CN1486985A

CN1486985A - Synthesis of anticancer medicine Raltiprexed

Info

Publication number: CN1486985A
Application number: CNA021310912A
Authority: CN
Inventors: 曹胜利
Original assignee: Capital Normal University
Current assignee: Capital Normal University
Priority date: 2002-09-30
Filing date: 2002-09-30
Publication date: 2004-04-07
Anticipated expiration: 2022-09-30
Also published as: CN1216883C

Abstract

The synthesis of anticancer medicine Raltitrexed with 2, 5-thienyl diformic acid and diethyl glutamate as initial material and through six reaction steps of monocondensation, rearrangement, N-methylation, e;limination of tert-butoxy carbonyl group, condensation with 6-bromomethyl-2-methyl-4-quinbolone and saponification. The present invention has total yield of 18.1%, higher than that of available synthesis line, less reaction steps, mild condition and simple operation, and is suitable for mass production.

Description

The synthesis technique of anticarcinogen Raltitrexed

Technical field

The invention belongs to a kind of technology of chemical synthetic drug, the new synthetic process of particularly a kind of anticarcinogen Raltitrexed (Raltitrexed).

Background technology

Raltitrexed is a kind of quinazoline antifol, it suppresses thymidylate synthase (Thymidylate synthase by specificity, TS) produce antitumor action, because this kind of enzyme can be transformed into single phosphoric acid deoxythymidine (dTMP) with single phosphoric acid deoxyuridine (dUMP), is one of key enzyme in the DNA biosynthetic process.Raltitrexed is metabolised to multiple polyglutamic acid form very soon and brings into play the enzyme inhibition stronger than parent drug in cell, in treatment to colorectal cancer, its curative effect is better than or share similar in appearance to 5 FU 5 fluorouracil and folinic acid, but toxic side effects and the complicated medication of having avoided 5 FU 5 fluorouracil to produce have become a line medicine for the treatment of the colorectal cancer in late period.This medicine also has certain curative effect to other cancer such as tumor of head and neck, prostate cancer, lung cancer, soft tissue sarcoma, leukemia etc.

Raltitrexed mainly is made up of quinazolinone, thiophene and L-L-glutamic acid three parts, document (QuinazolineAntifolate Thymidylate Synthase Inhibitors:Heterocyclic Benzoyl RingModifications, J.Med.Chem., 1991,34 (5), 1594-1605) and the synthetic route of patent specification (US4992550,1991) report as follows:

In this synthetic route, the introducing of methyl need be made strong alkali catalyst with sodium hydride on the N atom, and reaction must be carried out under strict anhydrous condition, and long reaction time; The introducing of carboxyl more needs with expensive n-Butyl Lithium reagent on the thiphene ring ,-78 ℃ low temperature and strict anhydrous reaction conditions, and the reaction times is also longer.Whole synthetic route needs the reaction of seven steps, and total recovery is 3%.

Summary of the invention

The purpose of this invention is to provide that a raw material is easy to get, the reaction conditions gentleness, be convenient to operate, total recovery is high and be suitable for the Raltitrexed new synthetic process of a large amount of preparations.

The technical solution adopted for the present invention to solve the technical problems is:

Synthetic route is as follows:

Wherein R represents C _1-6Alkyl, benzyl

The technical program is with 2, and 5-thiophene dioctyl phthalate is a starting raw material, and six-step process is as follows successively:

(1) by 2, N-(5-carboxyl-2-thenoyl)-L-glutamic acid diester I is produced in the condensation of 5-thiophene dioctyl phthalate and L-glutamic acid diester;

(2) I and the trimethyl carbinol, triethylamine carry out rearrangement reaction in the presence of diphenylphosphine acylazide (DPPA), produce N-[5-[N-(tertbutyloxycarbonyl) amino]-the 2-thenoyl]-L-glutamic acid diester II;

(3) II reacts with methyl iodide or methyl-sulfate in the presence of phase-transfer catalyst, alkali, produces N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-L-glutamic acid diester III;

(4) III removes tertbutyloxycarbonyl under acidic conditions, produces N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester IV;

(5) IV and 6-brooethyl-2-methyl-4-quinazolinone (is pressed document Quinazoline antifolatethymidylate synthase inhibitors:alkyl, substituted alkyl, and aryl substituents in theC2 position, J.Med.Chem.1990,33 (11), 3060-3067 produces) reaction in the presence of alkali, produce N-[5-(N-[(3,4-dihydro-2-methyl-4-oxygen-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-L-glutamic acid diester V;

(6) V in alcoholic solution with alkali soap acquisition end product Raltitrexed.

Compare with traditional synthesis process, the present invention has following advantage:

1. technical process is shorter.The technical process of prior art comprises the reaction of seven steps, and the starting raw material that the present invention selects for use is different from existing synthesis technique, according to a synthetic route needs six-step process of new starting raw material redesign.

