Summary of the invention
The object of the present invention is to provide a kind of preparation to comprise pemetrexed disodium the improving one's methods and the employed intermediate of this method of interior N-(pyrrolo-[2,3-d] pyrimidine-5-yl) acyl glutamic acid derivative, and this intermediates preparation.
In order to realize this purpose, the present invention relates to the compound and the salt thereof of a kind of general formula (VII),
In the formula:
Z is thiophene two bases, furans two bases, or replacement or unsubstituted 1,4-phenylene;
R
1, R
2Be hydrogen or carboxyl-protecting group, they can be identical, also can be inequality;
The carbon atom configuration that indicates * is the S type, the mixed type of R type or S, R.
The invention still further relates to the method for preparing general formula (VII) compound or its salt, it comprises:
(a) compound that general formula (VIII) is represented
Perhaps response derivative or their a kind of salt of this formula compound on carboxylic group reacts with a kind of compound of representing with general formula (IX) or its a kind of salt,
Z in the formula, R
1, R
2With the definition of * as above;
(b) Ren Xuan product decarboxylize protecting group with step (a);
(c) Ren Xuan product salify with step (a) or step (b).
On this basis, the invention further relates to preparation general formula (I) compound or its method of making medicinal salt,
The definition of Z and * as above in the formula.
This method comprises:
(a) as if R in general formula (VII) compound or its salt
1Or R
2When being carboxyl-protecting group, it is removed;
(b) will remove carboxyl-protecting group, i.e. R
1And R
2Be general formula (VII) compound or its salt of hydrogen under certain acid or alkali environment with the reductive agent effect;
(c) Ren Xuan product salify with step (b).
Pyrimidine ring and pyrrolopyrimidine ring numbering in the present invention related in the said structure formula are as follows,
Structure all may exist with the equilibrium mixture form of its tautomer in each compound of (I)~(VIII) each, and following local structure formula represents to carry out in the molecule tautomeric that part of structure,
For the convenience of narrating, in this manual only with regard to 4 (1H)-oxo forms in the tautomer with and relevant title discuss, but should be appreciated that such description comprises corresponding change 4-hydroxyl, 4 (3H)-forms such as oxo.
Have two chiral centres in general formula (VII) compound, their absolute configurations comprise S type, R type or its mixed type respectively alone, promptly this formula compound comprise one (S, S), (S, R), (R, S), (R, R) type and their mixed type.But the chiral centre of glutaminic acid residue is the S configuration normally, and another chiral centre is the S-R mixed type normally, so general formula (VII) the compound mixture of two diastereomers normally.
" alkali " herein is to include but not limited to that metal alkoxide is (as sodium methylate when not explaining in addition, sodium ethylate, sodium butylate and butanols potassium etc.), the oxyhydroxide of ammonium or basic metal or alkaline-earth metal is (as ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta, calcium hydroxide etc.), the carbonate of basic metal or alkaline-earth metal or supercarbonate are (as yellow soda ash, salt of wormwood, barium carbonate, lime carbonate, sodium bicarbonate, saleratus etc.), the phosphoric acid salt of basic metal or alkaline-earth metal or hydrophosphate are (as sodium phosphate, potassiumphosphate, Sodium phosphate dibasic, dipotassium hydrogen phosphate etc.), the organic acid salt of basic metal or alkaline-earth metal is (as sodium acetate, potassium acetate, sodium oxalate, Sodium Benzoate etc.), nitrogenous organic base is (as Trimethylamine 99, triethylamine, N-methylmorpholine, pyridine etc.), other material that plays the alkali effect is (as basic catalyst, and their mixture deacidite etc.).
" acid " herein is to comprise but do not limit mineral acid or inorganic acid salt (as hydrogenchloride or hydrochloric acid when not explaining in addition, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid, nitric acid, sodium pyrosulfate, sal enixum, SODIUM PHOSPHATE, MONOBASIC, potassium primary phosphate etc.), organic acid or organic acid salt are (as formic acid, acetate, trifluoroacetic acid, methylsulfonic acid, tosic acid, phenylformic acid, phthalic acid, O-phthalic hydrogen sodium, O-phthalic hydrogen potassium etc.), Lewis acid is (as aluminum chloride, zinc chloride, iron(ic) chloride etc.), other plays the material (an acidic catalyst of acid effect, and their mixture acidic ion exchange resin etc.).
