CN101365683A - Process for making montelukast and intermediates therefor - Google Patents
Process for making montelukast and intermediates therefor Download PDFInfo
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- CN101365683A CN101365683A CNA2006800507838A CN200680050783A CN101365683A CN 101365683 A CN101365683 A CN 101365683A CN A2006800507838 A CNA2006800507838 A CN A2006800507838A CN 200680050783 A CN200680050783 A CN 200680050783A CN 101365683 A CN101365683 A CN 101365683A
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Abstract
A process for making montelukast, a pharmaceutically useful compound of the following formula and salts thereof: using a compound of formula (11) is provided.
Description
According to 35 U.S.C. § 119 (e), the sequence number that the application requires to submit on November 18th, 2005 is 60/737,752, the sequence number of submitting on April 24th, 2006 is 60/794,429 and be 60/824 in the sequence number that on September 1st, 2006 submitted to, the right of priority of 382 U.S. Provisional Patent Application is incorporated the full content of each provisional application into this paper by reference.
Technical field
The present invention relates to the synthetic of medicinal substance Singulair (montelukast), and relate to useful as intermediates and method in this is synthetic.
Background technology
Singulair, chemical name are [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolyl) vinyl] phenyl]-3-[2-(1-hydroxyl-1-methylethyl) phenyl] propyl group] sulfenyl] methyl] cyclopropaneacetic acid, have following formula (1) structure:
Singulair one sodium salt (Menglusitena) is generally used for treating asthma and/or seasonal allergy.Its with the form of oral tablet, chewable tablet and granule with trade(brand)name
(Merck company) list marketing.
The U.S. Patent No. 5,565,473 of BELLEY etc. (seeing also corresponding EP 0 480717) discloses the pharmaceutically acceptable compound of a class that comprises Singulair and salt thereof.U.S.5,565,473 embodiment 161 146 disclose the synthetic of Menglusitena in conjunction with the embodiments, and this synthetic method is as follows:
Here used THP represents THP trtrahydropyranyl.
U.S.5 has proposed many other synthetic schemess that are used to prepare undersaturated hydroxyalkyl quinolinic acid in 565,473, and in general described hydroxyalkyl quinolinic acid can comprise Singulair.But, do not have a kind of preparation Singulair that specifically is applicable in these other schemes.For example, U.S.5, the method B in 565,473 comprises compound and the formula R that makes " general formula (XII) "
2The organometallic compound reaction of M is to produce the compound of " general formula (Ia) ".The corresponding substituting group of application Singulair, this method will be followed following scheme and carry out, and the compound of its Chinese style (2) is the representative compounds of " general formula (XII) ",
M advises being MgBr or Li in method A.The method of the compound of unique disclosed preparation " general formula (XII) " is for the preparation Singulair, i.e. the compound of the formula (2) of preparation supposition is unsatisfactory.Specifically, in method B, this method need be carried out linked reaction with the compound of " general formula (XI) ".If be applicable to the corresponding substituting group of Singulair, then this reaction is carried out following:
But this method can not provide the as above compound (2) of the R-configuration of suggestion by Stereoselective, and the compound of R-configuration (2) is the synthetic needed of Singulair.On the contrary, only can obtain the method that racemic product and not having proposes how this racemic modification to be split into single enantiomer.
A kind of appropriate method of Singulair for preparing is from methyl compound (18).
Compound (18) is the known compound (referring to the compounds X XVII among the EP 480717) of prior art and can produces by the step 1-2 of the embodiment 146 among the EP 480717.It can be with the isolated in solid form of monohydrate.
Among the patent application No.US-2005-0245568-A1 that is to submit on March 17th, 2005, the acetyl thioester compound of formula (20)
Intermediate as the method that is used for preparing Singulair is disclosed, and can be produced by compound (18) as shown in following reaction scheme:
Described compound (20) can be chosen wantonly at it and be converted into mercaptan compound (3) by handling with hydrazine
After (more complete description is arranged in above-mentioned US-2005-0245568), with the reaction of formula (5) compound,
In the formula (5), R is hydrogen or C1-C4 alkyl, and L is the leavings group that is selected from halogen or alkyl-sulfonyloxy or aryl-sulfonyloxy, forming as US 5,565, and the compound of the formula (2) in 473, the perhaps compound of formula (2a):
Wherein, R is the C1-C4 alkyl.Thereby, when R is hydrogen in formula (5), directly formed compound (2).When R is the C1-C4 alkyl in the formula (5), then form the compound of formula (2a).L is described to ordinary representation chlorine, bromine, mesyloxy, phenylsulfonyloxy or tosyloxy.This reaction can exist under the situation of alkali and preferably take place in inert solvent under inert gas atmosphere.As US 5,565, described in 473, formula (2) and compound (2a) can be converted into Singulair or its salt with methylmagnesiumhalide usually.
Among the US-2005-0245569-A1 that is to submit on March 17th, 2005 in the disclosed a kind of alternative response path, compound (20) is carried out reaction with lithium methide in inert solvent (for example tetrahydrofuran (THF)), to form the compound shown in the following reaction scheme (6):
In next procedure, by with the compound of formula (6) and hydrazine reaction and original position forms compound (4), and it can be converted into Singulair subsequently.This reaction scheme can be expressed as follows:
A kind of alternative of the preparation Singulair that is applicable to scale operation being provided and/or improving above-mentioned the whole bag of tricks, will be ideal.Specifically, can obtain good yield and highly purified method and the method that can control reliably is important in industrial pharmaceutical chemistry.
Summary of the invention
The method that the invention provides several new compounds (comprising the new solid intermediate that is used to prepare Singulair and/or Menglusitena) and prepare and use this new compound.
Aspect first, the present invention relates to a kind of newly, (it is (3R)-{ 3-[(E)-2 (7-chloro-2-quinolyl) vinyl] phenyl }-4 to the thiolactone compound shown in the preferred solid-state formula (11), 5-dihydro-3H-benzo [c] thia
-1-ketone) and salt:
Aspect second, the invention provides the method for the compound of preparation formula (11), this method comprises following order:
This method comprises separates and the described compound of (if desired) purifying (11).
Aspect the 3rd, the invention provides by utilizing compound (11), preferably prepare the method for Singulair by the compound (11) of separation and/or purifying.Advantageously, compound (11) be used to prepare Singulair or be converted into Singulair comprise following order:
Entire method has following advantage: providing can be with the suitable intermediate of solid-state separation and purifying, and does not need deleterious hydrazine is used for from the production method of compound (20) preparation compound (4).
The 4th aspect of the present invention relates to the tosylate or the benzene sulfonate of acid salt, the especially compound (4) of compound (4).Described salt can be with solid-state, and crystal state separates typically, and this may be favourable in Singulair synthetic.
The 5th aspect of the present invention relates to be used cerium (III) compound to prevent impurity and/or impels in preparation Singulair or its intermediate, and any reaction that is taken place in the reductive methylation reaction process between methylmagnesiumhalide (for example methylmagnesium-chloride, methylmagnesium-bromide or iodate methyl magnesium) and the ester group is finished.Such reaction comprises makes above-mentioned formula (20), (11), (2) or compound (2a) and methylmagnesiumhalide reaction.For the reaction of these types, the trivalent cerium compound, especially the existence of cerous compounds may be favourable.
