2The expression acyl group,
It is characterized in that, make 5 (4H) ,-azolactones of the 4-replacement of general formula I I
Figure G200580043754420070622D000051
In the formula, R 1Define as above,
With the acylated gamma-hydroxyl-propenyl cyanide reaction of general formula III,
In the formula, R 2The expression acyl group.
Another aspect of the present invention provides the technology of the 3-hydroxyl-4-cyano group-5-acyl-oxygen methyl-pyridine of the 2-replacement for preparing above-mentioned general formula I; wherein 5 (4H) ,-azolactones of the 4-of general formula I I replacement prepare by the following method: alternatively in the presence of alkali; N-formyl radical-a-amino acid with dehydration activator mutual-through type IV dewaters and cyclisation
Figure G200580043754420070622D000053
In the formula, R 1Definition as above.
Technology of the present invention also comprises other step:
3-hydroxyl-4-aminomethyl-5-methylol-the pyridinium salt that at first prepares the 2-replacement of general formula V,
In the formula, R 1Define as above, HX is salifiable acid,
Wherein, the 3-hydroxyl-4-cyano group-5-acyl-oxygen methyl-pyridine catalytic hydrogenation that will replace and use the enhydrite acid hydrolysis according to the 2-of the general formula I of above-mentioned preparation technology preparation;
Finally prepare the 2 3-hydroxyls-4 that replace of general formula VI, 5-two (methylol)-pyridinium salt,
Figure G200580043754420070622D000061
In the formula, R 1Define as above, HX is salifiable acid,
Wherein, the 3-hydroxyl-4-aminomethyl-5-methylol-pyridinium salt diazotization and the hydrolysis that will replace according to the 2-of the general formula V of above-mentioned preparation technology preparation.
Above about the substituent R in N-formyl radical-a-amino acid of formula IV and each compound formula II, V and VI 1Definition in, R 1Be the α substituting group of related these a-amino acids, i.e. L-Ala (R 1=methyl), Xie Ansuan (R 1=sec.-propyl), leucine (R 1=isobutyl-), Isoleucine (R 1=2-butyl), phenylalanine (R 1=phenmethyl), Serine (R 1=methylol), Threonine (R 1=1-hydroxyethyl), halfcystine (R 1=thiohydroxy methyl), tyrosine (R 1=para hydroxybenzene methyl) or methionine(Met) (R 1=methyl thio-ethyl), wherein under the situation of Serine, Threonine, halfcystine and tyrosine, substituent hydroxyl of each α or thiohydroxy are protected.Suitable protecting group can be low alkyl group (C 1-6Alkyl is suitable, preferable methyl or ethyl) or phenmethyl.These alkyl with 3 or more a plurality of carbon atoms can be straight or brancheds.Therefore, by the suitable protected R of Serine, Threonine, halfcystine and tyrosine-derived 1Base is respectively alkoxyl-methyl or benzyloxy methyl, 1-alkoxyl oxygen alkyl ethyl or 1 benzene methoxyethyl, alkylthiomethyl or phenmethyl sulphomethyl and to the alcoxyl phenmethyl or to the benzyloxy phenmethyl.Preferably, R 1Be methyl.
In 3-hydroxyl-4-cyano group-5-acyl-oxygen methyl-pyridine that 2-in the acylated gamma-hydroxyl of formula III-propenyl cyanide and be present in the formula I that forms equally in " core " of the present invention technology replaces by R 2The acyl group of expression is suitably straight or branched C 2-9(the C atom of carbonyl also be can be regarded as in 2-9 the carbon atom to alkyloyl, so moieties is C 1-8); Aryl-C 2-9-alkyloyl wherein connects the C of carbonyl and aryl 1-8Alkylene moiety is from C 2Straight or branched; Or aroyl.Aryl-C 2-9The aryl of-alkyloyl and aroyl can be specially not the phenyl that replaces or replace, and wherein substituting group is selected from one or more aptly and plants low alkyl groups (C particularly 1-6Alkyl), other conventional substituting group of halogen atom (particularly fluorine, chlorine and bromine), nitro and phenyl and other aryl.Preferably, acyl group is ethanoyl, benzoyl or phenylacetyl, most preferably ethanoyl.