" salt of general formula (VII) compound " is the salt of this compound and acid or alkali reaction preparation, and such salt is known acid additive salt or base addition salt.Not only have acidic-group but also have basic group on general formula (VII) compound structure, (work as R as the carboxyl of glutaminic acid residue
1Or R
2When being hydrogen), the hydroxyl on the pyrimidine ring, the α carbon of nitro etc. all has certain acidity, they can with the alkali salify that is fit to, particular certain cancers, sylvite; Amino on the pyrimidine ring has certain alkalescence, can with the sour salify that is fit to, preferred tosilate, hydrochloride.
" protecting group " is the such group of representative in " carboxyl-protecting group ": they are not present in the final compound usually; but in a certain step of building-up process, have a mind to introduce; if so that protect those not protect the group that just might react in the chemical operation process, they are removed subsequently.Because having the compound of this class protecting group mainly is as chemical intermediate, so its accurate structure is not crucial.The method that connects and remove protecting group is being known in the art.
Carboxyl can be protected with the form of ester group, described ester group fully can selectively be removed under the demulcent condition, thereby can not destroy needed molecular structure, said ester is meant the lower alkyl esters of 1~12 carbon atom especially, methyl ester for example, ethyl ester and on 1-or 2-position substituted lower alkyl esters, these substituting groups include but not limited to: (a) low alkyl group, as tertiary butyl ester etc.; (b) lower alkoxy is as methoxymethyl ester, 1-methoxyethyl ester and ethoxymethyl ester etc.; (c) lower alkylthio is as methylthiomethyl ester, 1-ethylmercapto group ethyl ester etc.; (d) halogen, as 2,2,2-three chloro-ethyl esters, 2-bromo-ethyl ester etc.; (e) one or two kind of phenyl, they every kind can be unsubstituted, as benzyl ester, benzhydryl ester etc., or by following groups single replace, two replacement or three replaces: the low alkyl group such as the tertiary butyl etc., lower alkoxy such as methoxyl group etc., hydroxyl, halogen such as chlorine etc., nitro etc., this class replaces ester such as 4-nitrobenzyl ester, two-(4-p-methoxy-phenyl) methyl; Or (f) aroyl, as benzoyl group methyl esters etc.In addition, the form of ester group also has the alkenyl ester of 2~6 carbon atoms, as vinyl acetate, propylene ester etc.; Aryl ester is as phenylester, nitrophenyl ester etc.; The Organosilyl ester is as trimethyl silyl ester etc.When a plurality of carboxyl, the blocking group of each carboxyl can be identical or different, but preferably identical.In above protecting group, preferable methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and benzyl, most preferable, ethyl.
" thiophene two bases, furans two bases " refer to a thiphene ring or furan nucleus, and wherein two hydrogen atoms are removed from two ring carbon atoms, for example thiophene-2,5-two bases, thiophene-3,5-two bases, thiophene-3,4-two bases, furans-2,5-two bases, furans-3,5-two bases, furans-3,4-two bases etc.
" 1 of replacement, 4-phenylene " refers to remove phenyl outside 1,4 locational hydrogen atom has been removed, and all the other positions also can be selected from halogen, hydroxyl, C by one or two
1~4Alkyl and C
1~4Substituting groups such as alkoxyl group replace.Preferred mono-substituted once more situation on the 2-position with respect to 1-position COR functional group.
General formula (VII) compound or its salt can be by the method preparation of scheme 1.
Scheme 1
Or
Response derivative or its salt+formula (IX) compound or its salt → formula (VII) compound on formula (VIII) the compound carboxyl
Salify again after if needed can or sloughing protecting group with gained formula (VII) compound salify.
Z wherein, R
1, R
2With the definition of * as above.
The preparation method of general formula (VII) compound or its salt comprises formula (VIII) compound or its salt and formula (IX) compound or its salt generation acylation reaction; this acylation reaction is carried out in the presence of condensing agent usually; used condensing agent includes but not limited to 2-chloro-4; 6-dimethoxy-1; 3,5-triazine, carbodiimide, diphenylphosphine acyl azide, diethyl idol phosphorous oxides etc.Wherein preferred 2-chloro-4,6-dimethoxy-1,3,5-triazines.The condensing agent consumption generally is 1~10 with respect to formula (VIII) compound molar equivalent, preferably 1~5.
When existing, more help the carrying out of acylation reaction as the catalyzer (comprising basic catalyst and an acidic catalyst) that promotes acylation reaction.Basic catalyst includes but not limited to aliphatic tertiary amine (as triethylamine, N-methylmorpholine etc.), aromatic nitrile base (as pyridine, α-, β-or γ-picoline, 2,6-lutidine, 4-Dimethylamino pyridine, 4-(1-pyridine alkyl) pyridine, N, accelerine, N, N-Diethyl Aniline etc.); An acidic catalyst includes but not limited to Lewis acid (as Zinc Chloride Anhydrous, Aluminum chloride anhydrous, Anhydrous Ferric Chloride, titanium tetrachloride, the complexing of tetrachloro borate ether etc.).Typically, when selecting 2-chloro-4 for use, when 6-dimethoxy-1,3,5-triazines was made condensing agent, preferred N-methylmorpholine was made alkali in the above-mentioned catalyzer.Catalyst levels generally is 0.01~10 with respect to the molar equivalent of condensing agent, preferably 0.1~2.0.
