CN101654426B - Method for preparing ilomastat - Google Patents

Method for preparing ilomastat Download PDF

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CN101654426B
CN101654426B CN 200810144968 CN200810144968A CN101654426B CN 101654426 B CN101654426 B CN 101654426B CN 200810144968 CN200810144968 CN 200810144968 CN 200810144968 A CN200810144968 A CN 200810144968A CN 101654426 B CN101654426 B CN 101654426B
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ilomastat
water
methylamine
reaction
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CN101654426A (en
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刘克良
韩寒
梁远军
许笑宇
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Institute of Pharmacology and Toxicology of AMMS
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Abstract

The invention relates to a new method for preparing ilomastat, which comprises the following steps of: reacting a tryptophan methyl ester hydrochloride with a methylamine to prepare tryptophanyl methylamine; performing a condensation reaction between the tryptophanyl methylamine and a tert-butyl acetate succinate derivative to prepare a midbody of a formula (IV); removing the tert-butyl from the midbody of formula (IV) to form a midbody of a formula (V); and performing a condensation reaction between the midbody of formula (V) and a free hydroxylamine to form the ilomastat. The method of the invention is simple in the process and low in the cost.

Description

The method for preparing Ilomastat
Technical field
The present invention relates to a kind of novel method for preparing Ilomastat.
Background technology
Ilomastat (English name: Ilomastat, chemical name: N-[(2R)-2-(azanol carbonyl methyl)-4-methylpent carbonyl]-L-tryptophyl methylamine), be a kind of wide spectrum, potent matrix metallo-proteinase inhibitor, its a plurality of members to matrix metalloproteinase family all have very strong restraining effect.The chemical structural formula of Ilomastat is as follows:
Figure G2008101449686D00011
The nineties in 20th century, U.S. Glycomed company at first researches and develops it as indication take the treatment keratohelcosis, and clinical trial shows that Ilomastat causes corneal injury to alkali good therapeutic action.In recent years, finding again that Ilomastat has slows down and improves facial wrinkles and prevent and treat bathomorphic effect.
WO 9209563 discloses a kind of method for preparing Ilomastat shown in following scheme:
Figure G2008101449686D00021
Disclosed the method at first makes intermediate tryptophyl methylamine hydrochloride among the WO 9209563, this compound is the moisture absorption very easily, preservation condition is harsh, feeding intake when being unfavorable for the next step weighed, in addition, the key intermediate monomethyl succinate derivative that this method makes is racemic modification, the mixture of a pair of diastereomer with obtaining after the condensation of tryptophyl methylamine hydrochloride, must just can obtain through column chromatography for separation the intermediate of required configuration, complex operation not only, and waste raw material (one of them diastereomer can not utilize).The method uses ethyl acetate that Ilomastat is carried out recrystallization, and experiment finds that even the solubleness of Ilomastat in hot ethyl acetate is also very little, ethyl acetate is not suitable as recrystallization solvent.
Other have document (Levy DE, Lapierre FL, the people such as Liang WS, J.Med.Chem., 1998,41 (2): 199-223) disclose a kind of method of utilizing the synthetic Ilomastat of asymmetric reaction and analogue thereof, the method is referring to following scheme:
In the disclosed methods such as above-mentioned Levy DE, at first utilize the chiral auxiliary(reagent) Stereoselective to obtain Succinic Acid list tert-butyl ester derivative, then use trifluoroacetic acid and remove tert-butyl ester protection, again esterification, last azanol solution obtains Ilomastat.Experiment is found: when utilizing trifluoroacetic acid to remove the tert-butyl ester, may be owing to contain indolyl radical in the structure, cause the products therefrom color darker, and in last handling process, need repeatedly solubilizing agent distillation ability Ex-all trifluoroacetic acid, thereby obtain solid-state intermediate, such operation is very loaded down with trivial details.
Therefore, need to provide a kind of technique of improving to be fit to the novel method of the molded standby Ilomastat of multiplying gauge.
