CN101343243A - Process for preparing 2-(substituted phenyl) - 2 - hydroxy-ethyl carbamates - Google Patents
Process for preparing 2-(substituted phenyl) - 2 - hydroxy-ethyl carbamates Download PDFInfo
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- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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Abstract
The invention concerns a new process for preparing (S)-(+)-2-(substituted phenyl)-2-hydroxy-ethyl carbamates and to novel intermediates used in this process. It further relates to polymorphic forms of said carbamates and to processes for preparing said polymorphic forms.
Description
The application is to be December 19, application number in 2002 the dividing an application for the application for a patent for invention of " method for preparing carboxylamine 2-(substituted-phenyl)-2-hydroxyl-ethyl ester " that be 02828112.8 (international application no is PCT/EP02/14843), denomination of invention the applying date.
Technical field
The new intermediate that the present invention relates to preparation (S)-(+)-carboxylamine-2-(substituted-phenyl)-2-hydroxyl-new method of synthesis for ethyl and in described method, use; The polymorphic form that also relates to described carbamate.
Background technology
Carboxylamine 2-(substituted-phenyl)-2-hydroxyl-ethyl ester and isomer thereof are at United States Patent (USP) 5,698,588 and 5,854, be described as being used for the treatment of the compound of central nervous system disease among 283 (its corresponding WO-97/26241), be used for the treatment of convulsions, epilepsy, apoplexy, muscle spasm, neuropathic and migraine specifically.This compounds has a unsymmetrical carbon on the position of benzyl, this carbon atom and phenyl ring are adjacent, belongs to the aliphatic carbon atom.This unsymmetrical carbon is preferably the S-configuration.Preferred compound is (S)-(+)-carboxylamine-2-(2-chloro-phenyl-)-2-hydroxyl-ethyl ester in this class carbamate, and this compound is called RWJ-333369 again.This compound and similarly optical purity carboxylamine halo 2-phenyl-1 ester introduced in 412 and 6,103,759 at United States Patent (USP) 6,127.
These compounds prepare by the following method: with suitable substituted-phenyl-1,2-ethylene glycol and dimethyl carbonate, generate corresponding carbonic acid phenyl-1, the 2-glycol ester, it generates the regional isomer of two carbamates subsequently with the amine reaction that is fit to, described isomer must separate by column chromatography.The stereoisomerism pure compound by similar approach from pure enantiomorph feedstock production.This method generates the mixture of being made up of two regional isomerism products, and one of them isomer need be removed, and this isomer has disadvantageous effect to yield.Two regional isomerism end products all need pass through chromatographic separation, and this separation is a miscellaneous process, and is especially true in scale operation.
A target of the present invention provides a kind of method, and this method is not only avoided the loss of separating step and incident unwanted regional isomer, and can also obtain high yield and highly purified end product, especially obtains the high purity enantiomorph.Another target provides the method that can expand the production in enormous quantities scale to, so that the raw material be convenient to prepare or the method for marketable material of adopting is provided.It also is a target that the method for saving cost and can not produce deleterious or the by product that is difficult to remove is provided.Another target of the present invention provides purification step method few in number, and particularly wherein part or all of intermediate need not the method for purifying.Another target provides the method for avoiding using excessive raw material and solvent.
Realize by these targets of method of the present invention.
Medicine is called the active pharmaceutical composition again, can occur by polymorphic form.Under nearly all situation, a kind of character of specific polymorphic form and the activeconstituents different in kind of no specific polymorphic form, or also different with the character of the another kind of polymorphic form of activeconstituents.The character of aspects such as relevant solvability, stability, flowability, handlability, compressibility may be different.And known these nature differences have influence on the preparation made by this activeconstituents and the character of last or final formulation thereof.The authorities that many countries are responsible for drug approval require the used activeconstituents of each medicine is carried out complete evaluation, comprise the discriminating and the control of polymorphic form.If the polycrystalline thing occurs in finished product, drug approval authorities require the manufacturers of described active substance to control its synthesis technique at least, so that make various corresponding polymorphic forms (if exist) batch with criticize between percentage consistent, and meet legal drug technique requirement.If be not controlled in building-up process, the percentage of the polymorphic form that provides just may fluctuate, thereby influences the character of active substance and medicine finished product, so that it no longer meets legal pharmaceutical standards.Therefore specifically just there is the constant basis polymorphic form, carries out strict control synthesis technology requirement and finished product.