Select 2-chloro-4 for use, 6-dimethoxy-1,3, the 5-triazine is made condensing agent, when N-methylmorpholine is made alkali, and both can be with formula (VIII) compound, 2-chloro-4,6-dimethoxy-1,3,5-triazines and N-methylmorpholine add the corresponding active ester of formation respectively, also can be earlier by 2-chloro-4,6-dimethoxy-1,3,5-triazine and N-methylmorpholine reaction generation 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-and 4-methylmorpholine muriate, generate corresponding active ester with the reaction of formula (VIII) compound again.Add fashionablely respectively, N-methylmorpholine is with respect to 2-chloro-4, and the molar equivalent of 6-dimethoxy-1,3,5-triazines generally is 1~5, and preferably 1~2; When using 4-(4,6-dimethoxy-1,3,5-triazines-2-yl)-4-methylmorpholine muriate, its molar equivalent with respect to formula (VIII) reactant generally is 1~10, preferably 1~3 times.If employed reactant is the salt that becomes with acid, then need add the acid that a part of N-methylmorpholine neutralizes and introduces, make whole reaction system be slightly acidic or neutrality or weakly alkaline.Select for use this kind condensing agent mainly to be because it is cheap and easy to get, the condensation condition gentleness, little to the racemization that chiral centre produces, not harsh to the anhydrous condition requirement of reaction system.
The preparation method of general formula (VII) compound or its salt also comprises response derivative or its salt and formula (IX) the compound or its salt generation acylation reaction on formula (VIII) the compound carboxylic group.
" response derivative on formula (VIII) the compound carboxylic group " is meant that formula (VIII) compound reacts the reactive derivative that can carry out acylation that obtains on carboxyl, include but not limited to the carboxylic acid halides (as acyl chlorides, acylbromide etc.) of formula (VIII) compound; The mixed acid anhydride that formula (VIII) compound and following material constitute: monoalkyl carbonic ether (as monomethyl carbonic ether, single ethyl carbonate ester, single propyl carbonate, single sec.-propyl carbonic ether, monobutyl carbonic ether, single isobutyl-carbonic ether, single sec-butyl carbonic ether, single tertiary butyl carbonic ether etc.), phosphodiester (as chlorooxon, di(2-ethylhexyl)phosphate ethyl ester, di(2-ethylhexyl)phosphate phenylester, di(2-ethylhexyl)phosphate benzyl ester etc.), phosphorous acid diester (as phosphorous acid dimethyl esters, phosphorous acid diethyl ester, phosphorous acid diphenyl, phosphorous acid dibenzyl ester etc.); The active ester of formula (VIII) compound is (as 4,6-dimethoxy-1,3,5-triazine-2-base ester, cyano group methyl esters, ethoxycarbonyl methyl esters, methoxymethyl ester, phenylester, ortho-nitrophenyl base ester, p-nitrophenyl ester, to the methoxycarbonyl phenylester, to cyano-phenyl ester, thiophenyl ester etc.); The sour trinitride of formula (VIII) compound.
" salt of formula (VIII) compound or its carboxy derivatives " had both comprised the salt that formula and the alkali that is fit to become, also comprised the salt that becomes with suitable acid.The salt that becomes with alkali includes but not limited to ammonium salt, an alkali metal salt such as sodium salt, sylvite, alkaline earth salt such as magnesium salts, calcium salt; The salt that becomes with acid includes but not limited to hydrochloride, hydrobromate, hydriodate, vitriol, phosphoric acid salt, tosilate, acetate etc.
" salt of formula (VII) compound " includes but not limited to hydrochloride, vitriol, phosphoric acid salt, preferably salt hydrochlorate.
The used suitable solvent of above-mentioned acylation reaction includes but not limited to that ether (as dme, diethyl ether, tetrahydrofuran (THF), diox, glycol dimethyl ether etc.), nitrile (as acetonitrile etc.), ester (as ethyl acetate etc.), halohydrocarbon (as methylene dichloride, chloroform, tetracol phenixin etc.), aromatic hydrocarbons (as benzene,toluene,xylene etc.), substituted amide are (as N; dinethylformamide; N-Methyl pyrrolidone, hexamethylphosphoramide etc.), the appropriate mixture of sulfone (as methyl-sulphoxide, tetramethylene sulfone etc.), acetone, Nitromethane 99Min., pyridine and two or more above-mentioned solvents.Wherein preferred ether such as tetrahydrofuran (THF), halohydrocarbon such as methylene dichloride and substituted amide such as N, dinethylformamide.