Summary of the invention
The purpose of this invention is to provide a kind of novel method of improving and simplifying the preparation Ilomastat of technique, reduction cost and suitable amplification scale.
Put it briefly, the invention provides a kind of method for preparing the Ilomastat of following formula (I),
Figure G2008101449686D00041
The method comprises:
(a) with tryptophan methyl ester hydrochloride and methylamine reaction, the tryptophyl methylamine of preparation formula (II);
Figure G2008101449686D00042
(b) in the presence of condensing agent, with the Succinic Acid list tert-butyl ester derivative of the tryptophyl methylamine of formula (II) and following formula (III) through condensation reaction, the intermediate of preparation following formula (IV);
Figure G2008101449686D00043
(c) intermediate with formula (IV) removes the tert-butyl ester, obtains the intermediate of lower formula V;
Figure G2008101449686D00044
(d) with the intermediate of formula (V) and free hydroxylamine through condensation reaction, obtain the Ilomastat of formula (I); And, optional
(e) Ilomastat of the formula (I) of gained is made with extra care by recrystallization method.
Further, use DMTMM or EDC/HOBT/DMAP as condensing agent in the step (b).Not purified next reactions steps that is directly used in of the crude product of gained intermediate (IV).Wherein four kinds of reagent D MTMM, EDC, HOBT and DMAP can obtain from commercial channels, and perhaps those skilled in the art can make according to prior art.Four kinds of corresponding chemical structures of reagent are as follows:
Figure G2008101449686D00051
Further, in step (c), use CeCl 37H 2O and NaI, and backflow removes the tert-butyl ester in acetonitrile.
Further, in the method for the invention, carry out purifying comprising the intermediate that operates formula (V) below adopting in step (c) with (d): the intermediate of formula (V) is dissolved in the potassium hydroxide aqueous solution, behind the organic solvent washing water, transfer aqueous pH values (preferably regulating pH value to 3) with dilute hydrochloric acid, use again the organic solvent extraction water, separate the intermediate that obtains formula (V) from organic phase.The intermediate of this formula (V) can be directly used in next reactions steps
Further, in step (d), use the carboxyl of mixed anhydride method activation formula (V) intermediate, the methanol solution with free hydroxylamine reacts again, obtains the Ilomastat of formula (I).
Further, in the method for the invention, the used reagent of described mixed anhydride method is selected from isobutyl chlorocarbonate and Vinyl chloroformate; The methanol solution of described free hydroxylamine is that the methanol solution by oxammonium hydrochloride mixes at low temperatures with the methanol solution of potassium hydroxide and makes.
Further, in the method for the invention, the methanol solution of the free hydroxylamine of gained is directly used in reaction without filtering Repone K wherein precipitates.
Further, in the method for the invention, after reaction finishes, in reactant, add ethyl acetate and water, the Ilomastat of formula (I) is slowly separated out in ethyl acetate.
Further, in the method for the invention, it also comprises and uses following steps that the Ilomastat of step (d) gained formula (I) is carried out purifying: the Ilomastat of formula (I) is dissolved in the potassium hydroxide aqueous solution, wash water with ethyl acetate, then use dilute hydrochloric acid water transfer phase (preferably regulating pH value to 3), separate out precipitation, filtering precipitate, wash drying with water.
Further, in the method for the invention, described recrystallization uses methanol/water mixed solvent, acetic acid/ethyl acetate mixed solvent to carry out successively.
Specifically, the present invention is achieved in the following ways: utilize asymmetric reaction to obtain Succinic Acid list tert-butyl ester derivative (III), carry out the synthetic of Ilomastat as raw material.Take tryptophan methyl ester hydrochloride as raw material, the intermediate tryptophyl methylamine (II) that obtains dissociating with the methylamine aminolysis, this intermediate (II) is compared with the tryptophyl methylamine hydrochloride in the former technique, has the deliquescence of being difficult for, the advantage of convenient preservation and use etc., and omitted in the operation of condensation reaction adding alkali with the neutralized salt hydrochlorate.