Among general formula V and the VI and by catalytic hydrogenation and hydrolysing step I-used salifiable acid or mineral acid HX deutero-negatively charged ion X among the V -Be suitably halogen ion (fluorion, chlorion, bromide anion or iodide ion), hydrogen sulfate ion (HSO 4 -), phosphoric acid hydrogen radical ion (H 2PO 4 -) or hydrogen phosphite radical ion (H 2PO 3 -), preferred chlorion.
The technology of the present invention that comprises the Michael addition (" core " processing step) of the compound of formula II and III can be carried out in the presence of substantially anhydrous, nonpolar or polar non-proton organic solvent and alkali easily, and carries out under relatively lower temp.As this organic solvent, preferred lower halogenated aliphatic hydrocarbons, for example methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride or sym.-tetrachloroethane; Lower aliphatic ether or cyclic ethers, for example diethyl ether, diisopropyl ether, t-butyl methyl ether or diethylene glycol dimethyl ether (diglyme), or aptly, tetrahydrofuran (THF) Huo diox; Rudimentary aliphatic ester, for example ethyl acetate, propyl acetate or butylacetate; Lower aliphatic hydrocarbon, for example butane, pentane, hexane, heptane, octane or V.M.. naphtha; Clicyclic hydrocarbon, for example tetramethylene, pentamethylene, hexanaphthene or cyclooctane; Aromatic hydrocarbon, for example benzene, toluene or dimethylbenzene; Or one or more plant the mixture of the concrete solvent of these types.As alkali, can use tertiary amine-type base usually, trialkylamine for example is as triethylamine; Pyridine or 4-dialkyl amino yl pyridines, for example 4-dimethylaminopyridine; Or diaza-bicyclo alkane alkene, for example 1,5-diazabicyclo [4.3.0]-5-nonene or 1,8-diazabicyclo [5.4.0]-7-undecylene.
The lesser temps that is suitable for carrying out this technology (Michael addition) is-100 to+60 ℃ approximately approximately, and is preferred approximately-80 to+20 ℃ approximately, most preferably from about-40 to about 0 ℃.
In addition, the mol ratio of 5 (4H) ,-azolactones that the 4-of the acylated gamma-hydroxyl of the formula III in the correlated response mixture-propenyl cyanide and formula II replaces is suitably for about 5: about 1: 1 of 1-, preferred about 2: about 1: 1 of 1-.
It is excessive to about twice that the relative quantity of 5 (4H) ,-azolactones that replace with respect to 4-of the alkali that exists in the reaction mixture is suitably about chemical equivalent; The azolactone of stating is activated (deprotonation) and becomes the nucleophilic solvent, and it is participated in the Michael addition with acylated gamma-hydroxyl-propenyl cyanide.Therefore, for every normal azolactone, the amount of alkali is suitably about 1-2 equivalent, preferably about 1-1.1 equivalent.
The reaction of 3-hydroxyl-4-cyano group-5-acyl-oxygen methyl-pyridine that the 2-of the formula I of formation expectation replaces was finished in about 30-60 minute usually.
For product is separated, can use ordinary method, for example column chromatography (preferably using silicon-dioxide or ion exchange resin) or recrystallization (preferably from ethanol) as stationary phase.
As mentioned above, another aspect of the present invention comprises the technology of 5 (4H) ,-azolactones (acylated gamma-hydroxyl-propenyl cyanide at this raw material and formula III carries out Michael addition reaction (" core " processing step) before) that the 4-of preparation formula II replaces.This technology comprises N-formyl radical-a-amino acid dehydration and cyclisation of the general formula I V that will above provide and define with the dehydration activator alternatively in the presence of alkali.
