CN101654426A - Method for preparing ilomastat - Google Patents
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- CN101654426A CN101654426A CN200810144968A CN200810144968A CN101654426A CN 101654426 A CN101654426 A CN 101654426A CN 200810144968 A CN200810144968 A CN 200810144968A CN 200810144968 A CN200810144968 A CN 200810144968A CN 101654426 A CN101654426 A CN 101654426A
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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
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:
The nineties in 20th century, U.S. Glycomed company is that indication is researched and developed it with the treatment keratohelcosis at first, 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:
Disclosed this method at first makes intermediate tryptophyl methylamine hydrochloride among the WO 9209563, this compound is the moisture absorption very easily, the preservation condition harshness, feeding intake when being unfavorable for the next step weighed, in addition, the key intermediate monomethyl succinate derivative that this method makes is a racemic modification, with obtaining after the condensation of tryptophyl methylamine hydrochloride is the mixture of a pair of diastereomer, must just can obtain the intermediate of required configuration through column chromatography for separation, complex operation not only, and waste raw material (one of them diastereomer can not utilize).This 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, people such as Liang WS, J.Med.Chem., 1998,41 (2): 199-223) disclose a kind of method of utilizing synthetic Ilomastat of asymmetric reaction and analogue thereof, this method is referring to following scheme:
In 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, use trifluoroacetic acid then and remove tert-butyl ester protection, esterification again, last azanol is separated and is obtained 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 provide a kind of technology of improving to be fit to amplify the novel method of macro preparation Ilomastat.
Summary of the invention
The purpose of this invention is to provide and a kind ofly improve and simplify technology, reduce cost and the novel method of the preparation Ilomastat of suitable amplification scale.
Put it briefly, the invention provides the method for the Ilomastat of a kind of preparation following formula (I),
This method comprises:
(a) with tryptophan methyl ester hydrochloride and methylamine reaction, the tryptophyl methylamine of preparation formula (II);
(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);
(c) intermediate with formula (IV) removes the tert-butyl ester, obtains down the intermediate of formula V;
(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 pairing chemical structures of reagent are as follows:
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 of operating 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 the organic solvent extraction water again, 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 to get by the methanol solution of the methanol solution of oxammonium hydrochloride and potassium hydroxide is mixed at low temperatures.
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, use dilute hydrochloric acid water transfer phase (preferably regulating pH value to 3) then, separate out precipitation, filtering precipitate, wash drying with water.
Further, in the method for the invention, described recrystallization uses methanol mixed solvent, acetate/ethyl acetate mixed solvent to carry out successively.
Specifically, the present invention realizes in the following manner: utilize asymmetric reaction to obtain Succinic Acid list tert-butyl ester derivative (III), carry out the synthetic of Ilomastat as raw material.With the tryptophan methyl ester hydrochloride is raw material, obtain free intermediate tryptophyl methylamine (II) with the methylamine aminolysis, this intermediate (II) is compared with the tryptophyl methylamine hydrochloride in the former technology, 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.
Be raw material with intermediate (II) and (III), adopting DMTMM is the preparation that condensing agent carries out intermediate (IV), and this condensing agent is with low cost, be easy to remove, and can in protic solvents such as methyl alcohol, use, help increasing 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 for use
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 technology.Intermediate (V) is dissolved in the potassium hydroxide aqueous solution of equivalent, with thorough washing waters such as organic solvent such as ether, chloroform, ethyl acetate or benzene, 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.