There is not polymorphic in many active substances, and whether new chemical active ingredient exists polymorphic form to be not easy prediction.The change of processing parameter can cause existing polymorphic form in various degree in finished product, this is unwanted as mentioned above.Therefore grasp the existence of polymorphic form and the knowledge of feature is the target that must reach.
Be that existing (S)-(+)-carboxylamine-2-(the substituted-phenyl)-2-hydroxyl-ethyl ester of finding occurs with the polymorphic form form that can be separated and characterize very unexpectedly.On the other hand, the invention provides the practicality method repeatably of these polymorphic forms of preparation.
Summary of the invention
The present invention relates to the method for preparation formula (I) compound,
Wherein:
R is a halogen;
R
1And R
2Independent is hydrogen or C
1-4Alkyl, optional by phenyl or substituted-phenyl replacement, wherein the substituting group of substituted-phenyl is selected from halogen, C
1-4Alkyl, C
1-4Alkoxyl group, amino, nitro and cyano group;
Described method feature is following steps:
(a) use the ester that is fit to become the ester of pure reductive agent reduction following formula:
Wherein:
P is the pure blocking group that is fit to;
R
3Be C
1-4Alkyl;
Thereby obtain the alcohol of following formula:
(b) alcohol of formula (III) and the carbonyl compound of following formula are reacted;
Wherein X and Y are suitable leavings group; And then with the reaction of the amine of following formula,
Thereby obtain following formula: compound:
(c) remove blocking group P, thus the formula of obtaining (I) compound.
In some cases, one or more substituent R
1, R
2And R
3Have unsymmetrical carbon, therefore can cause formula (I) compound to produce steric isomer.Such steric isomer will be included in the scope of the present invention.
Preferred formula (I) compound is that wherein R is 2-chlorine, R
1And R
2Compound for hydrogen.
The pure blocking group of group P for being fit to.Preferred group P has ether type structure.Particularly preferred blocking group P is 2-(2-methoxyl group) propyl group.
In embodiment preferred of present method, the carbonyl compound of formula (IV) is selected from 1,1 '-carbonyl-diimidazole and phenyl chloroformate.
R in specific embodiment of present method
3It is methyl.
The reductive agent of suitable ester change alcohol is metal hydride or complex metal hydride in another specific embodiment of present method.
On the other hand, the present invention relates to following formula: compound:
Wherein R, R
1And R
2Definition with claim 1 or 2, and P is the hydroxy-protective group that is fit to.
On the other hand, the present invention relates to following formula: compound:
Wherein the definition of R is with claim 1 or 2, and P is the hydroxy-protective group that is fit to.
Again on the one hand, the present invention relates to the compound of following formula:
Wherein the definition of R is with right 1 or 2, R
3Be C
1-4Alkyl; And the hydroxy-protective group of P for being fit to.
Preferred formula (IV), (III) or compound (II), wherein P is 2-(2-methoxyl group) propyl group.
The also compound of preferred formula (II), wherein R
3Be methyl.
Again on the one hand, the present invention relates to the method for preparation formula (VI) compound, be characterized as and adopt above-mentioned steps (a) and (b).
Again on the one hand, the present invention relates to the method for preparation formula (III) compound, be characterized as and adopt above-mentioned steps (a).
Again on the one hand, the present invention relates to the method for preparation formula (II) compound, be characterized as and adopt following step (d) and (e).
The present invention also provides the method for preparation formula (I) compound, is characterized as to adopt following (d) and (e) step and above-mentioned (a) and (b) and (c) step.
On the other hand, the present invention relates to the existence of (S)-(+)-carboxylamine-2-(substituted-phenyl)-2-hydroxyl-ethyl ester polymorphic form.Two polymorphic forms in particular to compound carboxylamine 2-(2-chloro-phenyl-)-2-(2-(2-methoxyl group) propyl group)-ethyl ester.
The invention still further relates to the method for these new polymorphic forms of preparation.
Detailed Description Of The Invention
Theme of the present invention is preparation formula (I) compound (as mentioned above), and above formula (II), (III), (IV) and (V) method of the intermediate of representative and definition.
Those compounds and the intermediate of preferred this paper definition, wherein R is a 2-chlorine, R
1And R
2Be hydrogen.A kind of formula (I) compound of implication was also referred to as ' RWJ-333369 ' after wherein substituting group had, available following structural formula representative:
Term " halogen " refers to fluorine, chlorine, bromine and iodine.
" C
1-4Alkyl " is defined as the straight or branched saturated hydrocarbyl with 1-4 carbon atom, for example methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl isophthalic acid-propyl group, 2-methyl-2-propyl group.