Dehydration and cyclization can carry out according to known method itself, for example Roczniki Chemii 35, 979-984 (1961), Macromolecules 19, the method among the 1547-1551 (1986) and separately as Tetrahedron 52(13), the method for an example of the experimental section of 4719-4734 (1996).In these currently known methodss, use N, N '-dicyclohexyl carbon imide (DCC) is as the dehydration activator, but dehydration and the formed N of cyclization, N '-dicyclohexylurea (DCU) is difficult to separate with post reaction mixture, thereby makes the application of DCC have specific difficulty.Alternative dehydration activator is phosgene, thionyl chloride; Carboxylic acid derivatives, for example Vinyl chloroformate; Acid anhydrides, for example diacetyl oxide; With other carbon imide.
According to the dehydration activator species of using, in the reaction mixture of 5 (4H) ,-azolactones that preparation 4-replaces, also may need alkali.Need alkali when using phosgene or thionyl chloride, under these circumstances, alkali is suitably aliphatic tertiary amine, particularly trialkylamine, for example triethylamine; Pyridine; Dimethyl aminopyridine; Or piperidines.
If use alkali, then its consumption can reach about 5: 1 with respect to the mol ratio of the amount of the N-formyl radical-a-amino acid of formula 1.This mol ratio is preferably about 2: 1.
The suitable solvent that is used for N-formyl radical-a-amino acid cyclisation and is dehydrated into 5 (4H) ,-azolactones that 4-replaces is polarity or nonpolar aprotic organic solvent, preferred polar solvent, comprise lower halogenated aliphatic hydrocarbons, for example methylene dichloride, chloroform and tetracol phenixin; Aromatic hydrocarbon, for example toluene; Aliphatic ether, for example diethyl ether and diglyme; And cyclic ethers, for example mixture of tetrahydrofuran (THF) and the solvent that two or more are such, for example mixture of lower halogenated aliphatic hydrocarbons and aliphatic ether.
Cyclisation and dehydration reaction are carried out under relatively lower temp usually, and described lesser temps is suitably-78 ℃ to+25 ℃ approximately approximately, preferred-20 ℃ to about 0 ℃ approximately.
Being easy to and dewatering activator reaction or promote the atmospheric water of the side reaction that other is not expected in the reaction system, reaction suits to carry out under rare gas element (for example nitrogen or argon) atmosphere.
A kind of following carrying out of concrete grammar of using 5 (4H)-oxazoles that phosgene replaces as the 4-of the preparation formula II of dehydration activator: the N-formyl radical-a-amino acid with formula IV under about 0 ℃-Yue 25 ℃ temperature is suspended in the methylene dichloride; handle this suspension with about 2-about 3.2 normal preferred bases triethylamines; after mixture being cooled to approximately-15 ℃, add the solution of phosgene in toluene.Then, by filter removing sedimentary hydrochloride, and concentrated filtrate under reduced pressure, the coarse products that obtains expecting.5 (4H) ,-oxazoles that the 4-of the formula II of gained replaces can directly (promptly not carry out intermediate purification) and be used for the reaction with the acylated gamma-hydroxyl-propenyl cyanide of formula III.In a similar fashion, can use thionyl chloride, also coarse products can be directly used in next reaction in the case as the dehydration activator.
N-formyl radical-a-amino acid of raw material formula IV can and be protected (if necessary by corresponding amino acid whose N-formylation; for example when amino acid is Serine, Threonine, halfcystine and tyrosine) prepare; this method is own known and abundant record is arranged in the literature; for example; can be about the N-formylation referring to J.M.Aizpurua and C.Palomo, Synth.Comm. 13(9), 745-752 (1983) can be referring to T.W.Greene and P.G.M.Wuts about protect above-mentioned concrete a-amino acid with suitable hydroxyl and thiohydroxy protecting group, Protective Groups in Organic Synthesis, 3 RdEdn.1999, John Wiley﹠amp; Sons, Inc.