The 6th aspect of the present invention relates to the compound of following formula (5b):
Wherein, R is the C1-C4 alkyl of straight or branched and is preferably methyl.This compound can be used for preparing in the multiple synthetic method of Singulair.
The 7th aspect of the present invention relates to acid salt, especially hydrochloride and the benzene sulfonate of the compound of formula (20).This acid salt can be used for the purifying of compound (20).
The 8th aspect of the present invention relates to the method that is used for purification of montelukast acid, at least one during this method comprises the following steps:
I) pass through the toluene solution that polar adsorbent (for example silica gel) filters montelukast acid, and optional this Singulair Acid precipitation that makes; And
Ii) under the lucifuge condition, make montelukast acid crystallization from protonic solvent (for example ethanol).These two steps can be used in combination and/or single step can be repeated one or many.
Unless otherwise indicated, otherwise compound that relates in this specification sheets or chemical formula comprise its base addition salt and acid salt.And the speech " isolating " that uses is meant target compound is separated so that reclaim the more target compound of conc forms from its environment of at least a portion in full.Usually, separating step relates to phase detachment technique, and target compound preferentially obtains mutually with a kind of in being separated, thereby easier of more conc forms recovery.The conventional example of isolation technique comprises precipitation and/or crystallization (for example, solid-liquid separates), evaporates or distills out all or part of solvent (for example solution-air separation), liquid-liquid phase separation (for example being undertaken by extraction or decantation) etc.Can and usually have purification effect really though separate, do not require that impurity itself is reduced or removes.
The raw material that is used to prepare compound of the present invention (11) is the compound of formula (20), and it can obtain by the method from methyl compound (18) beginning shown in the following reaction scheme:
Compound (18) is a kind of compound known.It can be with the isolated in solid form of monohydrate.Because compound (18) is a kind of completely specified solid matter, so it is a kind of fit closely raw material for whole Singulair synthetic.
The appropriate method that is used for compound (18) is converted into compound (20) comprises following order:
In a first step, at first the OH-group in (18) is become unstable by being translated into reactive group L (for example alkyl-sulfonyloxy or aryl-sulfonyloxy (preferred mesyloxy)).Product is the compound of general formula (19) and by being preferably the compound (19a) that carries mesyloxy:
Described methylsulfonyl reaction comprises contacts compound (18) with methylsulfonyl chloride in inert solvent under the situation that has suitable alkali (for example, the tertiary amine such as triethylamine).
Then by in inert solvent, reacting and unstable compounds (19) being converted into acetyl thioester compound (20) with thioacetic acid or its salt (for example sodium thioglycolate or thioacetic acid potassium).If then also should there be alkali (for example triethylamine) usually in the use thioacetic acid.Like this, unsettled L group is by CH
3-CO-S-group substitutes.This reaction is carried out in suitable inert solvent (for example toluene, dimethyl formamide or its mixture) usually, and usually near and comprise under the temperature (for example 0-60 ℃) of envrionment temperature and carrying out.
Behind the described reaction mixture of conventional aftertreatment, usually compound (20) is separated with free alkali form, it is a kind of oily product.Yet the present inventor finds that described alkali (20) can be converted into acid salt though be a kind of very weak alkali, and the number acid additive salt can be with the solid chemical compound isolated in form.With regard to this one side, preferred salt is hydrochloride (20a) and benzene sulfonate (20b):
What be fit to equally is tosilate (20c) and vitriol (20d).Compound (20) there is purification effect usually with isolated in solid form, because there are many by products to remain in the described reaction mixture.And, the optical purity the when optical purity of described separated product is separated with free alkali form usually above compound (20).
Described acid salt can prepare by compound (20) is contacted with corresponding acid in suitable solvent (for example C2-C8 aliphatic ketone for example acetone, C2-C8 aliphatic ester ethyl acetate, C1-C4 fatty alcohol Virahol, C2-C6 aliphatic amide dimethyl formamide and composition thereof for example for example for example).The contact temperature can be from-20 ℃ to solvent boiling point.This salt spontaneously precipitates usually and can separate at ambient temperature or at (usually under 0-35 ℃) under the temperature near envrionment temperature.With acid salt and after preferably separating with hydrochloride (20a), product can have 99% chemical purity or and 98% or higher optical purity at compound (20).
The salt of isolated compound (20) can be converted into free alkali again or be used for next reactions steps with the form of salt.Total advantage of these steps is: described compound (20) is with solid, stable and isolated in form that can fine processing, and the separation of described salt provides the possibility of purifying compounds (20) before the reactions steps below.Therefore, hydrochloride (20a) and benzene sulfonate (20b) have formed a special aspects of the present invention.
Described compound (20) or its acid salt can be converted into midbody compound (11) then.This conversion is usually by finishing compound (20) and methylmagnesiumhalide (preferred methylmagnesium-chloride, methylmagnesium-bromide or iodate methyl magnesium) reaction.Usually, this is reflected in the inert solvent (for example toluene) of the ethereal solution of the methylmagnesiumhalide with 2-3 molar equivalent and carries out.Temperature of reaction should be no more than 10 ℃ and preferably between 0 ℃ and 5 ℃ usually, but can use higher temperature, last stages that especially should reaction.Reaction times is preferably 1 to 6 hours.Reaction process can be monitored by suitable analytical technology (for example passing through HPLC).After this reaction is finished, reaction mixture handled by water (preferably using acidifying water, for example Xi Shi acetate) carries out aftertreatment, with product preferably with organic solvent extraction and with described separated from solvent.
If desired, technology by any appropriate of the solid crude product (11) that obtains like this (for example by crystallization or pass through column chromatography) can be further purified, to obtain the purity of desired level.Advantageously, compound (11) can pass through crystallization from solvent and purifying, and described solvent contains cyclic ethers liquid (for example tetrahydrofuran (THF) Huo diox) and is selected from second kind of mixtures of liquids of C1-C4 alcohol (for example methyl alcohol or ethanol), C2-C6 ester (for example ethyl acetate), C4-C8 hydrocarbon (for example toluene), C3-C8 ketone (for example acetone) and composition thereof.Described crystallization can be finished by the following method: (i) described compound (11) is dissolved in the solvent mixture of heat, with this solution of postcooling, (ii) by adding described second kind of liquid as anti-solvent to the cyclic ethers liquor of compound (11), the perhaps (iii) combination by these cooling technologies and anti-solvent technology.Alternately, purifying can be finished with the form crystallization of acid salt by making compound (11).Generally speaking, compound (11) is formed salt with organic acid or mineral acid treatment or with its merging.For example, contact formation hydrochloride (11a) with hydrochloric acid:
Described salt, and preferably salt hydrochlorate (11a) can separate from reaction mixture with solid-state, thus most of by product and residual reagent are retained in the mother liquor.This salt can be by handling with suitable organic bases or mineral alkali and be converted into free alkali again, thereby obtained the more compound of high level of purity (11), although do not need this step for the reactions steps of carrying out the back.