" C
1-4Alkoxyl group " is defined as the C that joins with Sauerstoffatom
1-4Alkyl group, for example methoxyl group, oxyethyl group, 1-propoxy-, 2-propoxy-, 1-butoxy, 2-butoxy etc.
" substituted-phenyl " phenyl for being replaced by above-mentioned substituting group.Preferred substituted-phenyl has 1,2 or 3 substituting group.Preferred substituted is halogen, more preferably chlorine.
P is suitable hydroxy-protective group as mentioned above.Preferred P makes it in the reduction step from (II) to (III) and be stable the reactions steps from (III) to (VI) subsequently.Preferred reduction step is used complex metal hydride as described below, and group P should be stable to this complex metal hydride and reactant thereof.Use the reduction reaction of complex metal hydride to need under alkaline condition, to carry out, so group P does not answer cracking under described alkaline condition.Preferred group P can remove under acidic conditions, and carbamate-functional can not cracking under this condition.Preferred especially blocking group P is about 1 or can remove a little more than 1 time at pH.
The group P of ether type is particularly useful.Enumerated the example of P below:
Methoxymethyl ether (MOM): can be by methoxymethyl chlorine or methylal preparation;
Tetrahydropyranyl ethers (THP ether) can prepare by dihydropyrane;
Tetrahydric thiapyran ether can be by the preparation of dihydro thiapyran;
Chlorine substituted tetrahydrofuran ether can be by the preparation of 2-chlorine tetrahydrofuran (THF);
Tetramethylene sulfide ether can prepare by dihydro-thiophene;
1-ethoxyethyl group ether can be by ethyl vinyl ether or the preparation of 1-ethoxy ethyl chloride;
1-methyl isophthalic acid-methoxy ethyl ether can prepare by methylvinylether, and this compound has special importance;
Triphenyl ether and suitable derivatives thereof can be by the preparations of corresponding chlorinated thing;
Benzylic ether and suitable derivatives thereof can be by corresponding bromide or iodide preparations;
4-methoxyl group tetrahydropyranyl ethers can be by 5,6-dihydro-4-methoxyl group-2H-pyrans preparation;
4-methoxyl group tetrahydric thiapyran ether can be by 5,6-dihydro-4-methoxyl group-2H-thiapyran preparation.
Another advantage of using this group P is to cause generating non-enantiomer mixture, and promptly the P group does not have asymmetric center.In some cases, for example depend on the character of reductive agent, can use specific silyl ether as suitable group P, particularly tert-butyl dimetylsilyl (TBDMS), triisopropyl silyl, tribenzyl silyl etc.
The preparation of step (a): 2-(substituted-phenyl)-2-(protection hydroxyl)-ethanol (III)
According to the first step of the inventive method, become the alcohol that pure reductive agent is reduced into ester (II) corresponding formula (III) with suitable ester.This reductive agent can be metal hydride or complex metal hydride, for example the lithium aluminium hydride or derivatives thereof.
In the presence of the catalyzer that is fit to, the concrete reductive agent of this reaction is the silane agent, for example trialkyl silane, dialkyl silane, trialkoxy silane and preferred polymethyl hydrogen siloxane (' PMHS ').Particularly catalyzer is transition metal halide or carboxylate salt, optimization acid's salt is zinc carboxylate, for example caproic acid zinc or derivatives thereof, more preferably 2 ethyl hexanoic acid zinc, condition is in the presence of following material: metal hydride, for example basic metal or alkaline earth metal hydride; Or aluminum hydride, for example lithium hydride, sodium hydride, potassium hydride KH, hydrolith; Or complex metal hydride, for example hydroborate or alanate, particularly alkali metal borohydride or alanate, for example lithium, sodium or potassium hydroborate or alanate.Most preferably the composition of 2 ethyl hexanoic acid zinc and sodium borohydride is as catalyst mixture.These and similarly reductive agent at patent application WO 96/12694 (1995) and at J.Ulman, The Alembic, 1999,59, page 1 and introducing in the page or leaf thereafter.
Being reflected at of present method step is fit to carry out in the solvent, for example ether or polyethers or hydrocarbon, particularly aromatic hydrocarbon.The specific examples that is fit to solvent comprises ether, propyl ether, isopropyl ether, butyl ether, diglyme and toluene.