Methanol solution with intermediate (V) and free hydroxylamine is a raw material, adopts one step of mixed anhydride method to make the Ilomastat crude product, and 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, with dilute hydrochloric acid water transfer phase pH=3, separates out precipitation behind the organic solvent thorough washing water, filter, 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:
The tryptophan methyl ester hydrochloride adds the aqueous methylamine solution or the alcoholic solution of 3～10 times of amounts, 0 ℃～40 ℃ following confined reactions 5～24 hours, be preferably the aqueous methylamine solution that adds 5 times of amounts, 25 ℃ of following confined reactions 12 hours, with dichloromethane extraction, be preferably the continuous extraction mode that adopts then, 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, react 2～18 hours down at 0 ℃～40 ℃ in methyl alcohol, obtain intermediate (IV), and this intermediate needn't be purified, can be directly used in next reactions steps.Condensation condition is feed ratio 1: 1: 1.2 preferably, and the methyl alcohol add-on is 10mL/g (II), reacts about 12 hours down at 25 ℃.
(IV) joins CeCl with intermediate
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.With the dissolving crude product of gained (V) in the potassium hydroxide aqueous solution of equivalent, with ether thorough washing water, 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.
(V) is dissolved in ether or tetrahydrofuran (THF) with intermediate, uses isobutyl chlorocarbonate or Vinyl chloroformate activated carboxyl, and temperature of reaction is 0 ℃ to-20 ℃, and the reaction times is 2～30 minutes.In this reaction, add the methanol solution of free hydroxylamine then, continue reaction 1 hour.Reaction conditions is to be solvent with the tetrahydrofuran (THF) preferably, selects for use isobutyl chlorocarbonate-15 ℃ of following activated carboxyls 3～5 minutes.After reaction finishes, add entry and ethyl acetate, thorough mixing separates organic layer, leaves standstill, and separates out the crude product of end product Ilomastat.This dissolving crude product in the potassium hydroxide aqueous solution of equivalent, behind ethyl acetate thorough washing water, with dilute hydrochloric acid water transfer phase pH=3, is separated out precipitation.Leach precipitation, wash with water, press dry, use methanol=1: 1 and acetate 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 tangible advantage, and for example: separate with the methylamine of tryptophan methyl ester hydrochloride and directly to make the tryptophyl methylamine, this midbody compound is difficult for deliquescence, preserves easily, and is easy to use; Adopting DMTMM is that condensing agent prepares intermediate (IV), not purified next reactions steps that is directly used in of condensation efficiency height, 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; Adopting mixed anhydride method, is that ammonia is separated agent and directly made the end product Ilomastat by intermediate (V) with the methanol solution of free hydroxylamine, and used azanol methanol solution needn't filter except that Repone K.Adopt alkali molten-method of organic solvent washing-Acid precipitation adopts multiple solvent 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 embodiment, still, should be understood to, these embodiment are only used for the more detailed usefulness that specifically describes, and are used for limiting in any form the present invention and should not be construed as.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-tryptophan methyl ester hydrochloride (144.74g, 0.57mol) mix with aqueous methylamine solution (25～30%) 430mL, sealing was at room temperature 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 P very down
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)
With 2R-isobutyl-fourth-1, the 4-diacid-4-tert-butyl ester (III) (64.27g 0.28mol) is dissolved in the 600mL anhydrous methanol, add again intermediate (II) (60.82g, 0.28mol).At room temperature stirred 10 minutes, (92.90g 0.34mol), at room temperature reacted 12 hours, removed methyl alcohol then under reduced pressure, added ethyl acetate, and organic phase is used H successively to add DMTMM then
2O, rare HCl, saturated NaCl solution, saturated NaHCO
3Solution, H
2O, saturated NaCl solution washing are used anhydrous MgSO then
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 promptly 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)
(115.68g is in 0.27mol) is dissolved in the 1300mL acetonitrile with intermediate (IV), adds CeCl
37H
2(150.48g, 0.40mol) (52.47g's O 0.35mol), refluxes reactant, uses the TLC monitoring reaction, and afterreaction finished in about 15 minutes, and acetonitrile is removed in underpressure distillation, adds ethyl acetate and dilute hydrochloric acid, and extraction separates, and obtains organic phase with anhydrous Na I.Then this organic phase is used H successively
2O, saturated NaCl solution washing, ethyl acetate is removed in underpressure distillation.Add the NaOH aqueous solution 500mL (0.3mol) of 0.6M then in 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,, merge organic phase with ethyl acetate (* 3) extraction.With the anhydrous MgSO of organic phase that merges
4Drying, underpressure distillation removes and desolvates, and 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 promptly 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
2OHHCl (26.9g, 0.40mol) (22.6g, 0.40mol) mixed 10 minutes, stand-by for solution in methyl alcohol (270.0mL) and KOH by the solution stirring in methyl alcohol (107.6mL).