Be hydrolyzed with enhydrite acid simultaneously by catalytic hydrogenation, can realize the preparation of 3-hydroxyl-4-aminomethyl-5-methylol-pyridinium salt that the 2-of formula V replaces, 3-hydroxyl-4-cyano group-5-acyl-oxygen methyl-pyridine next processing step afterwards that promptly prepares the 2-replacement of general formula I, this step can be based on the instruction of pertinent literature, and for example S.Shimada and M.Oki are at Chem.Pharm.Bull. 32(1), the utilization of describing among the 39-43 (1984) is reference T.Matsukaura and K.Shirakawa more early, TakugakuZasshi 71, 1498 (1951) method.English Patent (UKP) 1,062,843 provides about closely-related 2-methyl-3-hydroxyl-4-cyano group-5-methylol-pyridine is converted into the relevant details of the catalytic hydrogenation condition of Pyridoxylamine or its salt.Find, described hydrogenation can use loaded palladium catalyst (for example 5% palladium charcoal) to carry out easily in acidifying aqueous alcohol (methyl alcohol) medium (the 10-30% hydrochloric acid alcoholic solution of the about 20%vol/vol of for example about 0.5%vol/vol-, about 30% methanol hydrochloride solution of the about 5%vol/vol of preferably about 1%vol/vol-).Pressure is unimportant, and catalytic hydrogenation can under atmospheric pressure be carried out effectively.High temperature neither be necessary, at room temperature carries out processing step and can obtain good result.
Can for example comprise recrystallization from the alcohol such as methyl alcohol or ethanol by the product of known method separation and purifying formula V in the document.
After the processing step of 3-hydroxyl-4-aminomethyl-5-methylol-pyridinium salt that the 2-that finishes above-mentioned catalytic hydrogenation hydrolysis simultaneously accepted way of doing sth V replaces, can further optionally carry out diazotization and hydrolysis to it in the processing step, form the 2 3-hydroxyls-4 that replace of corresponding formula VI, 5-two (methylol)-pyridinium salt (pyridoxine hydrochloride is the important example of these the finished product).This processing step also can carry out according to methods known in the art, for example the method for describing in the document of above-mentioned S.Shimada etc. (by two about with the conversion example of the pyridinium salt of formula V 4-aminomethyl-pyridine derivate similar but inequality), or above-mentioned UKP 1, the method of describing in 062,843 (specifically in the embodiment 3).
As acyl group R 2During for ethanoyl, the acylated gamma-hydroxyl-propenyl cyanide of used formula III is a compound known in above-mentioned " core " processing step.Therefore; this acylated compounds (γ-ethanoyl-propenyl cyanide) and be disclosed in A.Nudelman and E.Keinan by the preparation method of known raw material; Synthesis (Communications) August 1982; in the document of 687-689 and above-mentioned S.Shimada etc., above-mentioned document example different preparation technologies.
γ-the hydroxyl of the γ-acidylate of other formula III-propenyl cyanide (that is R, 2Acyl group for non-ethanoyl) can prepare similarly by suitable known raw material.
By following examples technology of the present invention is described.
Embodiment 1
Preparation N-formyl radical L-Ala
To the D of 179.3g (2.01mol), carefully add the formic acid of 155ml in the suspension of L-L-Ala in the dimethyl formamide of 900ml, and under reflux temperature, heat this mixture, all dissolve (5 hours) up to L-Ala.Solvent evaporated then, and under high vacuum dried residue, obtain the rough N-formyl radical-L-Ala of 271.1g beige solid shape, it mainly forms (85 area %, gas-chromatography (GC)) by the N-formyl radical L-Ala of expectation.Impurity comprises L-Ala, alanine anhydride and dimethyl formamide.