Advantageously, compound (11) has at least 90% chemical purity and/or optical purity and can even show 98% purity or higher.
Hydrochloride shown in the formula (11a) has formed a special aspects of the present invention.Product (11), especially its salt (for example (11a)) can store under the condition of storage of routine and can not diminish quality, and this is particularly advantageous on technical scale.
In following step, compound (11) is converted into Singulair.In a typical scheme, intermediate or its salt shown in this method through type (4) carry out:
Compound (11) is chosen wantonly under the situation that has inertia cosolvent (for example toluene), in ether solvents (for example tetrahydrofuran (THF)), prepared compound (4) with methylmagnesiumhalide (being methylmagnesium-chloride, methylmagnesium-bromide or iodate methyl magnesium) processing.The methyl magnesium reagent of at least two molar equivalents is essential, but advantageously can use the 3-8 equivalent.Temperature of reaction is usually in-15 ℃ to 15 ℃ scope.
The impurity that has been found that serious amount appears in this reactions steps.This impurity is the ketone shown in the formula (12):
It is the primary product of the ring-opening reaction on the compound (11).People may expect that this ketone will react with next normal methylmagnesiumhalide and form the required tertiary alcohol (4), even but have the excessive methylmagnesiumhalide of big mole number and prolonging under the situation about handling, this reaction also just takes place to a certain extent and has this ketone of 10-20% to be retained in this reaction mixture usually.In theory, this is that this has stoped this compound further to react because described compound (12) is easy to enolization.Yet, the formation that has been found that compound in reaction mixture (12) can minimize to this reaction mixture by adding cerium (III) salt (for example cerous compounds), described cerium (III) thus salt has suppressed enolization and has caused compound (12) to transform more completely.Advantageously, described cerium (III) salt can be activatory cerium (III) salt.The activity of cerium (III) salt can be by for example cyclic ethers (for example tetrahydrofuran (THF)) is nursed one's health or incubation strengthens with ether solvents before it uses with this salt.Owing to this conditioning demonstrates the active cerium of enhanced (III) salt is " activatory cerium (III) salt ".Advantageously, cerium (III) salt is added in the solution or suspension of cyclic ethers (preferred tetrahydrofuran (THF)), by this before using this reagent, this salt and cyclic ethers have been in contact with one another at least 4 hours, be typically at least 8 hours, and be in contact with one another at least 12 hours in some embodiments.Like this, the activity of cerium (III) salt is fully strengthened, and makes to use " activatory cerium (III) salt ".In the situation of methylmagnesium-chloride or methylmagnesium-bromide, the existence of observing activatory cerium (III) salt is even more important, because this two kinds of halogenide otherwise low-down transformation efficiency can be provided.The amount of described cerium compound is at least 1 molar equivalent, and 2-4 molar equivalent advantageously.By utilizing cerium (III) salt, and preferably use activatory cerium (III) salt, the amount that is retained in the ketone compound (12) in the reaction mixture can be lower than 5% and even be lower than 1%.Reaction process can be monitored by suitable analytical procedure (for example passing through HPLC).
After conventional aftertreatment (with the magniferous complex compound of acidifying water decomposition), the compound in the inert solvent (4) solution can be used for next reactions steps immediately or can evaporate inert solvent earlier.Yet, in general, with compound (4) as described in greater detail below with the isolated in form of salt.
In an alternative method, described compound (4) also can come directly not need separating compound (11) from compound (20) preparation by using quite superfluous methylmagnesiumhalide (especially iodate methyl magnesium).This method proposes in CN 1420113 A.In this method, produced the same problem of ketone impurity (12), because this impurity also forms with sizable amount (5-10%).Have been found that cerium (III) salt (for example cerous compounds) and preferred activatory cerium defined above (III) salt can be used to activate methylmagnesiumhalide.Like this, the amount of described ketone impurity reduces to minimum and described method unexpectedly and is significantly improved.In addition, methylmagnesium-chloride or methylmagnesium-bromide can be used for this reaction after this modification, and the iodate methyl magnesium reacts because only observed in CN1420113 under the disclosed condition.
Compound (4), when above-mentioned synthetic method prepares arbitrarily, usually cannot be as alkali with solid-state separation.Therefore, its purifying (no matter when needing) is debatable.Yet compound (4) can be converted into acid salt, and it is a crystal.By be settled out crystalline salt from reaction mixture, total purity of compound (4) is improved, because many by products, and especially described ketone impurity is retained in the solution.
The salt of the suitable compound (4) that can go out with solid precipitation is hydrochloride (4a), tosylate (4b) and benzene sulfonate (4c):
In a favourable pattern, salt and the especially compound (4a) of compound (4), (4b) or (4c) can react with the respective acids of a great deal of at ambient temperature and with solid-state preparation by compound (4) solution in will (for example) toluene.Can add subsequently and induce or promote sedimentary anti-solvent (for example ethyl acetate) to improve this method.
In an example, the compound of initial 80% purity (4) can be brought up to the sedimentary tosylate (4b) or the benzene sulfonate (4c) of 96% purity by this simple method.Particularly, unwanted ketone impurity can be removed from product like this.
In addition, described salt is to be used for long-time storage compounds (4) and the appropriate means of not decomposing (compound (4) itself be very unstable compounds) substantially.With regard to this one side, compound (4b) and (4c) especially suitable separates because they can be used as stable crystalline substance.In addition, salt (4a), (4b) and (4c) can be used as analytical standard, the reaction process that is used to monitor the quality of compound (4) and/or utilizes compound (4).
For other step in the method that produces Singulair, described salt can be by easily being converted into compound (4) with suitable alkali neutralization again, and perhaps it can use with the form of salt.In next procedure, make compound (4) (as alkali and/or as its salt) stand reaction with the compound of following formula (5):
R can be hydrogen or C1-C4 alkyl in the compound of formula (5), and preferably methyl or ethyl.Leavings group L can be that halogen is or/and alkylsulfonyloxy or aryl-sulfonyl oxygen.
Mercaptan intermediate (4) particularly relates to thiol group and is oxidized to the disulphide group if be not converted into salt then be highly susceptible to taking place spontaneous side reaction.Therefore, no matter when use alkali (4) after cleavage step, the compound of formula (5) should add in the short period of time after it so that reduce impurity/by product; Generally in 3 hours, add and typically in 1 hour, add.Similarly, be alkali, then should carry out at once relatively after this transforms again with the reaction of compound (5) if compound (4) is converted into salt and goes back to again.This selection of time problem is not too important concerning the salt of compound (4), itself in addition can be provided with the back with solid-state storage and use.This more stable while of class side reaction of the salt pair of compound (4) still keeps reactivity enough and compound (5) reaction.In practice, if compound (4) is used with the form of its alkali, then with its dissolution in ether solvents (for example tetrahydrofuran (THF)).
