CN102127063A - New synthesis technology of anti-cancer drug Raltitrexed - Google Patents
New synthesis technology of anti-cancer drug Raltitrexed Download PDFInfo
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Abstract
The invention relates to a new synthesis technology of anti-cancer drug Raltitrexed. The technology comprises the following steps: 1) using L-glutamic acid as raw material to perform esterification with alcohol under the action of halogenating agent and obtain L-glutamic acid diester hydrochloride; 2) using 2-amino-5-methyl-benzoic acid as raw material to prepare 6-bromomethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline through cyclization, amination and bromination; 3) using 2-thienyl-propanedioic acid as raw material to prepare N-[5-[N-(tert-butoxycarbonyl)-N-methylamino]-2-thenoyl]-L-glutamic acid diethyl ester through nitrification, esterification, reduction, amino protection, N-methylation and device-esterification; 4) using L-glutamic acid diester hydrochloride and N-[5-[N-(tert-butoxycarbonyl)-N-methylamino]-2-thenoyl]-L-glutamic acid diethyl ester to prepare N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester through dehydrant condensation and deamination protection; and 5) using N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester and 6-bromomethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline to perform condensation under the catalysis of alkali, recycling preparative chromatography, purifying, and performing de-esterification to obtain Raltitrexed.
Description
Technical field
The present invention relates to the synthetic field of chemical synthetic drug, particularly a kind of new synthetic process of cancer therapy drug Raltitrexed.
Background technology
Colorectal carcinoma (CRC) is the second common tumour that is only second to lung cancer in the world, is the one of the main reasons that causes death.Over nearly 25 years, colorectal cancer has also become one of two kinds of the fastest malignant tumours of China's rate of increase, and it has increased by 100%.Along with the raising of people's living standard, the change of food habits, the sickness rate of colorectal cancer is with annual 4.2% speed increase, early 1990s just rises to 23.4/10 ten thousand people, now head and shoulders above this ratio.In flourishing Shanghai, existing colorectal cancer incidence rate is about 40,/10 ten thousand, near the western developed country level, rises to the 2nd by the 6th in the tumor invasion rank.The patient that colorectal carcinoma is suffered from by China has reached more than 100 ten thousand people, and has 50% colorectal cancer can develop into late period or metastatic cancer approximately, and mortality ratio is very high.
Raltitrexed (raltitrexed) is the thymus gland synthetase inhibitors, is a kind of stronger colorectal cancer tumor cell line activity inhibitor, and antitumous effect is definite, in states such as America and Europes as a line medication of carcinoma of the colon and rectum in late period.Compare with present same kind anti-cancer drugs (5 FU 5 fluorouracil, Rinotecan (Irinotecan) and oxaliplatin (Oxaliplatin)) on the market, Raltitrexed has remarkable advantages:
One, toxic side effect is little, and the drug combination scope is wide, and untoward reaction is light, and the widest 5 FU 5 fluorouracil of alternative domestic present use is the active drug of treatment colorectal cancer in late period.
Two, administration is convenient rapidly, is easily accepted by the patient.
Three, to compare specification less with other drug, and cost is lower.
Four, antitumor spectrum is wide, as tumor of head and neck, prostate cancer, lung cancer, leukemia etc. certain curative effect is arranged also.
As the first-line treatment medicine of colorectal cancer in late period, Raltitrexed has very big demand in China, and the raising of Raltitrexed medicine synthesis technique will be created good social benefit and economic benefit.The at present domestic also authentication code of this medicine is not optimized synthetic route, synthesis of high purity, and being suitable for the medicinal anticarcinogen Raltitrexed of medical science becomes cancer therapy drug synthetic one general objective.
Raltitrexed mainly is made up of quinazolinone, thiophene and L-L-glutamic acid three parts, document (Quinazoline Antifolate Thymidylate Synthase Inhibitors:Heterocyclic BenzoylRing Modifications, J.Med.Chem.1991,34,1594-1605) and United States Patent (USP) (US4992550,1991) provided two kinds of main methods in Raltitrexed synthetic in, a kind of method is to be starting raw material with the 2-thiophenic acid, and synthetic route is as follows:
Another kind method is to be starting raw material with 5-nitro-2-thiophenic acid, and synthetic route is as follows:
Yet preceding a kind of method needs with reagent such as butyllithium, severe reaction conditions, long reaction time, production cost height; A kind of method reaction conditions gentleness in back, easy to operate, but in N-methylation reaction process, very difficult control obtains single methylate, and monomethylation product separation difficulty, cause productive rate very low.
Summary of the invention
The object of the present invention is to provide a kind of new synthetic process of cancer therapy drug Raltitrexed, employing is converged synthesis method and is made Raltitrexed, and its raw material is easy to get, and cost is low, mild condition, and reaction is easy to control, good reproducibility, purity is high and be applicable to that a large amount of preparations are synthetic.
For achieving the above object, the invention provides a kind of new synthetic process of cancer therapy drug Raltitrexed, comprise that step is as follows:
Step 1, be that raw material makes L-glutamic acid diester hydrochloride with alcohol through esterification under the halogenating agent effect with L-L-glutamic acid;
Step 2, be that raw material makes 6-brooethyl-3 through cyclisation, amination, bromination with 2-amino-5-methyl-phenylformic acid, 4-dihydro-2-methyl-4-oxo-6-quinazoline;
Step 3, with the 2-thiophenic acid be raw material through nitrated, esterification, reduction, amido protection, N-methylate, de-esterifying makes N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester;
Step 4, with L-glutamic acid diester hydrochloride and N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester through the dewatering agent dehydrating condensation, take off amido protection and make N-[5-(N-methylamino)-2-thenoyl]-the L-glutamic acid diester;
Step 5, with N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester and 6-brooethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline is through the base catalysis condensation, the cycles prepare chromatogram purification is after de-esterifying promptly makes Raltitrexed.
Halogenating agent in the described step 1 is acyl chlorides or thionyl chloride.
Described step 2 comprises that step 2.1,2-amino-5-methyl-phenylformic acid and diacetyl oxide react under refluxing, and cyclisation makes 3,4-dihydro-2,6-dimethyl-4-oxo-6-Fenoxazoline; Step 2.2, with 3,4-dihydro-2, the reaction of 6-dimethyl-4-oxo-6-Fenoxazoline and inorganic amine or organic amine, amination makes 3,4-dihydro-2,6-dimethyl-4-oxo-6-quinazoline; Step 2.3, with 3,4-dihydro-2,6-dimethyl-4-oxo-6-quinazoline and N-bromosuccinimide (NBS) are under infrared lamp illumination, cause by light trigger, in dry organic solvent, bromo-reaction makes 6-brooethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline.