Reaction generally can be carried out in pH=1~14 scopes, and best pH scope is 5~9.During the pH of conditioned reaction mixture, can be as required to wherein adding acid, alkali or its mixture.Reaction up-to-date style (IX) compound generally is 1-20, preferably 1-5 with respect to the molar equivalent of formula (VIII) compound.Temperature of reaction is from making an appointment with-10 ℃ to the solvent for use boiling point, preferred-5~50 ℃.
The method of decarboxylation protecting group is well known to those skilled in the art; as can perhaps under suitable catalyzer (as palladium, platinum etc.), carrying out hydrogenolysis or/and alkali (as sodium hydroxide, potassium hydroxide etc.) is hydrolyzed under acting under acid (example hydrochloric acid, Hydrogen bromide, trifluoro ethyl ester, sulfuric acid, phosphoric acid etc.) effect.
During general formula (VII) compound salify, work as R
1And R
2When being carboxyl-protecting group, typically with the sour salify that is fit to, preferred tosic acid and hydrochloric acid.The consumption of acid generally is 1~10 of formula (VII) compound molar equivalent, preferably 1~3.Solvent includes but not limited to the appropriate mixture of alcohol (as methyl alcohol, ethanol, Virahol etc.), ether (as ether, tetrahydrofuran (THF), glycol dimethyl ether etc.), halohydrocarbon (as methylene dichloride, chloroform etc.), ketone (as acetone, pimelinketone etc.) and two or more above-mentioned solvents, wherein particular methanol, ethanol, Virahol, tetrahydrofuran (THF), acetone, most preferred ethanol.Temperature generally is-10 ℃ of boiling points to solvent for use during salify, and preferred room temperature is to the boiling point of solvent for use.
During general formula (VII) compound salify, work as R
1Or R
2When being hydrogen, typically with the alkali salify that is fit to, the salt particular certain cancers and the sylvite that are become.The consumption of alkali generally is 1~10 of formula (VII) compound molar equivalent, preferably 1~5.Solvent includes but not limited to that water, alcohol (as methyl alcohol, ethanol, Virahol etc.), ether (as tetrahydrofuran (THF), glycol dimethyl ether etc.), ketone (as acetone etc.), acid amides are (as N, dinethylformamide, N-Methyl pyrrolidone etc.), the appropriate mixture of sulfone (methyl-sulphoxide, tetramethylene sulfone etc.), pyridine and two or more above-mentioned solvents, preferably water, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetone and their appropriate mixture.Temperature generally is-10 ℃ of boiling points to solvent for use during salify, preferred 0 ℃ to room temperature.
The method of using such scheme 1 can include but not limited to by synthetic general formula (VII) compound:
N-[4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl] benzoyl]-the L-glutamate diethyl ester;
N-[4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl] benzoyl]-L-glutamate diethyl ester tosilate;
N-[4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl] benzoyl]-the L-diethyl glutamate hydrochloride;
N-[4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl] benzoyl]-L-L-glutamic acid;
N-[4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl] benzoyl]-the L-sodium glutamate;
N-[4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl] benzoyl]-the L-kaglutam.
General formula (VII) compound or its salt can prepare general formula (I) compound or its salt by the method for scheme 2.
Scheme 2
This preparation method comprises:
(a) work as R
1Or R
2When being carboxyl-protecting group, general formula (VII) compound or its salt is being hydrolyzed under the acid effect or under the alkali effect or in acid effect and alkali effect, perhaps under suitable catalyzer, is carrying out hydrogenolysis, removing protecting group;
(b) with R
1And R
2Be general formula (VII) compound or its salt of hydrogen under certain acid or alkali environment with the reductive agent effect;
(c) if needed, with the product salify of step (b).
End product is R in the step (a)
1And R
2It is general formula (VII) compound or its salt of hydrogen; The preferred hydrogenchloride of used acid (hydrochloric acid), hydrogen bromide (Hydrogen bromide), hydrogen iodide (hydroiodic acid HI), trifluoroacetic acid, sulfuric acid, phosphoric acid, methylsulfonic acid during hydrolysis, the preferred sodium hydroxide of alkali, oxygen potassium oxide.Consumption generally is 0.01-50, preferably 2-20 with respect to the molar equivalent of formula (VII) compound.Temperature of reaction can be 0~100 ℃, is generally 0~50 ℃, preferred room temperature.