Take intermediate (II) with (III) as raw material, adopting DMTMM is the preparation that condensing agent carries out intermediate (IV), this condensing agent is with low cost, be easy to remove, and can in the protic solvents such as methyl alcohol, use, be conducive to increase the solubleness of intermediate (II), improve condensation efficiency.The intermediate that obtains (IV) can be directly used in next reactions steps without any purifying, has simplified operation.
During preparation intermediate (V), select CeCl 37H 2O/NaI is as the reagent that removes of the tert-butyl ester, this reagent mild condition, products therefrom is easy to solidify, light, purity good, is better than the trifluoroacetic acid that uses in the former technique.Intermediate (V) is dissolved in the potassium hydroxide aqueous solution of equivalent, fully wash water with organic solvent such as ether, chloroform, ethyl acetate or benzene etc., dilute hydrochloric acid water transfer phase pH=3, again with the organic solvent extraction water, can be further purified product, the intermediate that obtains thus (V) can be directly used in next reactions steps.
Take the methanol solution of intermediate (V) and free hydroxylamine as raw material, adopt one step of mixed anhydride method to make the Ilomastat crude product, purity can reach more than 94%.The methanol solution of free hydroxylamine is made by the methanol solution of oxammonium hydrochloride and the methanol solution low-temperature mixed of potassium hydroxide, need not to remove by filter Repone K precipitation wherein, can be directly used in reaction, has simplified operation.Can adopt following operation purification of target thing: Ilomastat is dissolved in the potassium hydroxide aqueous solution of equivalent, and organic solvent fully washs behind the water with dilute hydrochloric acid water transfer phase pH=3, separates out precipitation, filters, and washing press dry.Subsequently, can adopt repeatedly the method for recrystallization that product is made with extra care.
Method of the present invention is implemented in explanation in more detail below:
Tryptophan methyl ester hydrochloride adds aqueous methylamine solution or the alcoholic solution of 3～10 times of amounts, 0 ℃～40 ℃ lower confined reactions 5～24 hours, be preferably the aqueous methylamine solution that adds 5 times of amounts, 25 ℃ of lower confined reactions 12 hours, then with dichloromethane extraction, be preferably the continuous extraction mode that adopts, continue 5～6 hours, methylene dichloride is removed in evaporation, obtains tryptophyl methylamine intermediate (II).
Intermediate (II), (III) and condensing agent DMTMM adopt the ratio of feed ratio 1: 1: 1.1～2, in methyl alcohol, under 0 ℃～40 ℃, reacted 2～18 hours, obtain intermediate (IV), this intermediate needn't be purified, can be directly used in next reactions steps.Condensation condition was feed ratio 1: 1: 1.2 preferably, and the methyl alcohol add-on is 10mL/g (II), about 12 hours of 25 ℃ of lower reactions.
Intermediate (IV) is joined CeCl 37H 2O and NaI are at CH 3In the mixture among the CN, reflux and remove the tert-butyl ester, obtain intermediate (V), the reaction times is 15～30 minutes preferably.The dissolving crude product of gained (V) in the potassium hydroxide aqueous solution of equivalent, is fully washed water with ether, dilute hydrochloric acid water transfer phase pH=3, again with the ethyl acetate extraction water, the intermediate that obtains thus (V) can be directly used in next reactions steps.
Intermediate (V) is dissolved in ether or tetrahydrofuran (THF), uses isobutyl chlorocarbonate or Vinyl chloroformate activated carboxyl, temperature of reaction is 0 ℃ to-20 ℃, and the reaction times is 2～30 minutes.Then methanol solution of adding free hydroxylamine continues reaction 1 hour in reacting to this.Reaction conditions is take tetrahydrofuran (THF) as solvent preferably, selects isobutyl chlorocarbonate-15 ℃ of lower activated carboxyls 3～5 minutes.React complete after, add entry and ethyl acetate, fully mix, separate organic layer, leave standstill, separate out the crude product of end product Ilomastat.With this dissolving crude product in the potassium hydroxide aqueous solution of equivalent, fully wash water with ethyl acetate after, with dilute hydrochloric acid water transfer phase pH=3, separate out precipitation.Leach precipitation, wash with water, press dry, use methanol/water=1: 1 and acetic acid again: ethyl acetate=mixed solvent carried out recrystallization to this product successively in 1: 1, can obtain purity and be the end product Ilomastat more than 98%.