Wherein, adopt 120～130 ℃ of back flow reaction in the described step 2.1; Inorganic amine is an ammoniacal liquor or a hydrazine hydrate in the step 2.2, and organic amine is an aniline; N-bromosuccinimide and 3 in the step 2.3,4-dihydro-2, the mol ratio of 6-dimethyl-4-oxo-6-quinazoline is 1.1-4.2: 1, the power of infrared lamp is 150-400W, light trigger is for there being Diisopropyl azodicarboxylate (ABIN), 2,2'-Azobis(2,4-dimethylvaleronitrile) (ABVN), benzoyl peroxide (BPO), peroxidized t-butyl perbenzoate (BPB), dicumyl peroxide (DCP), ditertiary butyl peroxide (DTBP), isopropyl benzene hydroperoxide (CHP), tertbutyl peroxide (TBH), peroxy dicarbonate diisobutyl ester (IBP), di-cyclohexylperoxy dicarbonate (DCPD) or peroxy dicarbonate two (to tertiary butyl cyclohexyl) (TBCP), dry organic solvent is exsiccant acetonitrile or exsiccant chloroform.
Described step 3 comprise step 3.1, with the 2-thiophenic acid in diacetyl oxide by the nitrated 5-of the making nitro of nitrosonitric acid-2-thiophenic acid; Step 3.2,5-nitro-2-thiophenic acid is made 5-nitro-2-ester thiohenic acid with alcohol through esterification under the halogenating agent effect; Step 3.3,5-nitro-2-ester thiohenic acid make 5-amido-2-ester thiohenic acid through the reductive agent reduction; Step 3.4,5-amido-2-ester thiohenic acid and amido protective reaction reagent react in reaction soln and make 5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate; Step 3.5,5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate make 5-[N-(tertbutyloxycarbonyl)-N-methylamino with the reaction of N-methylating reagent in the presence of phase transfer reagent, catalyzer, alkali] the thiophene-2-carboxylic acid methyl esters; Step 3.6,5-[N-(tertbutyloxycarbonyl)-N-methylamino] the ester hydrolysis reaction in the mixed solution of the water of alkali or organic solvent of thiophene-2-carboxylic acid methyl esters makes N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester.
Wherein, the temperature that drips nitrosonitric acid in the described step 3.1 is-10～0 ℃, the temperature of stirring at room is-10～0 ℃, the purifying water consumption of 5-nitro-2-thiophenic acid is 10-30mL/g, Heating temperature is 60～85 ℃, BaOH regulates pH value between 9-11, and the temperature that precipitation (mainly being 4-nitro-2-thiophenic acid) is separated out in cooling is-10～10 ℃, and hydrochloric acid is regulated pH value between 0-1; Halogenating agent described in the step 3.2 is acyl chlorides or thionyl chloride; Reductive agent is Fe/CH in the step 3.3
3COOH, Na
2S
2O
4Or Na
2S; The amido protective reaction reagent that uses in the step 3.4 is tert-Butyl dicarbonate, and reaction solvent is tetrahydrofuran (THF) (THF), and temperature of reaction is 56～66 ℃; The phase transfer reagent that uses in the step 3.5 is Tetrabutyl amonium bromide, catalyzer is an Anhydrous potassium carbonate, alkali is sodium hydroxide, and the N-methylating reagent is methyl iodide or methyl-sulfate, and the mol ratio of N-methylating reagent and 5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate is 1-2: 1; Alkali described in the step 3.6 is sodium hydroxide or potassium hydroxide, mixed solution is water/ethanol, and it is 1 that water/alcoholic acid is optimized volume ratio: 0.5-1: 1, or be water/ethanol/acetone, the optimization volume ratio of water/ethanol/acetone is 1: 1: 0.1-1: 1: 0.5, the concentration of alkali was 0.5-2N.
Above-mentioned steps 1-3 can carry out simultaneously.
Described step 4 comprises step 4.1, with N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-L-glutamate diethyl ester and L-glutamic acid diester hydrochloride under dewatering agent and catalyst action in solvent condensation make N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester; Step 4.2, with N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-reaction makes N-[5-(N-methylamino)-2-thenoyl to the L-glutamate diethyl ester under the effect of amido protection reagent taking off]-the L-glutamic acid diester.
Wherein, dewatering agent is N in the described step 4.1, and N '-dicyclohexyl carbon imide (DCC), catalyzer are I-hydroxybenzotriazole (HOBt), and solvent is exsiccant tetrahydrofuran (THF) and methylene dichloride (THF/CH
2Cl
2) mixed solvent, wherein the optimization volume ratio of tetrahydrofuran (THF) and methylene dichloride is 0.5: 1-5: 1; Taking off amido protection reagent in the step 4.2 is HBr and CH
3COOH, CF
3COOH or H
2/ Pd.
Described step 5 comprises step 5.1, with N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester and 6-brooethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline under the alkali effect in organic solvent condensation make N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester; Step 5.2, with N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester makes highly purified N-[5-[N-[(3 through the cycles prepare chromatogram purification, 4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester; Step 5.3, with N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the ester hydrolysis reaction in the mixed solution of the water of alkali or organic solvent of L-glutamate diethyl ester, promptly make highly purified Raltitrexed.
Alkali is 1 in the described step 5.1,2-lutidine or pyridine, and the organic solvent that uses is dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMAC) or dimethyl sulfoxide (DMSO) (DMSO), temperature of reaction is 50～120 ℃; The cyclical chromatography purifying adopts chloroform as moving phase in the described step 5.2; Alkali described in the described step 5.3 is sodium hydroxide or potassium hydroxide, mixed solution is water/ethanol, and it is 1 that water/ethanol is optimized volume ratio: 0.5-1: 1, or be water/ethanol/acetone, the optimization volume ratio of water/ethanol/acetone is 1: 1: 0.1-1: 1: 0.5, the concentration of alkali was 0.5-2N.
Beneficial effect of the present invention: 1, the present invention's employing is converged synthesis method and is made Raltitrexed, and employed raw material is easy to get, and cost is low, mild condition, and reaction is easy to control, and good reproducibility is applicable to a large amount of preparations; 2, the present invention has optimized the synthetic route of Raltitrexed, has avoided the reaction conditions of harshness in the prior art, has guaranteed single N-methylate; 6-brooethyl-3, the synthetic middle acetonitrile of using of 4-dihydro-2-methyl-4-oxo-6-quinazoline is as reaction solvent, and raw material is not separated out in reaction process, helps reacting completely, and has improved productive rate; Synthesizing of 5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate,, improved productive rate greatly by improving temperature of reaction and lengthening reaction times; 5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the ester hydrolysis reaction of the synthetic and Raltitrexed of 2-thiophenic acid, add acetone solvent in the reaction solvent, raw material is fully dissolved, can shorten the reaction times, improve productive rate; N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-introduce I-hydroxybenzotriazole (HOBt) as catalyzer in L-glutamate diethyl ester synthetic, improved the productive rate of condenses;
3, the present invention utilizes cycles prepare chromatogram purification intermediate product N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester, this intermediate product makes the highly purified of white through de-esterifying and can be used for clinical medical cancer therapy drug Raltitrexed.