Step (b) is with R
1And R
2Be general formula (VII) compound or its salt of hydrogen under certain acid or alkali environment with the reductive agent effect, be transformed into general formula (I) compound or its salt, its principle may be: nitro or aci-nitro group salt (nitronic acid salt) are reduced into oxime or aldehyde by certain reductive agent, with pyrimidine ring 6-bit amino cyclic condensation, obtain the pyrrolopyrimidine ring through double-bond rearrangement.
Reductive agent includes but not limited to titanous chloride, Sulfothiorine, hydrogen iodide, hydrogen sulfide, azanol, sodium amalgam, preferred titanous chloride, Sulfothiorine.The reductive agent consumption generally is 1~15 with respect to the molar equivalent of formula (VII) compound, preferred 1~5.The acid or alkali environment of reaction is according to different reductive agents and difference, the acid or alkali environment that is fit to can be provided by a certain amount of acid (example hydrochloric acid, sulfuric acid, phosphoric acid, acetate, formic acid etc.) or alkali (as sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, sodium acetate etc.), also can be provided by a certain amount of buffered soln (as Sodium phosphate dibasic/sodium dihydrogen phosphate, acetate/sodium acetate solution, ammonium acetate solution, ammonium chloride/ammonia solution, Potassium Hydrogen Phthalate solution etc.).As when using titanous chloride, pH preferred 1~12; When using Sulfothiorine, pH preferred 3~10.Temperature of reaction generally is-20~50 ℃, preferably-5 ℃ to room temperature.
The salt of the gained pharmaceutically acceptable salt (comprising its hydrate) of general formula (I) compound and alkali effect generation normally in the step (c) is as sodium salt, sylvite, calcium salt, magnesium salts, aluminium salt, ammonium salt etc.A preferred sodium salt and disodium salt, most preferably disodium salt.And different, as becoming disodium salt, pH preferred 7~9 according to institute's salifiable kind and salify degree for the pH of system during salify.Salifiable temperature generally is-10 ℃ of boiling points to solvent for use, and preferably room temperature is to the boiling point of solvent for use.
Each step solvent for use includes but not limited to that water, alcohol (as methyl alcohol, ethanol, Virahol etc.), ether (as tetrahydrofuran (THF), glycol dimethyl ether etc.), ketone (as acetone etc.), acid amides are (as N in the scheme 2, dinethylformamide, N-Methyl pyrrolidone etc.), the appropriate mixture of sulfone (methyl-sulphoxide, tetramethylene sulfone etc.), pyridine and two or more above-mentioned solvents, preferably water, methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), acetone and their appropriate mixture.Above-mentioned each step also can carry out under protection of inert gas.
The method of application scheme 2 can prepare a series of compounds that comprise pemetrexed (formula II compound) and disodium salt thereof.
General formula (VIII) compound can make by the method for scheme 3.
Scheme 3
R wherein
3Be carboxyl-protecting group, preferable methyl, ethyl; The Z definition as above.General formula (X) compound can make by disclosed method among the WO0011004.
This scheme is carried out in two steps, (a) formula (X) compound and alkali reaction decarboxylize protecting group is formed corresponding salt; (b) acid is joined in the reaction alkali lye of (a), regulation system is to acid.
The preferred sodium hydroxide of used alkali, oxygen potassium oxide in the step (a).The consumption of alkali generally is 3~15 with respect to the molar equivalent of formula (X) compound, preferably 4~7.The solvent preferably water.Temperature of reaction generally is 0~50 ℃, preferably room temperature.
In the step (b), the preferred hydrochloric acid of used acid, acetate, sulfuric acid.In this acid adjustment process, in order to reduce the generation of side reactions such as nitronic acid salt hydrolysis, should carry out at a lower temperature, generally be-20~30 ℃, preferably-10~10 ℃.The final pH of system generally transfers to 0~7, preferred 2~5.
The suitable time of scheme 1~3 reaction is that those of ordinary skills know, can be determined by the process of conventional chromatography and spectroscopic techniques (as TLC and HPLC) monitoring reaction.