2. because the improvement of synthetic route of the present invention; avoided must using in the prior art expensive n-Butyl Lithium, introduce the method for carboxyl with the dry ice reaction under-78 ℃ of low temperature and strict anhydrous, protection of inert gas condition, easy and simple to handle, mild condition and reagent cost are low.In the N-methylation reaction, the present invention uses mineral alkali cheap and easy to get and phase-transfer catalyst, make to react at room temperature and can finish in the short period of time (5-10 minute), yield height, post-treating method are easy, product even can be not purified and be directly used in the next step, and avoided the sodium hydride that the use valency is high in the prior art, and strict anhydrous reaction conditions.In the reaction that removes tertbutyloxycarbonyl, the present invention uses the dichloromethane solution of 50% trifluoroacetic acid, thin-layer chromatography detects and shows that being reflected at reaction in 1 hour can finish, than document (Quinazoline AntifolateThymidylate Synthase Inhibitors:Heterocyclic Benzoyl Ring Modifications, J.Med.Chem., 1991,34 (5), 1594-1605) shortened dramatically in used 16 hours.

3. total recovery is higher than prior art.Synthesis route provided by the invention, total recovery reaches 18.1%, and is higher 15.1 percentage points than the total recovery (3%) of prior art.

Embodiment

Synthetic route is as follows:

Synthesizing of the first step: N-(5-carboxyl-2-thenoyl)-L-glutamate diethyl ester (I):

With 2,5-thiophene dioctyl phthalate 2.93g (17.2mmol) is suspended in the 30mL dry tetrahydrofuran (THF), and cryosel is bathed cooling down, adds N, N '-dicyclohexylcarbodiimide (DCC) 3.55g (17.2mmol).Stir a moment, drip the L-glutamate diethyl ester 3.5g (17.2mmol) that is dissolved in the 20mL dry THF, the stirring at room reaction is spent the night.Filter, use the THF washing leaching cake, merging filtrate and washing lotion, rotary evaporation is removed THF.Resistates adds chloroform 15mL dissolving, adds sherwood oil again to muddy, and room temperature removes by filter the solid of separating out after placing.The filtrate rotary evaporation eliminates solvent, gets thick liquid 3.67g, yield 59.8%.

Second step: N-[5-[N-(tertbutyloxycarbonyl) amino]-the 2-thenoyl]-L-glutamate diethyl ester (II) synthetic

In reaction flask, add N-(5-carboxyl-2-thenoyl)-L-glutamate diethyl ester (I) 3.08g (8.6mmol), diphenylphosphine acylazide (DPPA) 2.73g (9.9mmol), triethylamine 1.0g (9.9mmol) and trimethyl carbinol 40mL, heating reflux reaction 7 hours.Rotary evaporation is removed the excessive trimethyl carbinol, and resistates adds an amount of acetic acid ethyl dissolution, uses 5%NaHCO successively ₃, 5% citric acid, saturated NaCl solution washing (each 10mL * 3), anhydrous Na ₂SO ₄Dry.Filter, washing removes and desolvates, and resistates dissolves with methylene dichloride, and last sample is to silica gel column chromatography, and ethyl acetate: sherwood oil=1: 1 (v/v) wash-out gets thick liquid 2.06g, yield 55.8%.

The 3rd step: N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-L-glutamate diethyl ester (III) synthetic

With N-[5-[N-(tertbutyloxycarbonyl) amino]-the 2-thenoyl]-L-glutamate diethyl ester (II) 0.5g (1.17mmol), tetra-n-butyl ammonium bromide (TBAB) 0.38g (1.17mmol) be dissolved in the 15mL ethyl acetate, adds the Anhydrous potassium carbonate 0.24g (1.75mmol) and the sodium hydroxide 0.07g (1.75mmol) of porphyrize.Under the vigorous stirring, slowly add the methyl iodide 0.50g (3.5mmol) that is dissolved in the 5mL ethyl acetate, stirring at room reaction 10 minutes.Remove by filter inorganic salt, and wash 3 times with ethyl acetate, merging filtrate and washing lotion, rotary evaporation removes and desolvates.Resistates adds acetic acid ethyl dissolution, saturated sodium-chloride water solution washing 3 times, and anhydrous sodium sulfate drying removes and desolvates, and (elutriant: methylene dichloride: ethyl acetate=1: 5 v/v), gets thick liquid 0.47g, yield 90.4% to crude product through the column chromatography purifying.