Compared with prior art, the method that the present invention prepares Ilomastat comprises having obvious advantage, and for example: the methylamine solution with tryptophan methyl ester hydrochloride directly makes the tryptophyl methylamine, and this midbody compound is difficult for deliquescence, preserves easily, and is easy to use; Adopting DMTMM is that condensing agent prepares intermediate (IV), and condensation efficiency is high, not purified next reactions steps that is directly used in of products therefrom; Utilize CeCl 37H 2O/NaI/CH 3The CN mixed system removes the tert-butyl ester and prepares intermediate (V), and the method that adopts alkali dissolution-organic solvent washing-acidifying-organic solvent extraction is to intermediate (V) purifying, and products obtained therefrom is directly used in next reactions steps; Adopt mixed anhydride method, directly make the end product Ilomastat by intermediate (V) take the methanol solution of free hydroxylamine as the agent of ammonia solution, used azanol methanol solution needn't filter except Repone K.Adopt alkali molten-method of organic solvent washing-Acid precipitation adopts the multi-solvents system that Ilomastat is carried out recrystallizing and refining to the Ilomastat purifying simultaneously.The extensive synthetic new effective way that provides of Ilomastat is provided above-mentioned advantage of the present invention.
Embodiment
Further specify the present invention below by concrete Preparation Example, still, should be understood to, these embodiment are only used for the more detailed usefulness that specifically describes, and should not be construed as for limiting in any form the present invention.In specification sheets of the present invention, as not specifying that used reagent, raw material, intermediate, solvent etc. all can obtain or prepare by method known to those skilled in the art from commercial channels.
1, The preparation of L-tryptophyl methylamine (II)
With L-Trp methyl ester hydrochloride (144.74g, 0.57mol) mix with aqueous methylamine solution (25～30%) 430mL, at room temperature sealing was stirred 7 hours, use methylene dichloride to carry out continuous extraction 5 hours, separate, the organic phase anhydrous magnesium sulfate drying with obtaining removes solvent under reduced pressure, obtain faint yellow solid, using very down P 2O 5After the drying, obtain the title compound of 117.07g, yield: 94.82%.
TLC analyzes: R f=0.32 (chloroform: methyl alcohol: ammoniacal liquor=10: 1: 0.5).
2, The preparation of 4-tert.-butoxy-2R-isobutyl-succinyl-L-tryptophyl methylamine (IV)
2R-isobutyl-fourth-Isosorbide-5-Nitrae-diacid-4-tert-butyl ester (III) (64.27g, 0.28mol) is dissolved in the 600mL anhydrous methanol, adds again intermediate (II) (60.82g, 0.28mol).At room temperature stirred 10 minutes, and then added DMTMM (92.90g, 0.34mol), at room temperature reacted 12 hours, then remove methyl alcohol under reduced pressure, add ethyl acetate, organic phase is used H successively 2O, rare HCl, saturated NaCl solution, saturated NaHCO 3Solution, H 2Then O, saturated NaCl solution washing use anhydrous MgSO 4Drying removes solvent under reduced pressure, obtains yellow blister solid, uses P under vacuum 2O 5After the drying, obtain the 115.68g title compound, its not purified next reactions steps that namely is directly used in.
TLC analyzes: R f=0.58[sherwood oil (60-90 ℃): ethyl acetate=1: 1].