Usually, alkaline hydrated oxide or alkoxide (for example lithium hydroxide or sodium methylate) are used as alkali in the nucleophilic substitution of compound (5) side chain.This reaction is carried out in solvent usually, normally a kind of solvent mixture that contains alcohol of described solvent, for example methyl alcohol/acetonitrile mixture or methyl alcohol/tetrahydrofuran compound.This reaction is carried out under the atmosphere of rare gas element (for example nitrogen or argon gas) usually.The side reaction that the combination of above-mentioned condition is used to make unwanted thiol group be transformed into the disulphide group minimizes.
In the patent application of the announcement of formerly mentioning, the compound that preferably is used to prepare the general formula (5) of Singulair is the bromo-ester of following formula (5a):
Yet the present inventor finds that this compound has experienced serious side reaction under required reaction conditions, particularly resets, and has produced the New cyclobutane derivative of ring structure (5-1), usually then is the product of structure (5-2) open loop.
The reactivity of these two kinds of by products is similar to compound (5a) itself, thereby has produced a series of and the impurity Singulair structurally associated, has only gruellingly just described impurity to be removed from required product.
With regard to this on the one hand with regard to, be used for the preferred reagent of Singulair synthetic and be formula (5b) to anisole sulphonyl oxygen compound,
Wherein, R ' is the alkyl of C1-C4 straight or branched and methyl preferably.
Existence to methoxyl group in this molecule provides to electronic effect, and this effect is high enough to the stability that realizes desired improvement, and enough is low to moderate the reactivity of having kept with the reaction gamete of expecting.
Methyl esters [(5b), the R=methyl] have and the corresponding similar chemical stability of bromo-compound (5a), but it is more stable than (for example) similar mesyloxy compound, tolysulfonyl oxycompound or phenylsulfonyloxy compound (to such an extent as to they so instability have only gruelling they could separation).This compound has lower proneness to the rearrangement and the ring-opening reaction of the bromo-compound shown in top.And it is fine detection under the UV-light of conventional wavelength 254nm, and this can be used for utilizing ultraviolet detection to monitor reaction process by HPLC.Therefore, the methyl esters of described compound (5b) and especially compound (5b) has formed a special aspects of the present invention.
Compound (5b) can be by any means production that is used to prepare the compound of general formula (5) as known in the art.Particularly, it can pass through the compound with following formula (15):
Wherein, R is the C1-C4 alkyl, produces according to following scheme reaction under the situation that has alkali (preferred pyridine) with to anisole sulfonic acid halide (particularly to the anisole SULPHURYL CHLORIDE):
It can be used for preparing in any method of Singulair, promptly not only can be used for the present invention in the reaction of preferred formula (4) compound, and (for example) also can be used in the method for compound as the reaction gamete with formula (2) or (3).
When the product with compound (5) reaction was the ester cpds of formula (1a), it transformed by hydrolysis usually required Singulair compound (1) is provided,
Wherein, R is the C1-C4 alkyl, and methyl normally.Preferred hydrolysising condition comprises alkaline hydrolysis.Advantageously, hydrolysis directly takes place in reaction mixture after compound (4) and compound (5) coupling.In order to realize this process, reaction mixture contains the water of equimolar amount at least (its can add or can be just to exist originally).
The end product of this method is a montelukast acid.Itself can be used for pharmaceutical application at (for example solid form), and is open among this U.S. Patent Publication US-2005-0107426-A1 that has been to submit on October 8th, 2004.Alternately, montelukast acid can be converted into different salt by currently known methods, wherein sodium salt is preferred.
Should comprise following important observation phenomenon:
A) other method that acts on the preparation Singulair that wherein methylmagnesiumhalide is used for reductive methylation on the ester group of cerium (III) compound also is important.For example, compound (2) disclosed with mentioned above is converted into the Singulair shown in the formula (1) and may suffers identical problem in disclosed patent application US-2005-0245568-A1 early, has promptly formed the stable ketone-intermediate that has formula (13) and (14) respectively:
And it can form impurity in required product.It is minimized method on a kind of quality entity that makes this impurity in the Singulair that cerous compounds (and preferred activatory cerous compounds) is added in the methylmagnesiumhalide.
B) make the minimum importance of by product (especially compound (12)) in the reaction process of Singulair produced according to the present invention, can carry out becoming apparent with this discovery of the essentially identical reaction path of main agents according to the by product shown in the formula (12).Therefore, no matter when exist as the impurity in the compound (4), it also all reacts with compound (5), and forms the impurity shown in the formula (13), is generally the methyl esters shown in the formula (13a):
After saponification generates montelukast acid under normal condition, it also saponification form the impurity shown in the formula (14), be difficult to this impurity is removed from producing the Singulair eventually.
Be further noted that in a word, fundamentally, methylmagnesiumhalide all may be faced the problem of the corresponding ketone-impurity that forms the compound that is similar to above-mentioned formula (12) as the production method that reagent any with ester group is used to prepare Singulair, and especially form the problem of compound (13) and (14).Therefore, must monitor the compound (12) of this reaction process, the existence of (13) and/or (14), and must take adequate measures to suppress their formation.A kind of such measure is illustrative cerium (III) salt to be added in the methylmagnesiumhalide as top, can not find other method but do not get rid of also, comprises purification process.Therefore, compound (12), (13) and (14) itself are useful chemical products, because they can particularly be used as reference standard from compound (20) when beginning to prepare in monitoring Singulair preparation method's step.Thereby, the method that is prepared Singulair by compound (20) can come advantageously to improve in such a way: the compound (12) of the production stage that monitoring is relevant (for example being used for step with the methylmagnesiumhalide reaction with compound (20), (11), (2) or (2a) as substrate), the suitable member's of (13) and (14) this group existence, and do not begin ensuing reactions steps, unless the content of this related compound is lower than described limit, this limit can be to be lower than 5%, but preferably is lower than 1%.Therefore, aforesaid method (have or do not have monitoring) can provide, and preferably provide really the content of any impurity (12), (13) and/or (14) be lower than 1% and/or chromatographic purity greater than 99% Singulair.Such high purity is favourable in drug manufacture.
Because several aspect of the present invention can be used for not relating to other relevant Singulair synthetic of the thiolactone compound shown in the formula (11), following schema has been illustrated the broad applicability to multiple synthetic schemes such as for example use of cerium salt, the use of compound (5b), the purifying of compound (20), the monitoring of some kind impurity, and all these is considered to part of the present invention.
It should be understood that shown reagent is not enforceable and does not illustrate all steps or condition.And, though all compounds are to be derived from compound (20) in this scheme, but in practice, many midbody compounds (for example compound (4) and (2)) can (for example) by general method of instructing in document Belley etc. from other feedstock production.
In case Singulair forms, usually expectation is purified acceptable quality to (for example) pharmacopedics.Usually, with montelukast acid purifying before it is converted into sodium salt.It is easier and more effective at the purification ratio in this stage final Menglusitena to be carried out purifying.Known montelukast acid can be converted into salt with dicyclohexylamine, and this thus conversion demonstrates purification effect.Yet the present inventor finds effectively this montelukast acid crude product of purifying and does not need to be translated into salt.The method of this improvement comprises at least one in the following step:
I) by the toluene solution of polar adsorbent (for example silica gel) filtration montelukast acid, optional then with its precipitation, and
Ii) crystallization from protonic solvent (for example ethanol) under the lucifuge condition.