Embodiment
The new synthetic process of cancer therapy drug Raltitrexed of the present invention comprises that step is as follows:
Step 1, be that raw material makes L-glutamic acid diester hydrochloride with alcohol through esterification under the halogenating agent effect with L-L-glutamic acid; Described halogenating agent is acyl chlorides or thionyl chloride.Its synthetic route is as follows:
R wherein
1Be C
1-6Alkyl or benzyl are worked as R
1Be C
1-4During alkyl, esterification drips halogenating agent under cryosel is bathed, and adds back room temperature activation 3-12h, post-heating back flow reaction 3-12h.
Step 2, be that raw material makes 6-brooethyl-3 through cyclisation, amination, bromination with 2-amino-5-methyl-phenylformic acid, 4-dihydro-2-methyl-4-oxo-6-quinazoline.This step comprises that step 2.1,2-amino-5-methyl-phenylformic acid and diacetyl oxide react under refluxing, and cyclisation makes 3,4-dihydro-2, and 6-dimethyl-4-oxo-6-Fenoxazoline wherein adopts 120～130 ℃ of back flow reaction; Step 2.2, with 3,4-dihydro-2, the reaction of 6-dimethyl-4-oxo-6-Fenoxazoline and inorganic amine or organic amine, amination makes 3,4-dihydro-2,6-dimethyl-4-oxo-6-quinazoline, described inorganic amine are an ammoniacal liquor or a hydrazine hydrate, organic amine is an aniline; Step 2.3, with 3,4-dihydro-2,6-dimethyl-4-oxo-6-quinazoline and N-bromosuccinimide (NBS) are under infrared lamp illumination, cause by light trigger, in dry organic solvent, bromo-reaction makes 6-brooethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline, described N-bromosuccinimide and 3,4-dihydro-2, the ratio (mol ratio) of 6-dimethyl-4-oxo-6-quinazoline is 1.1-4.2: 1, the power of infrared lamp is 150-400W, light trigger is for there being Diisopropyl azodicarboxylate (ABIN), 2,2'-Azobis(2,4-dimethylvaleronitrile) (ABVN), benzoyl peroxide (BPO), peroxidized t-butyl perbenzoate (BPB), dicumyl peroxide (DCP), ditertiary butyl peroxide (DTBP), isopropyl benzene hydroperoxide (CHP), tertbutyl peroxide (TBH), peroxy dicarbonate diisobutyl ester (IBP), di-cyclohexylperoxy dicarbonate (DCPD) or peroxy dicarbonate two (to tertiary butyl cyclohexyl) (TBCP), dry organic solvent is exsiccant acetonitrile or exsiccant chloroform.Wherein adopt acetonitrile as reaction solvent, raw material is not separated out in reaction process, helps reacting completely, and has improved productive rate.
The synthetic route of step 2 is as follows:
Step 3, with the 2-thiophenic acid be raw material through nitrated, esterification, reduction, amido protection, N-methylate, de-esterifying makes N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester.This step comprise step 3.1, with the 2-thiophenic acid in diacetyl oxide by the nitrated 5-of the making nitro of nitrosonitric acid-2-thiophenic acid, the temperature of described dropping nitrosonitric acid is-10～0 ℃, the temperature of stirring at room is-10～0 ℃, the purifying water consumption of 5-nitro-2-thiophenic acid is 10-30mL/g, Heating temperature is 60～85 ℃, regulate pH value between 9-11 with BaOH, the temperature that precipitation (mainly being 4-nitro-2-thiophenic acid) is separated out in cooling is-10～10 ℃, regulates pH value between 0-1 with hydrochloric acid; Step 3.2,5-nitro-2-thiophenic acid is made 5-nitro-2-ester thiohenic acid with alcohol through esterification under the halogenating agent effect, described halogenating agent is acyl chlorides or thionyl chloride; Step 3.3,5-nitro-2-ester thiohenic acid make 5-amido-2-ester thiohenic acid through the reductive agent reduction, and reductive agent is Fe/CH
3COOH, Na
2S
2O
4Or Na
2S; Step 3.4,5-amido-2-ester thiohenic acid and amido protective reaction reagent react in reaction soln and make 5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate, the amido protective reaction reagent that uses is tert-Butyl dicarbonate, reaction solvent is tetrahydrofuran (THF) (THF), and temperature of reaction is 56～66 ℃; Synthesizing of this 5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate,, can improve productive rate greatly by improving temperature of reaction and lengthening reaction times; Step 3.5,5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate make 5-[N-(tertbutyloxycarbonyl)-N-methylamino with the reaction of N-methylating reagent in the presence of phase transfer reagent, catalyzer, alkali] the thiophene-2-carboxylic acid methyl esters, wherein, the phase transfer reagent that uses is Tetrabutyl amonium bromide, catalyzer is an Anhydrous potassium carbonate, alkali is sodium hydroxide, the N-methylating reagent is methyl iodide or methyl-sulfate, and the ratio (mol ratio) of N-methylating reagent and 5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate is 1-2: 1; Step 3.6,5-[N-(tertbutyloxycarbonyl)-N-methylamino] the ester hydrolysis reaction in the mixed solution of the water of alkali or organic solvent of thiophene-2-carboxylic acid methyl esters makes N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester, described alkali is sodium hydroxide or potassium hydroxide, mixed solution is water/ethanol, water/alcoholic acid optimized proportion (volume ratio) is 1: 0.5-1: 1, or be water/ethanol/acetone, the optimized proportion of water/ethanol/acetone (volume ratio) is 1: 1: 0.1-1: 1: 0.5, the concentration of alkali was 0.5-2N; The wherein adding of acetone solvent is fully dissolved raw material, can shorten the reaction times, improves productive rate.
The synthetic route of step 3 is as follows:
R wherein
2Be C
1-6Alkyl or benzyl are worked as R
2Be C
1-4During alkyl, esterification drips halogenating agent under cryosel is bathed, and adds back room temperature activation 0-12h, post-heating back flow reaction 3-12h; R
3Expression amido blocking group is tertbutyloxycarbonyl, carbobenzoxy-(Cbz), 2-xenyl-2-third oxygen carbonyl, p-toluenesulfonyl or trityl.