Embodiment 2
Prepare 4-methyl-5 (4H)-azolactones by N-formyl radical L-Ala
In the flask that is precooled to the suspension in 0 ℃ and the methylene dichloride of N-formyl radical L-Ala at 150ml that contains 90g (76.9mmol) under argon atmospher, portioning adds the N of 15.9g (76.9mmol), N '-dicyclohexyl carbon imide.0 ℃ down stir 1 hour after, remove the N that generates by filtering through sinter funnel, N '-dicyclohexylurea (DCU), then under 20 ℃ and 200mbar (20kPa) by rotary evaporation removal methylene dichloride.At room temperature, under high vacuum (0.3mbar/30Pa), carefully coarse products is carried out the distillation of bottle bottle.Under-78 ℃, 4-methyl-5 (4H)-azolactones of purifying are collected in the receiving bottle.Purify receiving bottle with argon then, and add the dry methylene chloride of 10ml.It is 0.87M (separation yield is 11%) that Ce is Dinged the concentration of azolactone.The part of this solution is used for the subsequent step shown in the embodiment 3.
Embodiment 3
Preparation 2-methyl-3-hydroxyl-4-cyano group-5-acetyl-o-methyl-pyridine
At room temperature, to containing 408mg (3.26mmol; 1.01 in the flask under the argon atmospher of the solution of γ-acetoxyl group equivalent)-propenyl cyanide (preparation in an embodiment) in the 15ml methylene dichloride, add 454 μ l (3.26mmol, 1.01 triethylamine equivalent) at room temperature dropwise adds the dichloromethane solution that comprises 4-methyl-5 (4H)-azolactones that obtains among the embodiment 2 of 3.7ml then.Thermopositive reaction takes place.After the stirred reaction mixture 1 hour, under reduced pressure it is concentrated.Use that (1: mixture 9v/v) is the column chromatography of elutriant, isolates the 2-methyl-3-hydroxyl-4-cyano group-5-acetyl-o-methyl-pyridine (yield based on Yuan Liao azolactone is 53%) of 353mg expectation as stationary phase, methyl alcohol and methylene dichloride with silica gel.Can be easily from ethanol crystallization go out product, obtaining fusing point is the orange/yellow solid of 205-207 ℃ (being accompanied by decomposition).
Embodiment 4
Preparation γ-acetoxyl group-propenyl cyanide
At room temperature, in 30 minutes the reaction flask that contains the 375ml pure tetrahydrofuran of argon degasification, stir and add 3.94g (15.0mmol) triphenylphosphine, add 842mg (3.75mmol) acid chloride (II) then.Add finish after, with the clear orange solution restir of gained 30 minutes.Then, disposable interpolation 18.8g in the mixture in bottle (18.6ml, 150mmol) 2-acetoxy-3-crotononitrile, and stirred reaction mixture at room temperature, up to can not detecting raw material again with thin-layer chromatography and GC, this occurs in and adds after about 4 hours of the nitrile reactant.The dark brown solution of gained is under reduced pressure concentrated, and distill remaining concentrated solution, obtain 13.69g (109.4mmol; γ-acetoxyl group-the propenyl cyanide of light yellow liquid shape expectation yield 73%).To be used as the Michael acceptor in the embodiment 3 described methods by the product that E-and Z-isomer are formed.
Analytical data (the C of the E/Z-isomer mixture of the γ-acetoxyl group-propenyl cyanide of preparation 6H 7NO 2Molecular weight 125.13):
Boiling point 100-102 ℃/12mbar (1.2kPa);
R f(silica gel; Ethane: ethyl acetate 2: 1v/v): 0.3 (KMnO 4Tinting material);
1H-NMR(300MHz，CDCI 3)：δ＝2.10(s，3H)，2.11(s，3H)，4.71(m，2H)，4.86(m，2H)，5.52(d，J＝11.4Hz，1H)，5.59(d，J＝16.4Hz，1H)，6.51(dt，J＝5.7，5.7Hz，1H)，6.72(d，J＝16.4Hz，1H)；
13C-NMR(75MHz，CDCI 3)：δ＝20.48，20.51，61.9，62.3，101.1，101.6，114.7，116.4，147.3，147.7，169.9，107.3；
Mass spectrum: 125[M] +, 110,105,83,66,55,43,39m/z.