Toluene is a kind of favourable solvent of crystalline that is used for, because opposite with many other solvents, it can on two keys cis-trans isomerization not take place basically.Polar adsorbent has effectively been removed oxidation products, and described oxidation products especially forms when unsettled intermediate (4) is used for this building-up process.Alcoholic solvent has been removed the by product that is produced by compound (4) and (5) condensation effectively, especially passes through the product of the rearrangement formation of cyclopropane ring.Lucifuge minimizes cis-trans isomerization.
Advantageously, these two steps are all implemented in purge process.When utilizing more than a step, described step can use in order and arbitrary steps can repeat one or many with any.Like this, can obtain greater than 99%, and even greater than the Singulair of 99.5% purity.
Singulair can be montelukast salt, for example sodium salt by known technical transform.Useful solid-state form for MONTELUKAST sodium salt is an amorphous form.It can pass through Menglusitena and aliphatic C
5-C
10The varsol of straight or branched (for example sherwood oil, hexane, heptane and composition thereof) contact, and be settled out unbodied Menglusitena and prepare.The normally preferred solvent of normal heptane.Usually, (at least) with process that Menglusitena contacts in stir solvent.In a favourable pattern, montelukast acid is converted into Menglusitena as follows: it is contacted with sodium hydroxide or sodium alkoxide in the mixable organic solvent of water, remove this solvent afterwards, and enriched material (it is liquid or oily matter normally) slowly added in the hydrocarbon liquid of stirring, be settled out unbodied Menglusitena thus.Temperature of precipitation is envrionment temperature advantageously.
Embodiment
Further the present invention is described by following limiting examples.
Unless in whole specification sheets and opposite indication is arranged, in all chemical formulas, it is identical with configuration in the Singulair to be connected to two key had two substituent configurations of non--hydrogen of 7-chloro-2-quinoline ring.
Embodiment 1-compound (11)
Step 1-compound (20)
With 500 gram 2-((3S)-3-[2-(7-chloro-2-quinolyl)-vinyl]-phenyl)-3-hydroxypropyls)-methyl benzoate monohydrate [compound (18)] places reactor and adds 3000 milliliters of toluene.Component distillation goes out the mixture (800 milliliters) of toluene.Then this toluene solution is cooled to room temperature.This solution contains 480.11 gram anhydrides (18).
At room temperature 227.0 milliliters of triethylamines are added in this solution and and are added drop-wise in this solution so that temperature of reaction is no more than 40 ℃ with 110.2 milliliters of methylsulfonyl chlorides.Subsequently reaction mixture was stirred 1 hour down at 25-30 ℃.Then, 605 milliliters of triethylamines are added in this reaction mixture, add 156 milliliters thioacetic acid at room temperature 5 minutes afterwards.Subsequently this reaction mixture is heated to 40-45 ℃ and continues 3.5 hours.Adding 1000 ml waters stirred 15 minutes to this reaction mixture and with it.Separating layer distills most of toluene with organic layer with the washing of 2 * 1000 mL of saline and by vacuum distilling subsequently.The solution that obtains filtered and the toluene of remnants is evaporated to drying on rotatory evaporator, produce the orange-brown oily resistates of crude compound (20).
Yield is: 588 grams (104.3%)
Step 2-compound (11)
Under argon gas, operate
Digesting compound (20) (from the crude product of embodiment 1) with 24.40 is dissolved in 260 milliliters the dry toluene (distilling acquisition from benzophenone/Na).Solution is cooled to 0-5 ℃ (ice/water-bath).MeMgI in 41 milliliters of diethyl ether is added drop-wise in this solution so that temperature is no more than 5 ℃ (during 20 minutes).Reaction mixture is stirred and be cooled to 0-5 ℃.By HPLC monitoring reaction.Termination reaction and follow exterior cooling slowly to add 200 ml waters after 4.5 hours.Subsequently with reaction mixture with 12 milliliters of Glacial acetic acid acidifyings.Separating layer is also with 100 milliliters of toluene aqueous layer extracted.Organic extract is merged, and dry on sal epsom.Filter this mixture and, produce 25.52 gram crude compounds (11) solvent evaporation extremely dry (45 ℃ of heating baths).
1H NMR (solvent: CDCl
3, magnetic field [MHz]: 400)
Embodiment 2-compound (11)
Under argon gas, operate
Digesting compound (20) with 24.50 is dissolved in 180 milliliters the dry toluene (distilling acquisition from benzophenone/Na).Solution is cooled to 0-5 ℃ (dry ice/water-bath).41 milliliters of 3 M MeMgCl among the THF are added drop-wise in this solution so that temperature is no more than 5 ℃ (during 30 minutes).Reaction mixture is stirred and be cooled to 0-5 ℃.Do not observe precipitation.By HPLC monitoring reaction.Muddy-slight precipitation that reaction mixture becomes.Termination reaction and follow exterior cooling slowly to add 100 ml waters after 3 hours.Subsequently with reaction mixture with 3 milliliters of Glacial acetic acid acidifyings to pH=4-5.Separating layer, and with organic extract at anhydrous magnesium sulfate
Dry.Filter this mixture and, produce 20.05 gram thick thiolactone (11) alkali solvent evaporation extremely dry (45 ℃ of heating baths).
HPLC-evaporation back-80.69%
Embodiment 3-compound (11a)
2.586 gram thiolactones (11) are dissolved under 40 ℃ in 18 milliliters of toluene.Solution is cooled to room temperature and stirs the moisture HCl that adds 7.1 milliliters of 1M.At room temperature stirred this mixture 2 hours.The precipitated solid material is passed through isolated at suction and also at room temperature dry with 5 milliliters of toluene wash.
HPLC：95.43％
Yield is: 1.43 grams (63%).
Embodiment 4-compound (11a)
2.182 gram thiolactones (11) are dissolved under 40 ℃ in 15 milliliters of toluene.Solution is cooled to room temperature and stirs the moisture HCl that adds 10 milliliters of 1M.Thick precipitation appears, therefore with mixture with 5 milliliters of dilution with toluene.At room temperature stirred this mixture 2 hours.The precipitated solid material is passed through isolated at suction and also at room temperature dry with 5 milliliters of toluene wash.
HPLC：87.56％
Yield is: 1.48 grams (77.26%).
Embodiment 5-compound (11)
Moisture NaHCO with 9.6 milliliter 5%
3Solution is placed in 25 ml flasks and adds 10 milliliters of toluene.Stir this mixture and digest compound (11a) portioning and add 1.43.This suspension is heated to 40 ℃ (being heated to 42 ℃ oil bath) 1.5 hours (all solids material dissolves fully).Separating layer is also with 5 milliliters of toluene aqueous layer extracted.Toluene extract is merged and drying on anhydrous sodium sulphate.Filter this mixture and solvent evaporation to dry (45 ℃ of heating baths) produced foamed brown solid material.