Described step 1-3 can carry out the synthetic mesophase product simultaneously, at this step by step with better explanation.
Step 4, with L-glutamic acid diester hydrochloride and N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester through the dewatering agent dehydrating condensation, take off amido protection and make N-[5-(N-methylamino)-2-thenoyl]-the L-glutamic acid diester.This step comprises step 4.1, with N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-L-glutamate diethyl ester and L-glutamic acid diester hydrochloride under dewatering agent and catalyst action in solvent condensation make N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester, dewatering agent is N, N '-dicyclohexyl carbon imide (DCC), catalyzer is I-hydroxybenzotriazole (HOBt), the introducing of this catalyzer I-hydroxybenzotriazole HOBt, can improve the productive rate of condenses, solvent then is exsiccant tetrahydrofuran (THF) and methylene dichloride (THF/CH
2Cl
2) mixed solvent, wherein the optimized proportion of tetrahydrofuran (THF) and methylene dichloride (volume ratio) is 0.5: 1-5: 1; Step 4.2, with N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-reaction makes N-[5-(N-methylamino)-2-thenoyl to the L-glutamate diethyl ester under the effect of amido protection reagent taking off]-the L-glutamic acid diester, taking off amido protection reagent is HBr and CH
3COOH, CF
3COOH or H
2/ Pd.
Step 5, with N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester and 6-brooethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline is through the base catalysis condensation, the cycles prepare chromatogram purification is after de-esterifying promptly makes Raltitrexed.This step comprises step 5.1, with N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester and 6-brooethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline under the alkali effect in organic solvent condensation make N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester, alkali is 1,2-lutidine or pyridine, the organic solvent that uses is dimethyl formamide (DMF), N,N-DIMETHYLACETAMIDE (DMAC) or dimethyl sulfoxide (DMSO) (DMSO), temperature of reaction is 50～120 ℃; Step 5.2, with N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester makes highly purified N-[5-[N-[(3 through the cycles prepare chromatogram purification, 4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester, the cyclical chromatography purifying adopts chloroform as moving phase; Step 5.3, with N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the ester hydrolysis reaction in the mixed solution of the water of alkali or organic solvent of L-glutamate diethyl ester, promptly make highly purified Raltitrexed, described alkali is sodium hydroxide or potassium hydroxide, mixed solution is water/ethanol, water/alcoholic acid optimized proportion (volume ratio) is 1: 0.5-1: 1, or be water/ethanol/acetone, the optimized proportion of water/ethanol/acetone (volume ratio) is 1: 1: 0.1-1: 1: 0.5, the concentration of alkali was 0.5-2N; The wherein adding of acetone solvent is fully dissolved raw material, can shorten the reaction times, improves productive rate.
The synthetic route of step 4-5 is as follows:
R wherein
1Be C
1-6Alkyl or benzyl; R
3Expression amido blocking group is tertbutyloxycarbonyl, carbobenzoxy-(Cbz), 2-xenyl-2-third oxygen carbonyl, p-toluenesulfonyl or trityl.
The present invention is further illustrated below by embodiment, but the present invention is confined to scope of embodiments.
Embodiment:
1, the L-diethyl glutamate hydrochloride is synthetic
Add 60mL and newly steam dehydrated alcohol in the 100mL three-necked bottle that is connected with spherical condensation tube (connecing drying tube and tail gas receiving trap) and constant pressure funnel, cryosel newly steams SOCl with 26mL under bathing-10～-15 ℃
2(366mmol) drip in the system with 0.5h, be warming up to room temperature then, stir 3h by constant pressure funnel.Add 8.8g (56.2mmol) L-L-glutamic acid to system, one night of room temperature reaction.Be warming up to 65 ℃, about back flow reaction 1.5h, insoluble white suspension liquid becomes the light brown transparent liquid, the TLC monitoring reaction, and the 7h afterreaction is complete.Stopped reaction quenches, and steams and removes excessive SOCl
2And ethanol, ice-water bath solidifies, and 44 ℃ of baking oven inner drying 9h get white crystal L-diethyl glutamate hydrochloride 13.2g, yield 98.3%.Synthetic route is as follows:
1H-NMR(D
2O)：δppm：1.30(m，6H，CH
2CH
3)，2.27(m，2H，CHCH
2CH
2)，2.65(t，2H，COCH
2CH
2)，4.20(q，3H，OCH
2CH
3，CH)，4.32(q，2H，CH
3CH
2O)。
2, be that raw material makes 6-brooethyl-3 through cyclisation, amination, bromination with 2-amino-5-methyl-phenylformic acid, 4-dihydro-2-methyl-4-oxo-6-quinazoline
2.1,3,4-dihydro-2,6-dimethyl-4-oxo-6-Fenoxazoline synthetic
2.0g (13.3mmol) 2-amino-5-methyl-phenylformic acid and 10mL diacetyl oxide are joined in the three-necked bottle system 120-130 ℃ of stirring reaction 2h.Be spin-dried for solution, as far as possible after the drying, with the quick flush away diacetyl oxide of less water, thorough drying.Get solid product 2.1g, yield 89.1%.
1H-NMR(CDCl
3)：δppm：2.46(s，3H，ArCH
3)，2.47(s，3H，ACH
3)，7.43，7.46(d，1H，J＝8Hz，quinazolinone?6-H)，7.59，7.62(dd，1H，J＝2Hz?and?8Hz，quinazolinone?7-H)，7.98(s，1H，quinazolinone?9-H)。
2.2,3,4-dihydro-2,6-dimethyl-4-oxo-6-quinazoline synthetic
With 2.1g (11.8mmol) 3,4-dihydro-2,6-dimethyl-4-oxo-6-Fenoxazoline is dissolved in 35mL methyl alcohol, add the amination of 1.5 times of amount ammoniacal liquor, raw material disappears behind the 32h, is spin-dried for liquid, collect foaming shape solid, use the Glacial acetic acid recrystallization behind the solid drying, obtain white needle-like crystals product 1.5g, yield 75.1%.
1H-NMR(CD
3OD)：δppm：2.37(s，3H，ArCH
3)，2.40(s，3H，ACH
3)，7.44，7.45(d，1H，J＝8Hz，quinazolinone?6-H)，7.56，7.58(dd，1H，J＝2Hz?and?8Hz，quinazolinone?7-H)，7.90(s，1H，quinazolinone?9-H).