In sum; scheme 1~3 is preparation N-(pyrrolo-[2; 3-d] pyrimidine-5-yl) the acyl glutamic acid derivative provides a kind of novel method and a new intermediate; one of most important in this derivative is exactly pemetrexed and disodium salt thereof; according to the inventive method, the technology that typically prepares pemetrexed is:
The main difference of technology of the present invention and WO0011004 is: technology of the present invention is from compound IV, elder generation's basic hydrolysis deprotection base, get compounds X I (this step yield is generally greater than 95%) after the acidifying, obtain compounds X II (this step yield is generally greater than 80%) with the glutamate diethyl ester condensation again, and then slough the glutaminic acid residue protecting group through basic hydrolysis and obtain sodium salt compounds X III, after reduction, Cheng Huan obtain product compound II pemetrexed (last two step yields are generally greater than 45%); And WO0011004 is from compound IV, earlier obtain compound V (yield 57%) through scission reaction, the Cheng Huan of interior husband (Nef) aci-nitro group alkane, get compound VI (yield 62%) with the glutamate diethyl ester condensation again, last hydrolysis obtains product compound II pemetrexed (yield 73%).The total recovery for preparing pemetrexed from compound IV by technology of the present invention is about about 35%, and WO0011004's is 25.8%.Technology of the present invention is compared with WO0011004 technology, significantly improvements are: technology of the present invention is compared under the prerequisite that does not have to increase with WO0011004 in number of reaction stages and main raw material kind, improve reaction yield (having improved about 10 percentage points), simplified technological operation.
Technology of the present invention improves reaction yield, has mainly improved the yield with the L-glutamic acid condensation.This technology is better from compounds X I purity height (generally can reach more than 95%) and solubility property that compound IV obtains, with the glutamate diethyl ester condensation time, because of the impurity of its introducing few, few side effects to the condensing agent generation, and the solubleness in reaction solvent is bigger, so condensation yield higher (generally greater than 95%).The compound V that obtains from compound IV among the WO0011004 generally is difficult to purifying in actually operating, purity is generally about 80%, and solvability is relatively poor, thus with the glutamate diethyl ester condensation time yield lower (generally about 60%).
Among the WO0011004 with this step of L-glutamic acid condensation in, because of the relatively poor N that selects for use of the solvability of compound V in other aprotic solvent commonly used, dinethylformamide is made solvent, because N, the solvability of dinethylformamide is stronger, make by product such as condensing agent resistates also be dissolved in wherein, cause reaction product separation difficulty (needing post to separate).And in this step of the present invention, compounds X I solubility property is better, except at N, has in the dinethylformamide preferably outside the solvability, in other aprotic solvent (as tetrahydrofuran (THF) etc.) solvability is preferably arranged also; And in these solvents, the solubleness of above-mentioned by product is less.Therefore, in this technology, can simplify operation like this, optimize technology by filtering separated product.Become pyrrolopyrimidine in this step in cyclization in addition, WO0011004 is undertaken by the scission reaction mechanism of interior husband (Nef) aci-nitro group alkane, and side reaction is more, and product is difficult to purifying; Cyclization of the present invention realizes through reduction, is different from the method among the WO0011004 on reaction mechanism, cyclization method reaction conditions gentleness of the present invention, and product is easy to purifying, has further optimized technology.
Embodiment
The invention will be further described below in conjunction with embodiment, can make this area professional and technical personnel more fully understand the present invention, but the scope that does not limit the present invention in any way.Term that uses among the embodiment and abbreviation have common implication.As " ℃ ", " g ", " mmol ", " ml ", " L ", " IR ", "
1H NMR ", "
13C NMR ", " HPLC " be meant respectively degree centigrade, gram, mmole, milliliter, liter, infrared absorption spectrum, proton magnetic resonance (PMR), carbon-13 magnetic resonance, high performance liquid chromatography.In nuclear magnetic resonance data, " s " representative is unimodal, and " d " representative is bimodal, and " t " represents triplet, and " q " represents quartet, and " m " represents multiplet, and " br " represents broad peak.
Embodiment 1
4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl] phenylformic acid (compounds X I)
In the 1L reaction flask, with sodium hydroxide 32.0g (800mmol) and water 400ml wiring solution-forming, after being chilled to room temperature, add 4-[3-(2, the 6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-and 4-nitro butyl] ethyl benzoate (compound IV, press WO0011004 method preparation) 50.0g (133mmol), at room temperature stirred 1 hour, cool off this reaction system to 0~5 ℃ with ice bath, drip the dilute hydrochloric acid solution of 2mol/L, along with the adding of hydrochloric acid, system is separated out yellow solid gradually, the control rate of addition, make the interior temperature of system remain on 0~5 ℃, when system pH is 3~4, stop to drip; Filter, wash filter cake with water, drying gets 4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl] phenylformic acid 44.6g, faint yellow solid, yield 96.5%.