Yield is: 0.132 gram (89.90%)
HPLC：91.93％
Embodiment 6-compound (4)
Under argon gas atmosphere, operate
The 0.450 pulverous anhydrous cerium chloride of gram (III) is mixed with 1.44 milliliters of anhydrous THF and this mixture was at room temperature stirred 16 hours.Subsequently this mixture is cooled to 0 ℃ of MeMgCl (3M THF solution) that also drips (during 5 minutes) 0.96 milliliter.Stirred this mixture 2.5 hours down at 0 ℃.Simultaneously, 0.234 gram thiolactone (11) is mixed with 7 milliliters of dry toluenes, and this mixture heating up to 60 ℃ is dissolved until all solid matters.This solution is cooled to room temperature and drops to (in 5 minutes) subsequently under 0 ℃ to the mixture of organometallic reagent.Stirred reaction mixture also is cooled to 0 ℃.The reaction progress is monitored by HPLC:
After 50 minutes: R
T=13.12 minutes-94.54%
After 1 hour, stop this reaction, and follow exterior cooling its moisture HCl cancellation of 2.5 milliliters 1M with pH=4-5.Color by orange become light yellow.This mixture at room temperature stirred 15 minutes and allow layer separate.Ethyl acetate extraction water layer with 2 * 10 milliliters.Wash with the organic extract merging and with 10 mL of saline and with 10 milliliters of saturated sodium hydrogen carbonate solutions.Use the dried over sodium sulfate organic layer subsequently.Mixture is filtered and go up solvent evaporated and produce part crystalline yellow residue at rotatory evaporator (being heated to 45 ℃ bath).
Yield is: the thick material of 0.23 gram (93%)
Embodiment 7-compound (11a)
Step 1
Compound (20) (254.3 gram) is dissolved in the dry toluene (1870 milliliters).This solution is cooled to 0-5 ℃.3M MeMgCl solution (420 milliliters) in the tetrahydrofuran (THF) is dropped in compound (20) solution so that temperature is no more than 5 ℃ (during 40 minutes) by dropping funnel.Reaction mixture is stirred and be cooled to 0-5 ℃.By HPLC monitoring reaction.
After 3 hours, stop this reaction and follow exterior cooling slowly to be added to (foaming) in the reaction mixture in Glacial acetic acid (72 milliliters).End to cool off and reaction mixture was stirred 10 minutes.Subsequently with its water (500 milliliters) dilution and at room temperature stirred the mixture that obtains 15 minutes.Store in dark flask with layer separation and with organic extract.With it without being further purified or separating and be used for following step.
Step 2:
Dense HCl (54 milliliters) slowly is added in the thiolactone alkaline solution of preparation in the step 1.Mixture was at room temperature stirred 1.5 hours and stirred 1 hour in addition down at 0-5 ℃ then.The precipitated solid material is washed with toluene (2 * 150 milliliters) by isolated at suction and with filter cake.Thiolactone hydrochloride solid is at room temperature dry.
Embodiment 8-compound (4)
In the exsiccant glass device, under argon gas, operate.
The pulverous anhydrous cerous compounds of 2.15 grams is suspended in 6.90 milliliters of anhydrous tetrahydro furans, and this mixture was stirred 19 hours under laboratory temperature.This white suspension is cooled to 0 ℃ and be added dropwise to 2.91 milliliters of 3M methyl chloride magnesium solutions (4.5 equivalent) in the tetrahydrofuran (THF).With this mixture 0 ℃ stirred 1.5 hours down and during 20 minutes, be added dropwise to 1.00 in 14.60 milliliters of dry toluenes digest compound (20) (purity 87%, 1.938mmol).This mixture was stirred 265 minutes and was placed on then spend the night in the refrigerator (8 ℃) (19 hours) down at 0 ℃.When finding that by HPLC this reacts incomplete, be added dropwise to 1.94 milligrams 3M methyl chloride magnesium solution (3 equivalent) in the tetrahydrofuran (THF).Next this mixture was stirred 2.5 hours down at 8 ℃.
15 ml waters are added under 8 ℃ in the reaction mixture also with this mixture stirring 15 minutes.The pH value is adjusted to 4-5 with Glacial acetic acid (about 4 milliliters), filters this mixture, extract waterbearing stratums with the filtrate layers separation and with 10 milliliters of toluene.With the organic layer dry and filtration on anhydrous sodium sulphate that merges.
Concentrate toluene solution at last.
Yield is: 1.10 grams
Embodiment 9-compound (4b)
The toluene solution of compound (4) is begun to prepare from the compound (20) of 8.5mmol according to embodiment 8.
Dividing several parts with tosic acid monohydrate (1.5 gram) under room temperature and stirring is added in this solution (about 100 milliliters).At room temperature stirred this mixture 1 hour.Add 25 milliliters of ethyl acetate and next stirred this mixture 20 minutes.
Wash with 10 milliliters of ethyl acetate by solid collected by filtration and with it.
Yield is: 2.75 grams, 96% purity.
Embodiment 10-Singulair (compound (1))
1.00 gram tosylates (4b) are suspended in the mixture of 5.00 milliliters of anhydrous tetrahydro furans and 13.00 ml methanol.Then, add 0.42 and digest compound (5a).In 3.0 ml methanol 0.251 gram sodium methoxide solution was added drop-wise in 40 minutes in this mixture of stirring under 20 ℃.Under laboratory temperature, stirred this mixture 21.5 hours.Then, adding the gram of 0.31 in 1.5 ml waters sodium hydroxide at once also heats this mixture 105 minutes down at 55 ℃.Add 10 milliliters of toluene subsequently and on rotary vacuum evaporator (50 ℃), remove volatile solvent (methyl alcohol, tetrahydrofuran (THF)).Add 6 ml waters and the pH value is adjusted to 5 with 0.5 milliliter of Glacial acetic acid.Also allow it leave standstill in 15 minutes then this mixture stirring and be used for layer separation.Toluene with 2 * 10 milliliters under argon gas extracts the waterbearing stratum.
Concentrate the organic layer that merges, add 5 milliliters of methylene dichloride and once more that it is concentrated.Resistates is mixed with 10 milliliters of toluene, be heated to 35 ℃, the crystal inoculation of usefulness Singulair also kept 20 hours under this temperature.With mixture being cooled to 20 ℃ of after-filtration, with the toluene wash of solid matter with 2 * 2 milliliters.With solid crystallized product 20 ℃ of following lucifuge dryings.
Yield is: 0.47 gram.Purity (HPLC) is 96.93%.The content of ketone compound (14) is 0.03%.
Embodiment 11-compound (4)
98 gram anhydrous cerium chlorides (III) are mixed with 370 milliliters of anhydrous tetrahydro furans and with this mixture 20-25 ℃ time stirring 13 hours.Then this mixture is cooled to 0-5 ℃, and in 5 minutes, is added dropwise to 132 milliliters of 3M methyl chloride magnesium solutions in the tetrahydrofuran (THF).Under 0-5 ℃, stirred the mixture 2.5 hours.