3, The preparation of 4-hydroxyl-2R-isobutyl-succinyl-L-tryptophyl methylamine (V)
Intermediate (IV) (115.68g is in 0.27mol) is dissolved in the 1300mL acetonitrile, adds CeCl 37H 2O (150.48g, 0.40mol) and anhydrous Na I (52.47g, 0.35mol) reflux reactant, use the TLC monitoring reaction, afterreaction was complete in about 15 minutes, and acetonitrile is removed in underpressure distillation, add ethyl acetate and dilute hydrochloric acid, extraction separates, and obtains organic phase.Then this organic phase is used H successively 2O, saturated NaCl solution washing, ethyl acetate is removed in underpressure distillation.Then the NaOH aqueous solution 500mL (0.3mol) that adds 0.6M in the resistates, concussion is until clarification.The buck layer with ether (* 3) washing, is used dilute hydrochloric acid water transfer phase pH=3-4 again under the ice bath cooling, with ethyl acetate (* 3) extraction, merge organic phase.With the anhydrous MgSO of organic phase that merges 4Drying, underpressure distillation, desolventizing obtains golden yellow blister solid, uses P under vacuum 2O 5After the drying, obtain the title compound of 109.3g, its not purified next reactions steps that namely is directly used in.
TLC analyzes: R f=0.15 (CHCl 3: CH 3OH: CH 3COOH=10: 1: 0.5).
4, N-[(2R)-2-(azanol carbonyl methyl)-4-methylpent carbonyl]-L-tryptophyl methylamine (Ilomastat, I) preparation
(A) under the ice bath cooling, with NH 2Solution and KOH (22.6g, 0.40mol) the solution stirring in methyl alcohol (107.6mL) of OHHCl (26.9g, 0.40mol) in methyl alcohol (270.0mL) mixed 10 minutes, and be stand-by.
(B) with intermediate (the V) (109.3g of step 3 gained, in 0.27mol) be dissolved in the 800mL anhydrous tetrahydro furan, be cooled to-15 ℃, stir the lower N-methylmorpholine (NMM that adds, 39.0mL, 0.35mol), slowly drip again isobutyl chlorocarbonate (42.1mL, 0.32mol), make temperature be no more than-10 ℃.Add complete after, maintain under this low temperature reaction 5 minutes.The NH that adds fresh preparation in the step (A) in the above-mentioned reaction 2The OH/ methanol solution, reaction is 30 minutes in ice bath, at room temperature reacts 30 minutes again.Underpressure distillation, desolventizing adds entry and ethyl acetate again, and rapidly concussion extraction is separated.Organic phase is cooled off in ice bath, slowly separated out solid, fully place, filter, collect solid, wash twice with water, with the ether washing once, under vacuum, use P again 2O 5Drying obtains the 54.3g crude product.In addition, obtain again the 3.4g crude product with same operation from the aqueous phase of above separation.Merge two parts of crude products, amount to 57.7g.This crude product is joined in the potassium hydroxide aqueous solution of equivalent, make its dissolving, the buck layer with ethyl acetate washing three times, is used dilute hydrochloric acid water transfer layer pH=3 again, separate out a large amount of white solids.With this solid filtering, wash with water, press dry, use again methanol/water (1: 1) recrystallization, get colourless hour hand shape crystallization 48.4g.Then use acetic acid: ethyl acetate (1: 1) is carried out secondary recrystallization to this hour hand shape crystallization, gets the title compound of white solid 24g.
M.p.190-191 ℃ (decomposition).
TLC analyzes: R f=0.43 (CHCl 3: CH 3OH=10: 1).
D=13.5 ° of specific optical rotation [α] (c=1, methyl alcohol).
Purity 〉=98% (HPLC method).