Embodiment 5
Prepare 2-from N-formyl radical L-Ala via 4-methyl-5 (4H)-azolactone (not separating this azolactone) Methyl-3-hydroxyl-4-cyano group-5-acetyl-o-methyl-pyridine
The method of following example has been avoided by the caused difficulty of fractionation by distillation intermediate 4-methyl-5 (4H)-azolactones, and this method comprises two reactions steps.
Under room temperature (about 25 ℃), under argon atmospher, in the suspension of 3.2g (27.3mmol) N-formyl radical L-Ala in the 100ml chloroform, add 8.8g (12.2ml, 87.45mmol, 3.2 equivalents) triethylamine, and the opaque solution of gained is cooled to-15 ℃.In N-formyl radical L-Ala suspension, the phosgene of 20% (v/v) that dropwise adds 15ml is at toluene (1.05 equivalent COCl 2) in solution, the speed of dropping should make internal temperature be no more than-10 ℃, and the conversion by GC monitoring N-formyl radical L-Ala.Transform fully to occur in and dripped beginning about 45 minutes afterwards.
Under 0 ℃, in the orange-brown solution of gained, dropwise add 3.42g (27.33mmol, 1 equivalent) γ-acetoxyl group-propenyl cyanide with dropping funnel, and with 16 hours with the mixture heating up that obtains to room temperature.After described mixture adds 50ml toluene, the precipitation that obtains is filtered out and with twice of 25ml toluene wash.Then, slow evaporating solvent under 60 ℃/100mbar (10kPa), at room temperature, distillation residue under the decompression of 0.01mbar (1Pa), reclaim 783mg (6.26mmol with-78 ℃ dry ice trap, 0.23 unconverted γ-acetoxyl group-propenyl cyanide equivalent) if desired can be with its recycle.Under 50 ℃ remaining solid residue being dissolved in the ethanol, and at 4 ℃ of following recrystallizations, obtaining main products 2-methyl-3-hydroxyl-4-cyano group-5-acetyl-o-methyl-pyridine: 3.78mmol of 780mg, is 14% based on the yield of raw material N-formyl radical L-Ala.Yet this product in addition is retained in the mother liquor, and is separable.
Also can be by column chromatography with this product separation, rather than the dehydration by N-formyl radical L-Ala obtains above-mentioned orange-brown solution and finally separates 2-methyl-3-hydroxyl-4-cyano group-5-acetyl-o-methyl-pyridine by crystallization with cyclisation as mentioned above.
In this alternative, in orange-brown solution, dropwise add 3.42g (27.3mmol, 1 equivalent) γ-acetoxyl group-propenyl cyanide with dropping funnel down at 0 ℃, and the gained mixture slowly is heated to 6 ℃ with 2 hours.Then at the following slow evaporating solvent of 60 ℃/100mbar (10kPa).With column chromatography by silica gel with coarse products (resistates) purifying, obtain 1.43g (6.9mmol) 2-methyl-3-hydroxyl-4-cyano group-5-acetyl-o-methyl-pyridine, this product volume means that the yield based on raw material N-formyl radical L-Ala is 25%.The purity of product is 63%, and (area %, GC), and the unconverted gamma-acetoxyl group-propenyl cyanide that reclaims can reach 2.29g (18.35mmol, circulation as required).2-methyl-3-hydroxyl-4-cyano group-5-acetyl-o-methyl-pyridine (C of preparation 10H 10N 2O 3, molecular weight 206.2) analytical data:
Fusing point: 205-207 ℃ (following decomposition);
R f(silica gel, methylene dichloride: methyl alcohol 9: 1v/v): 0.2 (Ultraluminescence, 330nm);
1H-NMR(300MHz，DMSO-D 6)：δ＝2.07(s，3H)，2.45(s，3H)，5.12(s，2H)，8.09(s，1H)；
13C-NMR(75MHz，DMSO-D 6)：δ＝19.6，20.3，61.4，106.5，113.7，130.9，138.2，149.4，153.6，169.9；
IR (KBr): v=2933,2579,2217,1751,1533,1467,1376,1234,1046cm -1Mass spectrum (electron spray(ES), negative ion mode): 205.0[M-H] -
Mass spectrum: retention time (RT)=12.96min., 206[M] +, 164,147,136,119,10,43m/z; Trimethyl silane is derived: RT=14.37min., 278[M] +, 236,221,205,118,73m/z;
Liquid chromatography/MS:RT=10.52min.[M+H] +
UV spectrum: 230 (max), 255,360nm;
Ultimate analysis: calculated value C 58.25, H 4.89, and N 13.59, and O 23.38%; Observed value C 58.10, H4.97, N 13.56O 23.47%.