1H-NMR(DMSO-d
6)：δppm：2.47(s，3H，ArCH
3)，2.60(s，3H，ACH
3)，7.71，7.73(d，1H，J＝8Hz，quinazolinone?6-H)，7.78，7.80(dd，1H，J＝2Hz?and?8Hz，quinazolinone?7-H)，7.97(s，1H，quinazolinone?9-H).
2.3,6-brooethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline synthetic
With 1.5g (8.8mmol) 3,4-dihydro-2,6-dimethyl-4-oxo-6-quinazoline, 0.7g (3.8mmol) NBS and 0.02g (0.08mmol) benzoyl peroxide are dissolved in the dry CH of 50mL
3Among the CN.Under the irradiation of 250W incandescent light, electric mantle slowly is heated to 60-62 ℃, behind the stirring reaction 5h, is spin-dried for solvent, and ethyl alcohol recrystallization obtains white solid product 1.4g, yield 62.8%.
1H-NMR(DMSO-d
6)：δppm：2.35(s，3H，ACH
3)，4.89(s，2H，ArCH
2Br)，7.55，7.57(d，1H，J＝8Hz，quinazolinone?6-H)，7.83，7.86(dd，1H，J＝2Hz?and?8Hz，quinazolinone?7-H)，8.16(s，1H，quinazolinone?9-H)。
Above-mentioned is that raw material makes 6-brooethyl-3 through cyclisation, amination, bromination with 2-amino-5-methyl-phenylformic acid, and the synthetic route of 4-dihydro-2-methyl-4-oxo-6-quinazoline is as follows:
3, with the 2-thiophenic acid be raw material through nitrated, esterification, reduction, amido protection, N-methylate, de-esterifying makes N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester
3.1,5-nitro-2-thiophenic acid synthetic
Thermometer is being housed, in the 100mL there-necked flask of agitator and constant pressure funnel, add 25.6g 2-thiophenic acid (200mmol), the 30mL diacetyl oxide, ice bath is cooled to below-10 ℃, slowly drip 48mL mixing liquid (18mL nitrosonitric acid and 30mL diacetyl oxide) under the agitation condition, controlled temperature must not be above 0 ℃, about 3h adds, continuous dropping along with nitrosonitric acid, there is yellow powder shape solid to separate out, continue to stir 10h about-5～0 ℃, discharging gets brown oil in the frozen water, extracted with diethyl ether, and organic phase is washed 3 times with distillation, saturated sodium-chloride water solution washes twice, obtains yellow powder shape solid 5-nitro-2-thiophenic acid and 4-nitro-2-thiophenic acid mixture 32.6g after the drying.
Under agitation condition the 32.6g mixture of above-mentioned gained and the compound of 550mL water are heated to 80 ℃, the solid dissolving slowly adds hydrated barta and regulates pH to 10, solution becomes brownish black by yellow, and has flocks to produce, cooling, there is precipitation to separate out, filters out precipitation, get red-brown filtrate.Stir down and slowly drip concentrated hydrochloric acid, transfer pH to 1, cooling has yellow needle-like crystal to separate out.Suction filtration, drying get yellow needle-like crystal 5-nitro-2-thiophenic acid 6.6g, yield 19.3%.
1H-NMR(CDCl
3)：δppm：7.82(d，1H，J＝4Hz，thiophene?4-H)，7.93(d，1H，J＝4Hz，thiophene?3-H)，11.12(s，1H，COOH)。
3.2,5-nitrothiophene-2-methyl-formiate synthetic
The ice bath cooling joins 2.9g (167mmol) 5-nitro-2-thiophenic acid in the 47mL methyl alcohol down, slowly drips 10mL (360mmol) sulfur oxychloride, back flow reaction 8h, and solvent evaporated gets 5-nitrothiophene-2-methyl-formiate 2.9g.Yield 92.0%.
1H-NMR(CDCl3)：δppm：3.98(s，3H，COOCH3)，7.71(d，1H，J＝4Hz，thiophene?4-H)，7.88(d，1H，J＝4Hz，thiophene?3-H).
3.3,5-aminothiophene-2-methyl-formiate synthetic
15.3g (274.4mmol) iron powder is added in the 120mL glacial acetic acid, and vigorous stirring adds 3.6g (19.1mmol) 5-nitrothiophene-2-methyl-formiate, in 50 ℃ of stirring reaction 5h in batches.Remove solvent under reduced pressure, add the 350mL methylene dichloride, leach the residue iron powder, 600mL saturated sodium bicarbonate extraction three times, washing twice, saturated sodium-chloride once, anhydrous sodium sulfate drying, distill crude product.Crude product is crossed the flash post and is got 5-aminothiophene-2-methyl-formiate 2.2g productive rate: 71.8%.
1H-NMR(CDCl3)：δppm：3.75(s，3H，COOCH3)，4.28(s，2H，NH2)，6.21(d，1H，J＝4Hz，thiophene?4-H)，7.49(d，1H，J＝4Hz，thiophene?3-H).
3.4,5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate synthetic
1.5g (9.6mmol) 5-aminothiophene-2-methyl-formiate is dissolved in the 6.8mL tetrahydrofuran (THF), adds tert-Butyl dicarbonate 2.5 (11.5mmol), back flow reaction 48h, after add tert-Butyl dicarbonate 0.5 (2.3mmol) three times, continue back flow reaction 48h.Steaming desolventizes, and adds the 10mL anhydrous diethyl ether, stirs a moment, separates out the off-white color solid, filters, and gets 5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate 2.24g.Yield 92.0%.
1H-NMR(CDCl3)：δppm：1.47(s，9H，COOC(CH3)3)，3.78(s，3H，COOCH3)，4.28(s，2H，NH2)，6.49(d，1H，J＝4Hz，thiophene?4-H)，7.52(d，1H，J＝4Hz，thiophene?3-H).
3.5,5-[N-(tertbutyloxycarbonyl)-N-methylamino] thiophene-2-carboxylic acid methyl esters synthetic
1.8g (7.0mol) 5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate is dissolved in the 45mL ethyl acetate, add Anhydrous potassium carbonate 2.3g (14.2mmol), sodium hydroxide 0.7g (14.0mmol), Tetrabutyl amonium bromide 2.6g (7.0mmol) successively, under the vigorous stirring, slowly add the solution that 1.2g (8.4mmol) methyl iodide is dissolved in the 5mL ethyl acetate, room temperature reaction 90min.Remove by filter inorganic salt, ethyl acetate (15mL * 3) washing, merging filtrate and washing lotion, steaming desolventizes.The resistates acetic acid ethyl dissolution, saturated sodium-chloride water solution (15mL * 3) washing, anhydrous sodium sulfate drying removes and desolvates, and gets light yellow solid 5-[N-(tertbutyloxycarbonyl)-N-methylamino] thiophene-2-carboxylic acid methyl esters 1.7g.Yield 88.8%.