(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 and add N-methylmorpholine (NMM down, 39.0mL, 0.35mol), slowly drip isobutyl chlorocarbonate (42.1mL again, 0.32mol), make temperature be no more than-10 ℃.After interpolation finishes, maintain under this low temperature and reacted 5 minutes.The NH that in above-mentioned reaction, adds prepared fresh in the step (A)
2The OH/ methanol solution, reaction is 30 minutes in ice bath, at room temperature reacts 30 minutes again.Underpressure distillation removes and desolvates, and adds entry and ethyl acetate again, and concussion extraction rapidly 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 the 3.4g crude product with same operation again from above isolating aqueous phase.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 methanol (1: 1) recrystallization again, get colourless hour hand shape crystallization 48.4g.Use acetate then: 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 (10)
1, the method for the Ilomastat of preparation following formula (I),
This method comprises:
(a) with tryptophan methyl ester hydrochloride and methylamine reaction, the tryptophyl methylamine of preparation formula (II);
(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);
(c) intermediate with formula (IV) removes the tert-butyl ester, obtains down the intermediate of formula V;
(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.
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 is characterized in that: in step (c), use CeCl
37H
2O and NaI, and backflow removes the tert-butyl ester in acetonitrile.
4, method according to claim 1, carry out purifying comprising the intermediate of operating 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 the organic solvent extraction water again, separate the intermediate that obtains formula V from organic phase.
5, method according to claim 1 is characterized in that: 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).
6, method according to claim 5, the used reagent of described mixed anhydride method is selected from isobutyl chlorocarbonate and Vinyl chloroformate; The methanol solution of described free hydroxylamine is to get by the methanol solution of the methanol solution of oxammonium hydrochloride and potassium hydroxide is mixed at low temperatures.
7, method according to claim 6 is characterized in that: the methanol solution of the free hydroxylamine of gained is directly used in reaction without filtering Repone K wherein precipitates.
8, method according to claim 5 after reaction finishes, adds ethyl acetate and water in reactant, the Ilomastat of formula (I) is slowly separated out in ethyl acetate.
9, 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, use dilute hydrochloric acid water transfer phase then, separate out precipitation, filtering precipitate washes with water, drying.
10, method according to claim 1, described recrystallization use methanol mixed solvent, acetate/ethyl acetate mixed solvent to carry out successively.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435514A (en) * | 2013-08-01 | 2013-12-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Matrix metalloproteinase inhibitor and purpose thereof |
| CN105884674A (en) * | 2015-01-05 | 2016-08-24 | 南开大学 | Tryptophan derivative, preparing method and application in preventing and treating plant viruses, killing bacteria and killing insects |
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|---|---|---|---|---|
| GB0421308D0 (en) * | 2004-09-24 | 2004-10-27 | Amersham Plc | Enzyme inhibitor imaging agents |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103435514A (en) * | 2013-08-01 | 2013-12-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Matrix metalloproteinase inhibitor and purpose thereof |
| 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 |
| CN105884674A (en) * | 2015-01-05 | 2016-08-24 | 南开大学 | Tryptophan derivative, preparing method and application in preventing and treating plant viruses, killing bacteria and killing insects |
| CN105884674B (en) * | 2015-01-05 | 2019-07-26 | 南开大学 | Tryptophan derivative and preparation method and the application in terms of prevention and treatment plant virus, sterilization, desinsection |
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