IR(KBr):3505,3469,3402,3363,3222,3164,2924,1701,1678,1642,1614,1541,1485,1434,1379,1340,1277,1179,792,765,685cm
-1。
1H?NMR(400MHz,DMSO-d
6)δ(ppm):12.74(1H,br?s),9.80(1H,br?s),7.82(2H,d),7.23(2H,d),6.06(2H,s),5.95(2H,s),5.04~4.99(1H,t),4.79~4.75(1H,q),3.40(1H),2.69~2.61(m,1H),2.55~2.47(1H,m),2.18~2.09(1H,m),1.75~1.66(1H,m)。
13C?NMR(400MHz,DMSO-d
6)δ(ppm):167.81,163.16,162.47,153.97,147.90,129.72,128.77,128.52,84.46,77.90,35.36,33.31,31.63。
Embodiment 2
N-[4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl] benzoyl]-L-glutamate diethyl ester (compounds X II)
In 1L exsiccant reaction flask, add 4-[3-(2, the 6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-and 4-nitro butyl] phenylformic acid 40.0g (115mmol) and tetrahydrofuran (THF) 600ml, be chilled to 0~5 ℃ with ice bath, add 2-chloro-4,6-dimethoxy-1,3,5-triazine 26.2g (149mmol) and N-methylmorpholine 32.7g (323mmol) stir 40 fens kinds down at 0~5 ℃; Disposable then adding L-diethyl glutamate hydrochloride 35.7g (149mmol), deicing is bathed, and at room temperature reacts 2 hours; Filter; with tetrahydrofuran (THF) filter wash cake; merging filtrate and washing lotion; remove tetrahydrofuran (THF) under reduced pressure and get yellow solid; get N-[4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl at 50 ℃ of following drying under reduced pressure] benzoyl]-L-glutamate diethyl ester 50.5g; yellow solid, yield 82.5%.
IR(KBr):3457,3355,3217,2980,2929,1732,1625,1545,1498,1437,1377,1342,1210,1101,1020,852,792。
1H?NMR(400MHz,DMSO-d
6)δ(ppm):9.81(1H,s),8.64(1H,d),7.78(2H,d),7.23(2H,d),6.07(2H,s),5.97(2H,s),5.05~5.01(1H,t),4.80~4.76(1H,q),4.45~4.40(1H,m),4.14~4.01(4H,m),3.41(1H,br?s),2.68~2.61(1H,m),2.55~2.50(1H,m),2.48~2.17(2H,m),2.15~2.08(2H,m),2.06~1.97(1H,m),1.75~1.68(1H,m),1.20~1.04(6H,m)。
13C?NMR(400MHz,DMSO-d
6)δ(ppm):172.48,172.07,166.92,163.13,162.32,153.97,146.45,131.47,128.18,127.82,84.47,77.87,60.82,60.18,52.27,35.34,33.16,31.71,30.47,26.05,14.26。
Embodiment 3
N-[4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl] benzoyl]-L-glutamate diethyl ester tosilate
In the 250ml there-necked flask, add N-[4-[3-(2, the 6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-and 4-nitro butyl] benzoyl]-L-glutamate diethyl ester 10.0g (18.7mmol), tosic acid monohydrate 5.4g (28.2mmol) and dehydrated alcohol 100ml, reflux 20 minutes, stir cooling, have a large amount of white solids to separate out, to be cooledly to room temperature, continue to stir 1 hour; Filter and collect the solid of separating out,, get N-[4-[3-(2 at 50 ℃ of following drying under reduced pressure with dehydrated alcohol filter wash cake; the 6-diaminostilbene; 4-dihydro-4-oxo pyrimidine-5-yl)-and 4-nitro butyl] benzoyl]-L-glutamate diethyl ester tosilate 11.6g, white solid, yield 88.0%.