Embodiment 6
Preparation 2-methyl-3-hydroxyl-4-aminomethyl-5-methylol-pyridine (Pyridoxylamine) dihydrochloride
At room temperature, 214mg (1.04mmol) 2-methyl-3-hydroxyl-4-cyano group-5-acetyl-o-methyl-pyridine is dissolved in the methyl alcohol of 12mol of the hydrochloric acid that contains 300 μ l 30%.In solution, add the palladium carbon catalyst of the 5w/w% of 40mg, under room temperature and normal atmosphere, mixture is carried out hydrogenation then.Then, remove catalyzer, and under reduced pressure remove the solvent of filtrate by filtering.With resistates recrystallization in ethanol, obtain 208mg (0.86mmol) beige solid shape two hydrochloric acid Pyridoxylamines, this scale shows that yield is 83%.Analytical data by this product is obtained ( 1H and 13CNMR, LC, LC/MS and UV) compare with the data of the two hydrochloric acid Pyridoxylamines that can obtain by commercial sources, the result shows that this product expects.
Embodiment 7
Preparation 2-methyl-3-hydroxyl-4,5-two (methylol)-pyridine (pyridoxol) hydrochloride
At room temperature, in the solution of 208mg (0.863mmol) two hydrochloric acid Pyridoxylamines in 8.6ml water, add the vitriol oil of 125 μ l (2.3mmol) 16M.With mixture heating up to 90 ℃, and under agitation dropwise add 119mg (1.726mmol, the 2 equivalents) solution of Sodium Nitrite in 3.9ml water.Reaction mixture was stirred other 2 hours.Then, in hot solution, add the solution of 56.2mg (2.3mmol) barium chloride dihydrate in 3.9ml water, and post reaction mixture is cooled to room temperature.Filter to remove solid, and with twice of the water washing of 5ml.The aqueous solution that vapourisation under reduced pressure merges, and with the ethanol that seethes with excitement resistates is ground, (86w/w%, HPLC) pyridoxine hydrochloride, its yield are 25% to obtain 44mg.

Claims (19)

1. the technology of 3-hydroxyl-4-cyano group-5-acyl-oxygen methyl-pyridine of replacing of the 2-of preparation general formula I,
Figure FSB00000107640400011
In the formula, R 1Expression methyl, sec.-propyl, isobutyl-, 2-butyl or phenmethyl, or as the case may be for the protected methylol of hydroxyl or thiohydroxy wherein, 1-hydroxyethyl, thiohydroxy methyl or to the oxybenzene methyl, or the methyl thio-ethyl; R 2Expression straight or branched C 2-9Alkyloyl, benzoyl or phenyl acetyl,
It is characterized in that, make 5 (4H) ,-azolactones of the 4-replacement of general formula I I
In the formula, R 1Define as above,
With the acylated gamma-hydroxyl-propenyl cyanide reaction of general formula III,
Figure FSB00000107640400013
In the formula, R 2Definition as above.