1H-NMR(CDCl
3)：δppm：1.59(s，9H，COOC(CH
3)
3)，3.39(s，3H，NCH
3)，3.84(s，3H，COOCH
3)，6.46(d，1H，J＝4Hz，thiophene?4-H)，7.62(d，1H，J＝4Hz，thiophene?3-H)。
3.6,5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-thiophenic acid synthetic
With 1.8g (6.6mmol) 5-[N-(tertbutyloxycarbonyl)-N-methylamino] the thiophene-2-carboxylic acid methyl esters is dissolved in 20mL ethanol and the 20m L acetone, adds the sodium hydroxide solution 20mL of 1molL-1, room temperature reaction 2h.Underpressure distillation is steamed and is removed ethanol and acetone, transfers pH=4 with 1molL-1 hydrochloric acid, obtains off-white color solid 5-[N-(tertbutyloxycarbonyl)-N-methylamino]-2-thiophenic acid 1.5g.Yield 85.1%.
1H-NMR(CDCl
3)：δppm：1.59(s，9H，COOC(CH
3)
3)，3.41(s，3H，NCH
3)，6.55(d，1H，J＝4Hz，thiophene?4-H)，7.76(d，1H，J＝4Hz，thiophene?3-H)，11.0(s，1H，COOH)。
Above-mentioned with the 2-thiophenic acid be raw material through nitrated, esterification, reduction, amido protection, N-methylate, de-esterifying makes N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-synthetic route of L-glutamate diethyl ester is as follows:
4, with L-glutamic acid diester hydrochloride and N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester through the dewatering agent dehydrating condensation, take off amido protection and make N-[5-(N-methylamino)-2-thenoyl]-the L-glutamic acid diester;
4.1, N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-L-glutamate diethyl ester synthetic
0.12g (0.05mmol) the L-diethyl glutamate hydrochloride is dissolved in 3mL CH
2Cl
2In, drip 0.3mL Et
3N, ice bath stir 30min down.Ice bath cooling down, with 0.1g (0.4mmol) N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester is dissolved in CH
2Cl
2Among/the THF (3mL/2mL), be added drop-wise in the L-glutamate diethyl ester system, stir a moment, add 0.07g I-hydroxybenzotriazole (HOBt), stir a moment, with 0.1g (0.5mmol) N, N '-dicyclohexyl carbon imide (DCC) and CH
2Cl
2/ THF (3mL/2mL) drips of solution is added in the L-glutamate diethyl ester system, stirs a moment, gets back to the stirring at room reaction and spends the night, and filters, and uses the tetrahydrofuran (THF) washing leaching cake, and merging filtrate and washing lotion are steamed and removed tetrahydrofuran (THF).The resistates acetic acid ethyl dissolution, respectively wash 3 times with saturated sodium bicarbonate solution and saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, remove desolvate thick liquid N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-L-glutamate diethyl ester 0.16g, yield 92.3%.
1H-NMR(CDCl
3)：δppm：1.24，1.30(m，6H，CH
2CH
3)，1.57(s，9H，COOC(CH
3)
3)，2.13，2.24(m，2H，CHCH
2CH
2)，2.44(t，2H，COCH
2CH
2)，3.38(s，3H，NCH
3)，4.12(q，2H，OCH
2CH
3)，4.23(q，2H，CH
3CH
2O)，4.76(q，1H，CH
2CH(NH)CO).6.46(d，1H，J＝4Hz，thiophene?4-H)，6.56(m，1H，NH)，7.40(d，1H，J＝4Hz，thiophene?3-H)。
4.2, N-[5-(N-methylamino)-2-thenoyl]-L-glutamate diethyl ester synthetic
With 0.15g (0.34mmol) N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the 2mL methylene dichloride dissolving of L-glutamate diethyl ester, add the 1mL trifluoroacetic acid again, stirring at room 1.5h.Steam and remove methylene dichloride and trifluoroacetic acid, resistates is dissolved in the 15mL methylene dichloride, adding the 10mL saturated sodium bicarbonate solution fully stirs, divide water-yielding stratum, with methylene dichloride (8mL * 3) extraction, combined dichloromethane solution, anhydrous sodium sulfate drying, remove desolvate thick liquid, chloroform: ethyl acetate=5: 1 obtains compound N-[5-(N-methylamino)-2-thenoyl]-L-glutamate diethyl ester 0.07g for the developping agent column chromatography.Yield 63.8%.
1H-NMR(CDCl
3)：δppm：1.24，1.30(m，6H，CH
2CH
3)，2.10，2.26(m，2H，CHCH
2CH
2)，2.45(t，2H，COCH
2CH
2)，2.92(s，3H，NCH
3)，3.48(s，3H，NH)，4.11(q，2H，OCH
2CH
3)，4.22(q，2H，CH
3CH
2O)，4.75(q，1H，CH
2CH(NH)CO)，5.92(d，1H，J＝4Hz，thiophene?4-H)，6.46(m，1H，CH
2CH(NH)CO)，7.24(d，1H，J＝4Hz，thiophene?3-H)。
5, with N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester and 6-brooethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline is through the base catalysis condensation, and the cycles prepare chromatogram purification is after de-esterifying promptly makes Raltitrexed
5.1, N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-L-glutamate diethyl ester synthetic
With 0.066g (0.19mmol) N-[5-(N-methylamino)-2-thenoyl]-the L-glutamate diethyl ester is dissolved among the 3mL DMF, add 6-brooethyl-2-methyl-4-quinazolinone 0.1mg (0.41mmol) and 2,6-lutidine 0.3g (0.3mmol) spends the night in 55 ℃ of stirrings.Removal of solvent under reduced pressure, residuum adds ethyl acetate, stir a moment, filter, solvent evaporated gets thick liquid, ethyl acetate is the developping agent column chromatography, obtain N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-L-glutamate diethyl ester 0.057g, yield 57.2%.
1H-NMR(CDCl
3)：δppm：1.22，1.29(m，6H，CH
2CH
3)，2.27(m，2H，CHCH
2CH
2)，2.43(t，2H，COCH
2CH
2)，2.57(s，3H，quinazolinone?CH
3)，3.03(s，3H，NCH
3)，4.11(q，2H，OCH
2CH
3，)，4.21(q，2H，CH
3CH
2O)，4.59(s，2H，ArCH
2N)，4.75(q，1H，CH2CH(NH)CO)，5.87(d，1H，J＝4Hz，thiophene?4-H)，6.53(d，1H，J＝8Hz，quinazolinone?6-H)，7.28(d，1H，J＝4Hz，thiophene?3-H)，7.66(dd，2H，J＝2Hz?and?8Hz，quinazolinone?7-H，9-H)，8.13(m，1H，CH
2CH(NH)CO)，10.90(m，1H，C(NH)CO)。
5.2, cycles prepare chromatogram purification N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester, moving phase is the pure chloroform of top grade.