IR(KBr):3339,3242,2981,1725,1637,1587,1541,1439,1380,1353,1207,1102,1022,856,790cm
-1。
1H?NMR(400MHz,DMSO-d
6)δ(ppm):11.57(1H,br?s),8.63(1H,d),7.83(2H,s),7.79(2H,d),7.50(2H,d),7.23(2H,d),7.13(2H,d),7.03(2H,s),5.00~4.95(1H,t),4.85~4.80(1H,q),4.45~4.39(1H,m),4.14~4.02(4H,m),3.52(1H,br?s),2.66~2.57(2H,m),2.45~2.41(2H,t),2.13~1.96(3H,m),1.80~1.74(1H,m),1.20~1.14(6H,m)。
13C?NMR(400MHz,DMSO-d
6)δ(ppm):172.42,172.00,166.80,160.48,152.36,151.08,145.93,144.17,139.03,131.52,128.63,128.11,127.77,125.74,84.97,77.10,60.75,60.12,52.24,34.14,32.79,31.13,30.45,25.99,20.97,14.24。
Embodiment 4
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-L-L-glutamic acid (pemetrexed, Compound I I)
In the there-necked flask of 250ml; add sodium hydroxide 15.0g (375mmol) and water 60ml and be made into sodium hydroxide solution; after waiting to be chilled to room temperature; add N-[4-[3-(2; the 6-diaminostilbene; 4-dihydro-4-oxo pyrimidine-5-yl)-and 4-nitro butyl] benzoyl]-L-glutamate diethyl ester 20.0g (37.6mmol), at room temperature stir 1 hour (promptly getting the aqueous solution of compounds X III).With the cryosel bath this reaction solution is cooled to-5~0 ℃, adds 15% titanium trichloride aqueous solution 58.0g (56.5mol), stirred 30 minutes; Transfer about this system pH to 12 with hydroxide liquid, filter; Filtrate is regulated pH to 3~4 with dilute hydrochloric acid, has yellow solid to separate out, and filters and collects the solid of separating out, and with ethanol/water (1/1) mixed solution recrystallization, gets 7.5g at 50 ℃ of following drying under reduced pressure, white solid, yield 46.7%.HPLC purity: 98.3%.Hydrogen spectrum data are consistent with report among the WO0011004.
1H?NMR(400MHz,DMSO-d
6)δ:12.47(2H,br?s),10.60(1H,s),10.14(1H,s),8.51(1H,d),7.78(2H,d),7.28(2H,d),6.30(1H,s),5.99(2H,s),4.41~4.36(1H,m),2.97(2H,t),2.85(2H,t),2.35(2H,t),2.13~2.04(1H,m),1.99~1.91(1H,m)。
By above-mentioned preparation method, with N-[4-[3-(2,6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-4-nitro butyl] benzoyl]-L-glutamate diethyl ester tosilate is that raw material in like manner can make pemetrexed.
In addition, this embodiment also prepares pemetrexed according to the reaction principle among the WO0011004.
In the 500ml there-necked flask, add sodium hydroxide 9.0g (225mmol) and water 110ml and be made into sodium hydroxide solution, after waiting to be chilled to room temperature, add N-[4-[3-(2, the 6-diaminostilbene, 4-dihydro-4-oxo pyrimidine-5-yl)-and 4-nitro butyl] benzoyl]-L-glutamate diethyl ester 20.0g (37.6mmol), at room temperature stirred 2 hours; This alkali lye is added dropwise to by vitriol oil 36.8g (376mmol) and water 150ml forms and be chilled in 0~5 ℃ the sulphuric acid soln, the dropping time was controlled at 1.0~1.5 hours; After drip finishing, 0~5 ℃ of reaction 1 hour down, transfer system pH to 7 with caustic lye of soda then again, at room temperature reacted again 1 hour; Transfer system pH to 3~4 with acetate; Filter, get green filter cake, filter cake with ethanol/water (1/1) mixed solution recrystallization, is separated out less yellow-green colour solids, HPLC purity: 78.5%.
Embodiment 5
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-L-disodium glutamate salt (pemetrexed disodium)
In the 500ml there-necked flask, add N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-yl) ethyl] benzoyl]-L-L-glutamic acid 7.0g (0.0164mol), water 40ml and 1mol/L sodium hydroxide solution 25ml, stirring and dissolving, regulate this system pH to 7.5~8.5 with hydrochloric acid soln or the 1mol/L sodium hydroxide solution of 2mol/L again, heat this reaction solution to 50 ℃, add ethanol 350ml, stir cooling, system is separated out a large amount of off-white color solids in this process, after system is reduced to room temperature; Solid collected by filtration, absolute ethanol washing gets pemetrexed disodium 7.3g at 50 ℃ of following drying under reduced pressure, the off-white color solid.
1H?NMR(400MHz,DMSO-d
6)δ(ppm):7.75(2H,d),7.34(2H,d),6.49(1H,s),4.31~4.28(1H,q),3.04~2.98(4H,m),2.29~2.13(2H,m),2.12~2.07(1H,m),2.02~1.93(1H,m)。
13C?NMR(400MHz,DMSO-d
6)δ(ppm):182.86,179.65,170.33,162.40,153.69,152.26,148.12,132.58,130.23,128.68,119.79,116.86,100.50,57.33,37.21,35.95,30.37,28.60。
The front has been described the present invention in detail, comprises its embodiment preferred.But, should be understood that and consider content disclosed by the invention that those skilled in the art can change the present invention and/or improve in the spiritual scope of following claims.