The 4th step: N-[5-(N-methylamino)-2-thenoyl]-synthetic (IV) of L-glutamate diethyl ester synthetic

Containing N-[5-[N-(tertbutyloxycarbonyl)-N-methylamino]-the 2-thenoyl]-reaction flask of L-glutamate diethyl ester 0.72g (1.63mmol) in, add methylene dichloride 4mL stirring and dissolving, add trifluoroacetic acid (TFA) 4mL again, stirring at room reaction 1 hour.Rotary evaporation is removed methylene dichloride and excessive TFA, and resistates adds an amount of methylene dichloride, and rotary evaporation is removed again, and repeats once.Resistates is dissolved in the 15mL methylene dichloride, adds the saturated NaHCO of 30mL ₃Solution fully stirs, and divides water-yielding stratum, and with dichloromethane extraction (10mL * 2), merges CH ₂Cl ₂Solution, anhydrous Na ₂SO ₄Dry.(elutriant: methylene dichloride: ethyl acetate=4: 1, v/v) purifying gets oily matter 0.51g, yield 91.1% through column chromatography to remove the back gained thick liquid that desolvates.

The 5th step: N-[5-[N-[(3,4-dihydro-2-methyl-4-oxygen-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-L-glutamate diethyl ester (V) synthetic

At N-[5-(N-methylamino)-2-thenoyl]-L-glutamate diethyl ester (IV) 0.8g (2.34mmol) and 15mL N, in dinethylformamide (DMF) solution, add 6-brooethyl-2-methyl-4-quinazolinone 0.65g (2.57mmol) and 2,6-lutidine 0.25g (2.34mmol) spends the night in 55～60 ℃ of stirring reactions then.Rotary evaporation removes and desolvates, and (elutriant: methylene dichloride: ethanol=90: 10, v/v) purifying gets off-white color solid 0.89g, yield 74.2% to resistates with silica gel column chromatography.

The 6th step: N-[5-[N-[(3,4-dihydro-2-methyl-4-oxygen-6-quinazolyl) methyl]-N-(methylamino)-2-thenoyl]-L-L-glutamic acid (Raltitrexed, VI) synthetic

With N-[5-[N-[(3,4-dihydro-2-methyl-4-oxygen-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-L-glutamate diethyl ester (V) 0.79g (1.54mmol) is dissolved in the 15mL ethanol, add 1N aqueous sodium hydroxide solution 15.4mL (15.4mmol), stirring at room reaction 2 hours.Rotary evaporation is removed ethanol, and the aqueous solution with 2N HCl accent pH=5～6, filters the solid of separating out, and uses the deionized water thorough washing under the ice-water bath cooling, and dry back gets solid phase prod 0.62g, yield 88.6% with methyl alcohol-anhydrous diethyl ether recrystallization.

Claims

1. the synthesis technique of anticarcinogen Raltitrexed (Raltitrexed), synthetic route is as follows:

Wherein R represents C _1-6Alkyl, benzyl;

It is characterized in that the technical program with 2,5-thiophene dioctyl phthalate is a starting raw material, and six-step process is as follows successively:

(5) IV and 6-brooethyl-2-methyl-4-quinazolinone reacts in the presence of alkali, produces N-[5-[N-[(3,4-dihydro-2-methyl-4-oxygen-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-L-glutamic acid diester V;

2. the synthesis technique of anticarcinogen Raltitrexed as claimed in claim 1, it is characterized in that with the L-glutamic acid diester with wait mole or excessive 2,5-thiophene dioctyl phthalate N, N-(5-carboxyl-2-thenoyl)-L-glutamic acid diester I is produced in N '-dicyclohexylcarbodiimide (DCC) condensation.

3. the synthesis technique of anticarcinogen Raltitrexed as claimed in claim 1 is characterized in that II is at tetra-n-butyl ammonium bromide (TBAB), K ₂CO ₃Exist down with NaOH, with the synthetic N-[5-[N-(tertbutyloxycarbonyl) of iodomethane reaction-N-methylamino]-the 2-thenoyl]-L-glutamic acid diester III.

4. the synthesis technique of anticarcinogen Raltitrexed as claimed in claim 1 is characterized in that III removes tertbutyloxycarbonyl with the dichloromethane solution of 50% trifluoroacetic acid, produces N-[5-(N-methylamino)-2-thenoyl]-L-glutamic acid diester IV.

5. the synthesis technique of anticarcinogen Raltitrexed as claimed in claim 1, it is characterized in that IV and 6-brooethyl-2-methyl-4-quinazolinone is in DMF solution, carry out condensation reaction in 55-60 ℃, produce N-[5-[N-[(3,4-dihydro-2-methyl-4-oxygen-6-quinazolyl) methyl]-the N-methylamino]-the 2-thenoyl]-L-glutamic acid diester V.

6. the synthesis technique of anticarcinogen Raltitrexed as claimed in claim 1 is characterized in that V uses 1N NaOH saponification in ethanolic soln, produce the end product Raltitrexed.