5.3, Raltitrexed synthetic
With 0.20g (0.38mmol) N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester is dissolved in 10mL ethanol and the 10mL acetone, add 3molL-1 aqueous sodium hydroxide solution 14mL, stirring at room reaction 3h.The underpressure distillation steaming removes ethanol and acetone, uses 2molL-1 hydrochloric acid to transfer pH=4, filters, and gets pale brown look solid, with methyl alcohol-anhydrous diethyl ether recrystallization, gets light yellow solid Raltitrexed 0.14g, yield 80.1%.
1H-NMR(DMSO-d
6)：δppm：1.88，2.04(m，2H，CHCH
2CH
2)，2.31(t，2H，COCH
2CH
2)，2.34(s，3H，quinazolinone?CH
3)，3.04(s，3H，NCH
3)，4.30(q，1H，CH
2CH(NH)CO)，4.65(s，2H，ArCH
2N)，5.99(d，1H，J＝4Hz，thiophene?4-H)，7.56(d，1H，J＝9Hz，quinazolinone?6-H)，7.58(d，1H，J＝4Hz，thiophene?3-H)，7.65(dd，1H，J＝2Hz?and?9Hz，quinazolinone?7-H)，7.94(dd，1H，J＝2Hzquinazolinone?9-H)，8.10(m，1H，CH
2CH(NH)CO)，12.21(m，1H，C(NH)CO)，12.41(s，2H，COOH)。
Above-mentioned with L-glutamic acid diester hydrochloride and N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester through the dewatering agent dehydrating condensation, take off amido protection and make N-[5-(N-methylamino)-2-thenoyl]-the L-glutamic acid diester; with N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester and 6-brooethyl-3; 4-dihydro-2-methyl-4-oxo-6-quinazoline is through the base catalysis condensation, the cycles prepare chromatogram purification after de-esterifying to make the synthetic route of Raltitrexed as follows:
In sum, the present invention's employing is converged synthesis method and is made Raltitrexed, and employed raw material is easy to get, and cost is low, mild condition, and reaction is easy to control, and good reproducibility is applicable to a large amount of preparations; Optimize the synthetic route of Raltitrexed, avoided the reaction conditions of harshness in the prior art; Utilize cycles prepare chromatogram purification intermediate product N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester, this intermediate product makes the highly purified of white through de-esterifying and can be used for clinical medical cancer therapy drug Raltitrexed.
The above for the person of ordinary skill of the art, can make other various corresponding changes and distortion according to technical scheme of the present invention and technical conceive, and all these changes and distortion all should belong to the protection domain of claim of the present invention.
Claims (10)
1. the new synthetic process of a cancer therapy drug Raltitrexed is characterized in that, comprises that step is as follows:
Step 1, be that raw material makes L-glutamic acid diester hydrochloride with alcohol through esterification under the halogenating agent effect with L-L-glutamic acid;
Step 2, be that raw material makes 6-brooethyl-3 through cyclisation, amination, bromination with 2-amino-5-methyl-phenylformic acid, 4-dihydro-2-methyl-4-oxo-6-quinazoline;
Step 3, with the 2-thiophenic acid be raw material through nitrated, esterification, reduction, amido protection, N-methylate, de-esterifying makes N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester;
Step 4, with L-glutamic acid diester hydrochloride and N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester through the dewatering agent dehydrating condensation, take off amido protection and make N-[5-(N-methylamino)-2-thenoyl]-the L-glutamic acid diester;
Step 5, with N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester and 6-brooethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline is through the base catalysis condensation, the cycles prepare chromatogram purification is after de-esterifying promptly makes Raltitrexed.
2. the new synthetic process of cancer therapy drug Raltitrexed as claimed in claim 1 is characterized in that, the halogenating agent in the described step 1 is acyl chlorides or thionyl chloride.
3. the new synthetic process of cancer therapy drug Raltitrexed as claimed in claim 1, it is characterized in that described step 2 comprises step 2.1,2-amino-5-methyl-phenylformic acid and diacetyl oxide backflow are reacted down, cyclisation makes 3,4-dihydro-2,6-dimethyl-4-oxo-6-Fenoxazoline; Step 2.2, with 3,4-dihydro-2, the reaction of 6-dimethyl-4-oxo-6-Fenoxazoline and inorganic amine or organic amine, amination makes 3,4-dihydro-2,6-dimethyl-4-oxo-6-quinazoline; Step 2.3, with 3,4-dihydro-2,6-dimethyl-4-oxo-6-quinazoline and N-bromosuccinimide are under infrared lamp illumination, cause by light trigger, in dry organic solvent, bromo-reaction makes 6-brooethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline.
4. the new synthetic process of cancer therapy drug Raltitrexed as claimed in claim 3 is characterized in that, adopts 120～130 ℃ of back flow reaction in the described step 2.1; Inorganic amine is an ammoniacal liquor or a hydrazine hydrate in the step 2.2, and organic amine is an aniline; N-bromosuccinimide and 3 in the step 2.3,4-dihydro-2, the mol ratio of 6-dimethyl-4-oxo-6-quinazoline is 1.1-4.2: 1, the power of infrared lamp is 150-400W, light trigger is for there being Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile), benzoyl peroxide, peroxidized t-butyl perbenzoate, dicumyl peroxide, ditertiary butyl peroxide, isopropyl benzene hydroperoxide, tertbutyl peroxide, the peroxy dicarbonate diisobutyl ester, di-cyclohexylperoxy dicarbonate or peroxy dicarbonate two (to tertiary butyl cyclohexyl), dry organic solvent are exsiccant acetonitrile or exsiccant chloroform.
5. the new synthetic process of cancer therapy drug Raltitrexed as claimed in claim 1 is characterized in that, described step 3 comprise step 3.1, with the 2-thiophenic acid in diacetyl oxide by the nitrated 5-of the making nitro of nitrosonitric acid-2-thiophenic acid; Step 3.2,5-nitro-2-thiophenic acid is made 5-nitro-2-ester thiohenic acid with alcohol through esterification under the halogenating agent effect; Step 3.3,5-nitro-2-ester thiohenic acid make 5-amido-2-ester thiohenic acid through the reductive agent reduction; Step 3.4,5-amido-2-ester thiohenic acid and amido protective reaction reagent react in reaction soln and make 5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate; Step 3.5,5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate make 5-[N-(tertbutyloxycarbonyl)-N-methylamino with the reaction of N-methylating reagent in the presence of phase transfer reagent, catalyzer, alkali] the thiophene-2-carboxylic acid methyl esters; Step 3.6,5-[N-(tertbutyloxycarbonyl)-N-methylamino] the ester hydrolysis reaction in the mixed solution of the water of alkali or organic solvent of thiophene-2-carboxylic acid methyl esters makes N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester.