1H-NMR(DMSO-d6)δ：10.79(s，1H)，10.42(s，1H)，8.78(s，1H)，8.01-7.99(d，1H)，7.87-7.86(q，1H)，7.56-7.54(d，1H)，7.31-7.29(d，1H)，7.11-6.94(m，3H)，3.13-2.93(m，2H)，2.66-2.63(m，1H)，2.55-2.50(m，3H)，2.09-1.90(m，2H)，1.34-1.28(m，2H)，0.99-0.96(m，1H)，0.79-0.72(dd，6H)。

Claims (9)

1. the method for preparing the Ilomastat of following formula (I),
Figure FSB00000792861400011
The method comprises:
(a) with tryptophan methyl ester hydrochloride and methylamine reaction, the tryptophyl methylamine of preparation formula (II);
Figure FSB00000792861400012
(b) in the presence of condensing agent, with the Succinic Acid list tert-butyl ester derivative of the tryptophyl methylamine of formula (II) and following formula (III) through condensation reaction, the intermediate of preparation following formula (IV);
Figure FSB00000792861400013
(c) intermediate with formula (IV) removes the tert-butyl ester, obtains the intermediate of lower formula V;
Figure FSB00000792861400014
(d) with the intermediate of formula (V) and free hydroxylamine through condensation reaction, obtain the Ilomastat of formula (I); And, randomly
(e) Ilomastat of the formula (I) of gained is made with extra care by recrystallization method;
It is characterized in that, in step (c), use CeCl 37H 2O and NaI, and backflow removes the tert-butyl ester in acetonitrile.
2. method according to claim 1 is characterized in that: use DMTMM or EDC/HOBT/DMAP as condensing agent in the step (b).
3. method according to claim 1, carry out purifying comprising the intermediate that operates formula (V) below adopting in step (c) with (d): the intermediate of formula (V) is dissolved in the potassium hydroxide aqueous solution, behind the organic solvent washing water, transfer aqueous pH values with dilute hydrochloric acid, use again the organic solvent extraction water, separate the intermediate that obtains formula (V) from organic phase.
4. method according to claim 1 is characterized in that: in step (d), use the carboxyl of mixed anhydride method activation formula (V) intermediate, again with the methanol solution reaction of free hydroxylamine, obtain the Ilomastat of formula (I).
5. method according to claim 4, the used reagent of described mixed anhydride method is selected from isobutyl chlorocarbonate and Vinyl chloroformate; The methanol solution of described free hydroxylamine is that the methanol solution by oxammonium hydrochloride mixes at low temperatures with the methanol solution of potassium hydroxide and makes.
6. method according to claim 5 is characterized in that: the methanol solution of the free hydroxylamine of gained without filtering wherein the Repone K precipitation and be directly used in reaction.
7. method according to claim 4 after reaction finishes, adds ethyl acetate and water in reactant, and the Ilomastat of formula (I) is slowly separated out in ethyl acetate.
8. method according to claim 1, it also comprises and uses following steps that the Ilomastat of step (d) gained formula (I) is carried out purifying: the Ilomastat of formula (I) is dissolved in the potassium hydroxide aqueous solution, wash water with ethyl acetate, then use dilute hydrochloric acid water transfer phase, separate out precipitation, filtering precipitate washes with water, drying.
9. method according to claim 1, described recrystallization uses methanol/water mixed solvent, acetic acid/ethyl acetate mixed solvent to carry out successively.
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CN103435514B (en) * 2013-08-01 2015-11-25 中国人民解放军军事医学科学院毒物药物研究所 Matrix metallo-proteinase inhibitor and uses thereof
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101076357A (en) * 2004-09-24 2007-11-21 通用电气健康护理有限公司 Enzyme inhibitor imaging agents

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101076357A (en) * 2004-09-24 2007-11-21 通用电气健康护理有限公司 Enzyme inhibitor imaging agents

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Daniel E. Levy, et al..Matrix Metalloproteinase Inhibitors: A Structure-Activity Study.《J. Med. Chem.》.1998,第41卷(第2期),第199-223页. *
李杰 等.基质金属蛋白酶抑制剂伊洛马司他的合成.《中国新药杂志》.2007,第16卷(第4期),第300-303页. *
范学森 等.三氯化铈促进的反应及其在有机合成中的应用.《有机化学》.2005,第25卷(第9期),第1029-1038页. *

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