2. technology as claimed in claim 1, the R among its Chinese style I and the II 1Be methyl.
3. technology as claimed in claim 1, the wherein R in the formula III 2Be ethanoyl, benzoyl or phenyl acetyl.
4. as any one technology among the claim 1-3, carry out under the wherein said existence that is reflected at water-free substantially nonpolar or polar organic solvent and alkali.
5. technology as claimed in claim 4, wherein said solvent is methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, 1,1,2,2-tetrachloroethane, diethyl ether, diisopropyl ether, t-butyl methyl ether, diethylene glycol dimethyl ether, tetrahydrofuran (THF), diox, ethyl acetate, propyl acetate, butylacetate, butane, pentane, hexane, heptane, octane, V.M.. naphtha, tetramethylene, pentamethylene, hexanaphthene, cyclooctane, benzene, toluene or dimethylbenzene, perhaps one or more plant the mixture of this kind solvent.
6. technology as claimed in claim 4, wherein said alkali are tertiary amine-type base, or diaza-bicyclo alkane alkene.
7. technology as claimed in claim 4, wherein said alkali are pyridine or 4-dialkyl amino yl pyridines.
8. as any one technology among the claim 1-3, wherein said being reflected at-100 ℃ carried out to+60 ℃ temperature.
9. technology as claimed in claim 8, wherein said being reflected at-80 ℃ carried out to+20 ℃ temperature.
10. technology as claimed in claim 9, wherein said being reflected at-40 ℃ carried out to 0 ℃ temperature.
11. as any one technology among the claim 1-3, the mol ratio of 5 (4H) ,-azolactones that the 4-of the γ-hydroxyl of the formula III in the wherein said reaction mixture-propenyl cyanide and formula II replaces is 5: 1-1: 1.
12. as the technology of claim 11, the mol ratio of 5 (4H) ,-azolactones that the 4-of the γ-hydroxyl of the formula III in the wherein said reaction mixture-propenyl cyanide and formula II replaces is 2: 1-1: 1.
13. technology as claimed in claim 4, the equivalence ratio scope of 5 (4H) ,-azolactones that the 4-of wherein said alkali and formula II replaces is 1-2: 1.
14. as the technology of claim 13, the equivalence ratio scope of 5 (4H) ,-azolactones that the 4-of wherein said alkali and formula II replaces is 1-1.1: 1.
15. the technology of 3-hydroxyl-4-cyano group-5-acyl-oxygen methyl-pyridine that the 2-of preparation general formula I as claimed in claim 1 replaces, wherein the N-formyl radical-a-amino acid of 5 (4H) ,-azolactones that replace of the 4-of general formula I I by mutual-through type IV dewaters and cyclisation prepares,
Figure FSB00000107640400021
In the formula, R 1Definition is as claim 1.
16. as the technology of claim 15, the R among its Chinese style I, II and the IV 1Be methyl.
17. as the technology of claim 15, the R in the formula III wherein 2Be ethanoyl, benzoyl or phenyl acetyl.
18. the technology of 3-hydroxyl-4-aminomethyl-5-methylol-pyridinium salt that the 2-of preparation general formula V replaces, it is characterized in that, 3-hydroxyl-4-cyano group-5-acyl-oxygen methyl-pyridine that 2-according to the general formula I of the prepared of claim 1 is replaced carries out catalytic hydrogenation and is hydrolyzed with enhydrite acid
Figure FSB00000107640400031
In the formula, R 1Definition is as claim 1, and HX is salifiable acid.
19. the 2 3-hydroxyls-4 that replace of preparation general formula VI, the technology of 5-two (methylol)-pyridinium salt, it is characterized in that 3-hydroxyl-4-aminomethyl-5-methylol-pyridinium salt that the 2-according to the general formula V of the prepared of claim 18 is replaced carries out diazotization and hydrolysis
Figure FSB00000107640400032
In the formula, R 1Definition is as claim 1, and HX is salifiable acid.
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