Independently, with 50.5 digest compound (11) place 2 liters flask and with its 20-25 ℃ of following stirring and dissolving in 550 milliliters anhydrous tetrahydro furan.The mixture that subsequently this solution is cooled to-10 to-15 ℃ of Cerium II Chloride/methylmagnesium-chlorides of refrigerative in advance that also will prepare had been added to during 3 minutes under-10 ℃ to-15 ℃ in compound (4) solution.Under HPLC control, stirring this mixture under the identical temperature and termination reaction after 50 minutes.Under-5 to 0 ℃, 36 milliliters of glacial acetic acid solutions in 250 ml waters slowly were added in 2 minutes in this reaction mixture and at room temperature stirred this mixture 15 minutes.Separating layer is also with 100 milliliters of tetrahydrofuran (THF)s washing waterbearing stratums.With the organic extract that merges with 3 * 100 milliliters of saturated moisture NaHCO
3With with 200 milliliters salt water washing, with dried over mgso and filter, obtain 950 milliliters of compound (4) solution in the tetrahydrofuran (THF).Purity is: 96.00% (HPLC, IN)
The solid peracid additive salt of embodiment 12-(20)
A) compound (20a)
With 152 digest compound (20) and 457 the gram ethyl acetate mix and with this mixture heating up to 65-70 ℃.Gas HCl (at least one molar equivalent) bubbling is fed in the solution that stirs (NB. alternately also can use the saturated HCl solution in ethyl acetate, ethanol or the Virahol).The suspension that obtains is cooled to 0-5 ℃ and stirred 2 hours.The crystal that forms is washed by filtering separation and with cold ethyl acetate.Crystal is under reduced pressure following dry 12 hours in 60 ℃.Yield is: 153 gram yellow crystals, fusing point is 168 ℃.
B) compound (20b)
With 15.6 digest compound (20) and 24 the gram acetone be heated with stirring to 30-40 ℃.5.3 gram Phenylsulfonic acids are added in this solution.After about 3 minutes, begin the crystal of emanating out.This suspension is cooled to 25 ℃ and stirred 30 minutes.Solid product is passed through filtering separation also with cold washing with acetone.Crystal is under reduced pressure following dry 12 hours in 60 ℃.Yield is: 9 gram yellow crystals, fusing point is 96-97 ℃.
C) compound (20c)
Digest compound (20) with 17.9 and be suspended in the mixture of 16 gram acetone and 47 gram Virahols, and this mixture is heated with stirring to 60 ℃.Add 7.3 gram tosic acid monohydrates, the mixture that obtains is cooled to 25 ℃ and stirred 8 hours.Crystal is restrained cold washed with isopropyl alcohol by filtering separation and with 20.Crystal is under reduced pressure following dry 12 hours in 60 ℃.Yield is: 12.4 gram yellow crystals, fusing point is 78.5 ℃.
D) compound (20d)
With 17.2 digest compound (20) and 120 gram acetone mix and, under agitation slowly add 3.7 and restrain 98% sulfuric acid.This mixture is cooled to 25 ℃.Solid product is restrained cold washing with acetone by filtering separation and with 20.Crystal is under reduced pressure following dry 12 hours in 60 ℃.Yield is: 4.1 gram yellow crystals, fusing point is 90 ℃.
Embodiment 13-compound (5b) [R=methyl]
Under argon gas, operate
Digesting compound (15) [R=methyl] with 14.71 is dissolved in 41 milliliters of anhydrous pyridines.With this mixture be cooled to 0 ℃ and in 7 minutes portioning add 25.05 grams to the anisole SULPHURYL CHLORIDE so that temperature is no more than 7 ℃.Stirred this mixture 6 hours down at 0 ℃.Monitor this conversion by TLC (silica gel 60 F254 Merck, the acetone of 10% (v/v) in the toluene, UV 254nm).With this mixture-10 ℃ down with 100 milliliters of methylene dichloride dilutions, 34.2 milliliters of concentrated hydrochloric acids so that temperature is no more than 0 ℃ mode slowly adds, and are allowed the two separate of formation.With 50 milliliters of dichloromethane extraction waterbearing stratums (pH＜1), and with the organic layer that merges with 50 ml waters, 50 milliliters of saturated moisture NaHCO
3Wash with 50 mL of saline.Organic layer is passed through MgSO
4Dry and evaporate volatile matter under holding in the palm at 35 ℃ and 20.Yield is: 34.12 gram light yellow oil.
Embodiment 14-Singulair (1)
Digesting compound (5b) with 1.89 is dissolved in 15 milliliters the toluene and this solution is cooled to 5 ℃.Then, the methanol solution that adds 3.5 milliliter 24% sodium methylate.Under identical temperature, during 6 minutes, be added dropwise to 2.37 in 44 milliliters of tetrahydrofuran (THF)s and digest compound (4) solution.Under HPLC control, this mixture was stirred 23 hours down at 10 ℃.
This mixture is cooled to 0 ℃.Then with 1.44 milliliters of acetic acid solutions among 25 milliliter 5% the moisture NaCl so that temperature is no more than 2 ℃ mode adds.Contain 2% NaHCO with the separation of clarifying waterbearing stratum and with organic layer with 4 * 20 milliliters
3With the aqueous solution washing of 5% NaCl, wash with 20 mL of saline subsequently.Then organic layer is also under reduced pressure evaporated volatile matter in dry on the MgSO4, filtration under 45 ℃.Be dissolved in the yellow oil that obtains in 3 milliliters of hot toluenes and this mixture at room temperature stirred and spend the night.Filter and drying solid throw out acquisition 2.48 gram light yellow solid materials.
The purifying of embodiment 15-Singulair
Under 96 ℃, be dissolved in 19.7 gram Singulairs (purity is 93.2%) in 180 milliliters the toluene and this solution is cooled to 65 ℃.Add 2.0 gram silica gel (Merck company, SiO
260,40-63 micron, 230-400 order) and with this mixture stirring 10 minutes.Silica gel is leached and wash with 20 milliliters of hot toluenes (65 ℃).Filtrate is cooled to 28 ℃ gradually, filter out the precipitated solid product and with it with the washing of cold toluene of 2 * 5 milliliters.Yield is: the Singulair of 16.39 gram prepurifications, (HPLC is 97.54% IN) to purity, and optical purity (HPLC, chiral column) is 99.5%.
Under 100 ℃, be dissolved in the Singulairs of 16.10 gram prepurifications in 160 milliliters the toluene and this mixture is cooled to 25 ℃ gradually.Filter out solid product and with it with the washing of cold toluene of 2 * 5 milliliters.Yield is: the Singulair of 15.43 gram purifying, (HPLC is 98.24% IN) to purity.
The sublimed Singulair of 15.20 grams is dissolved in 77 milliliters the dehydrated alcohol and this mixture is cooled to 25 ℃ 80 ℃ of (bathe temperature) lucifuges.Filter out solid product and with its cold washing with alcohol with 2 * 5 milliliters.Yield is: the pure Singulair of 12.97 grams, (HPLC is 99.0% IN) to purity, and optical purity is 99.65%.