6. the new synthetic process of cancer therapy drug Raltitrexed as claimed in claim 5 is characterized in that, the temperature that drips nitrosonitric acid in the described step 3.1 is-10～0 ℃; Halogenating agent described in the step 3.2 is acyl chlorides or thionyl chloride; Reductive agent is Fe/CH in the step 3.3
3COOH, Na
2S
2O
4Or Na
2S; The amido protective reaction reagent that uses in the step 3.4 is tert-Butyl dicarbonate, and reaction solvent is a tetrahydrofuran (THF), and temperature of reaction is 56～66 ℃; The phase transfer reagent that uses in the step 3.5 is Tetrabutyl amonium bromide, catalyzer is an Anhydrous potassium carbonate, alkali is sodium hydroxide, and the N-methylating reagent is methyl iodide or methyl-sulfate, and the mol ratio of N-methylating reagent and 5-(N-tertbutyloxycarbonyl)-aminothiophene-2-methyl-formiate is 1-2: 1; Alkali described in the step 3.6 is sodium hydroxide or potassium hydroxide, mixed solution is water/ethanol, and it is 1 that water/alcoholic acid is optimized volume ratio: 0.5-1: 1, or be water/ethanol/acetone, the optimization volume ratio of water/ethanol/acetone is 1: 1: 0.1-1: 1: 0.5, the concentration of alkali was 0.5-2N.
7. the new synthetic process of cancer therapy drug Raltitrexed as claimed in claim 1, it is characterized in that, described step 4 comprises step 4.1, with N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-L-glutamate diethyl ester and L-glutamic acid diester hydrochloride under dewatering agent and catalyst action in solvent condensation make N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester; Step 4.2, with N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-reaction makes N-[5-(N-methylamino)-2-thenoyl to the L-glutamate diethyl ester under the effect of amido protection reagent taking off]-the L-glutamic acid diester.
8. the new synthetic process of cancer therapy drug Raltitrexed as claimed in claim 7, it is characterized in that, dewatering agent is N in the described step 4.1, N '-dicyclohexyl carbon imide, catalyzer is an I-hydroxybenzotriazole, solvent is exsiccant tetrahydrofuran (THF) and methylene dichloride mixed solvent, and wherein tetrahydrofuran (THF) and methylene dichloride optimization volume ratio is 0.5: 1-5: 1; Taking off amido protection reagent in the step 4.2 is HBr and CH
3COOH, CF
3COOH or H
2/ Pd.
9. the new synthetic process of cancer therapy drug Raltitrexed as claimed in claim 1, it is characterized in that, described step 5 comprises step 5.1, with N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester and 6-brooethyl-3,4-dihydro-2-methyl-4-oxo-6-quinazoline under the alkali effect in organic solvent condensation make N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester; Step 5.2, with N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester makes highly purified N-[5-[N-[(3 through the cycles prepare chromatogram purification, 4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the L-glutamate diethyl ester; Step 5.3, with N-[5-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-the ester hydrolysis reaction in the mixed solution of the water of alkali or organic solvent of L-glutamate diethyl ester, promptly make Raltitrexed.
10. the new synthetic process of cancer therapy drug Raltitrexed as claimed in claim 9, it is characterized in that alkali described in the step 5.1 is 1,2-lutidine or pyridine, the organic solvent that uses is dimethyl formamide, N,N-DIMETHYLACETAMIDE or dimethyl sulfoxide (DMSO), and temperature of reaction is 50～120 ℃; The cyclical chromatography purifying adopts chloroform as moving phase in the step 5.2; Alkali described in the step 5.3 is sodium hydroxide or potassium hydroxide, mixed solution is water/ethanol, and it is 1 that water/alcoholic acid is optimized volume ratio: 0.5-1: 1, or be water/ethanol/acetone, the optimization volume ratio of water/ethanol/acetone is 1: 1: 0.1-1: 1: 0.5, the concentration of alkali was 0.5-2N.
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| CN102424679A (en) * | 2011-11-15 | 2012-04-25 | 扬子江药业集团有限公司 | Preparation method of Raltitrexed |
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| CN106957312B (en) * | 2016-12-29 | 2019-11-01 | 南京正大天晴制药有限公司 | Raltitrexed hydrate crystal forms and preparation method thereof |
| CN106957312A (en) * | 2016-12-29 | 2017-07-18 | 南京正大天晴制药有限公司 | Raltitrexed hydrate crystal forms and preparation method thereof |
| CN107129492A (en) * | 2017-07-19 | 2017-09-05 | 南京普氟生物检测技术有限公司 | A kind of Raltitrexed is condensed the preparation method of impurity |
| CN109280052A (en) * | 2017-07-21 | 2019-01-29 | 南京正大天晴制药有限公司 | The related substance F of Raltitrexed and its preparation and application |
| CN107721995A (en) * | 2017-09-11 | 2018-02-23 | 南京正大天晴制药有限公司 | The relevant material G of Raltitrexed and its preparation and application |
| CN107616976A (en) * | 2017-09-11 | 2018-01-23 | 南京正大天晴制药有限公司 | A kind of pharmaceutical composition of Raltitrexed and preparation method thereof |
| WO2019062027A1 (en) * | 2017-09-29 | 2019-04-04 | 新发药业有限公司 | Green preparation method for n-substituted-l-pyroglutamic acid ester |
| CN108658931A (en) * | 2018-03-20 | 2018-10-16 | 山东百诺医药股份有限公司 | A kind of preparation method of Raltitrexed key intermediate |
| CN108658931B (en) * | 2018-03-20 | 2020-08-04 | 山东百诺医药股份有限公司 | Preparation method of raltitrexed key intermediate |
| CN113666907A (en) * | 2021-08-25 | 2021-11-19 | 都创(上海)医药开发有限公司 | Method for rapidly preparing 4-nitrothiophene-2-formic acid based on microchannel reaction technology |
| WO2023160562A1 (en) * | 2022-02-28 | 2023-08-31 | 中国科学院上海药物研究所 | Methotrexate, and use of pharmaceutical composition thereof in tumor immunotherapy |
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