Embodiment 16-Menglusitena amorphous substance
2.0 gram Singulairs are dissolved under 50 ℃ in toluene-carbinol mixture (4:1 v/v) of 5 milliliters.The solution stirring that this is muddy is cooled to 25 ℃.Under this temperature, in 20 minutes, be added dropwise to 0.33 milliliter aqueous NaOH solution (0.15 the gram, 3.75mmol).This solution was remained on this temperature following 30 minutes, add 0.05 gram gac and filter this suspension by kieselguhr filter.With the toluene wash of this diatomite with 2 * 2 milliliters.Under 38 ℃ bath temperature, that the solution vapourisation under reduced pressure that merges is almost extremely dry.Obtain yellow heavy-gravity oily matter.
This oily matter is added drop-wise in the normal heptane of 10 milliliters of stirrings and and stirred 15 minutes down at 25 ℃ with it.Form the throw out of white.Then this mixture was then stirred under 25 ℃ 17 hours.Throw out is passed through suction filtration, washs also lucifuge drying at room temperature with 2 * 10 milliliters normal heptanes.Yield is the white amorphous solids of 1.85 grams.
The preparation and the purifying of embodiment 17-compound (11)
3.10 kilograms of compounds (20a) (purity is 95%) are dissolved in 31 liters of dry toluenes.This solution is cooled to 0 ℃ and the 3M MeMgCl among 5.84 liters of THF is added drop-wise in this solution so that temperature can be above 5 ℃ during 60 to 75 minutes.Temperature is increased to 15 ℃ also to be stirred this reaction mixture 3 hours down at 15 ℃.Slowly add 18 premium on currency then.Give off the waterbearing stratum and use 1.50 kg of ice acidifying with acetic acid in 13.0 kg water to pH=4-5 subsequently reaction mixture.Also under reduced pressure subsequently (35 ℃) partial concentration is extremely only about half of with saturated aqueous carbonic acid hydrogen sodium extraction with layer separation and with organic extract.The solution that has concentrated is warming up to 85 ℃, adds 3.0 kilograms of ethyl acetate and 2.0 kilograms of ethanol and this mixture that will reflux is cooled to 0 ℃.Solid product filtered obtain 1.6 kilograms of rough thiolactones (11) alkali (HPLC purity〉95%).
This thiolactone alkali is dissolved under 60 ℃ in 7.5 kilograms the tetrahydrofuran (THF), in 30 minutes, stirs and add methyl alcohol (7.5 kilograms) and this solution is slowly cooled to 0 ℃.The precipitated solid material filtered out and with 500 gram methanol wash.Yield is 1.56 kilograms of HPLC purity〉99% compound (11).
Above mentioned each patent, patent application and journal article are all incorporated this paper by reference into.The present invention thereby described, it will be apparent to those skilled in the art that, the present invention can change in many ways and not deviate from spirit of the present invention, and all such modification all are included within the scope of the present invention described in the following appending claims.
Claims (14)
1. reductive methylation method wherein makes methylmagnesium-chloride, iodate methyl magnesium or methylmagnesium-bromide and following formula (11), (20), (2) or the reaction of compound (2a):
Wherein, described being reflected under the existence of cerium (III) salt carried out.
2. method according to claim 1, wherein said cerium (III) salt is cerous compounds.
3. method according to claim 1 and 2, this method comprises the compound that makes following formula (11):
With the methylmagnesiumhalide reaction that is selected from methylmagnesium-chloride, methylmagnesium-bromide, iodate methyl magnesium and combination thereof, to form the compound of following formula (4)
Or its acid salt.
4. according to the described method of claim 1-3, wherein said being reflected in the inert solvent that also contains the ether cosolvent carried out.
5. method according to claim 4, wherein said being reflected in the solvent system that contains toluene and tetrahydrofuran (THF) adopts the normal described methylmagnesiumhalide of 3-8 to carry out.
6. according to the described method of claim 1-5, wherein by with ether solvents, preferred cyclic ethers contact and activate described cerium (III) salt.
7. according to the described method of claim 4-6, wherein described cerium (III) is added in the solution or suspension with described ether solvents.
8. according to the described method of claim 3-7, this method also comprises the steps:
The compound of optional purifying formula (4); And
Make the compound reaction of the compound and the following formula (5) of formula (4):
Wherein, R is hydrogen or C
1-C
4Alkyl, and methyl preferably, and L is the leavings group that is selected from halogen, alkylsulfonyloxy and aryl-sulfonyl oxygen, to form the compound of following formula (1a):
Wherein, R is hydrogen or C
1To C
4Alkyl, and the optional compound that the compound hydrolysis of formula (1a) is formed following formula (1):
Or its salt.
9. method according to claim 8, wherein said leavings group are to the anisole sulfonyloxy.
10. according to Claim 8 or 9 described methods, wherein said purification step comprises the form crystallization with hydrochlorate of the compound that makes formula (4), and preferably forms described hydrochlorate with the acid that is selected from hydrochloric acid, toluenesulphonic acids and Phenylsulfonic acid.
11. method according to claim 1, this method also comprises the compound that makes as shown in the formula (20)
With the methylmagnesiumhalide reaction that is selected from methylmagnesium-chloride, methylmagnesium-bromide and iodate methyl magnesium, forming the compound of described formula (11), and optional described compound (11) is converted into described acid salt, preferably be converted into hydrochloride (11a).
12. method according to claim 1, this method comprises the compound that makes formula (20)
With the methylmagnesiumhalide reaction that is selected from methylmagnesium-chloride, methylmagnesium-bromide or iodate methyl magnesium, to form the compound of following formula (4)
13. method according to claim 12, this method comprises that also the compound with formula (4) is converted into acid salt, preferably be converted into tosylate or benzene sulfonate, and further the tosylate or the benzene sulfonate of the compound of formula (4) be converted into Singulair or its salt.
14. cerium (III) salt or the purposes of activatory cerium (III) salt in the reductive methylation method of the compound of described preparation formula (1), (1a), (4) or (11).
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| CNA2006800507838A Pending CN101365683A (en) | 2005-11-18 | 2006-11-20 | Process for making montelukast and intermediates therefor |
| CN2006800507876A Expired - Fee Related CN101356158B (en) | 2005-11-18 | 2006-11-20 | A new intermediate for making montelukast and related compounds |
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| CN1420113A (en) * | 2001-11-16 | 2003-05-28 | 北京上地新世纪生物医药研究所 | Method for preparing Menglusitena and intermediate preparation thereof |
| CN1171873C (en) * | 2001-12-26 | 2004-10-20 | 北京上地新世纪生物医药研究所 | Preparation method of Menlust sodium and its preparation intermediate |
| US20050107612A1 (en) * | 2002-12-30 | 2005-05-19 | Dr. Reddy's Laboratories Limited | Process for preparation of montelukast and its salts |
| US7501517B2 (en) * | 2004-04-30 | 2009-03-10 | Synthon Ip, Inc. | Process for making montelukast and intermediates therefor |
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Application publication date: 20090211 |