Described reductive agent can be by in independent reaction vessel, stirring reagent E RS A and reagent E RS B the mixture preparation (ERS=ester restoring system can be from Rohm ﹠amp; Haas buys).ERS A is NaBH
4Tetraethylene glycol dimethyl ether solution, and ERS B is Zn (carboxylic acid)
2* H
2The tetraethylene glycol dimethyl ether solution of O particularly is Zn (2 ethyl hexanoic acid)
2* H
2The tetraethylene glycol dimethyl ether solution of O.Preferred ERS A and ERS B are mixed under comparatively high temps, for example 50-90 ℃ temperature range, and particularly in 70 ℃ of stirred for several minute, for example 30 minutes.Mixture with ERSA and ERS B joins ester (II) afterwards, adds ERS C again.ERS C is a polymethyl hydrogen siloxane.
Described reductive agent also can original position produce in described reaction vessel, and this is significant especially.In this diverse ways, (II) is dissolved in suitable solvent with intermediate, preferably is dissolved in the toluene that temperature is increased to 80-90 ℃.Add a ERS B earlier, add a ERSA again.And then added ERS C then in 1 hour, control simultaneously keeps higher temperature, particularly about 95 ℃.
Initial mandelate (II) is prepared as follows, and can separate and optional purifying, and former state is used in reduction step.After ester (II) also can prepare in solvent, keep being dissolved in this solvent, former state is used in reduction step.
The preferred mandelate (II) that replaces is a methyl esters.
In the specific embodiments of present method step, initial ester (II) is dissolved in the solvent of back reaction and uses, perhaps also dissolve in the suitable solvent, ether for example, as be dissolved in n-butyl ether, or preferably be dissolved in toluene and use.Get the part reductive agent of preparation as stated above, join gained solution, in 1 hour, add ERS C then.Before adding ERS C, can choose wantonly described reaction mixture temperature is heated to 90 ℃.Temperature is risen to 90 ℃ then, keep this temperature to show that until process control transformation efficiency reaches 99% at least.Reaction times is about 1 hour.After the reduction, this mixture is cooled to 15-20 ℃ fully,, uses the alkali metal hydroxide aqueous solution hydrolysis again, preferably use excess NaOH solution hydrolysis slightly (for example 1.3 molar equivalents are used 30% solution) earlier with the careful hydrolysis of methyl alcohol.
Subsequently, this mixture was refluxed about 1 hour at about 50 ℃, at room temperature each layer of gained separated.At room temperature, with the organic layer water with saturated NaCl solution washing.
The amount of ERS C particularly in 2.2-3 molar equivalent scope, is preferably used the ERS C of 2.3 molar equivalents in 2-4 molar equivalent scope.Reaction was finished after about 1 hour usually.
After described reduction reaction is finished, excessive ERS C can be destroyed, particularly use ethyl acetate with the ester that is fit to.Add after the described ester, the gained mixture was stirred 1 hour, add alkaline aqueous solution again, preferred NaOH or KOH solution (for example 33% solution), and the further preferred methyl alcohol that uses are 90 ℃ of following hydrolysis.Subsequent disposal comprises the separation organic layer, with alkaline aqueous solution (for example 33%KOH solution), water washing.
The methyl ester that generates is an oil, if desired, can pass through distillation purifying.
Step (b): the preparation of carboxylamine 2-(substituted-phenyl)-2-(protection hydroxyl)-ethyl ester (VI)
In this step, the alcohol of formula (III) and the carbonyl compound of following formula are reacted,
Wherein X and Y are suitable leavings group.One of preferred X or Y are stronger than another reactivity.X and Y can be halogen, chlorine or bromine particularly, but preferred X and Y are imidazole group.If X is a halogen, preferred aryloxy of Y or alkoxyl group.In the later case, (V) be halo formic acid alkyl or aryl ester.(IV) concrete aromatic yl group is phenyl or substituted-phenyl, for example halogenophenyl or C
1-4Alkyl.(IV) preferred embodiment is chloroformic acid phenylester or 1,1 '-carbonyl-diimidazole.
Be reflected in the suitable solvent and carry out, for example hydrocarbon, particularly aromatic hydrocarbon, for example toluene or ether, for example THF.Temperature of reaction depends on the reactive behavior of reagent (IV), but normally in room temperature or be lower than under the room temperature and carry out.Work as N, when N '-carbonyl dimidazoles was used as reaction reagent, preferred reaction was at room temperature carried out (just at about 25 ℃).
This reaction can be finished after for example about 1/2 hour usually less than 1 hour.The reactant of this reaction does not separate usually; It can be represented by following formula:
Wherein the Y definition is the same, particularly is imidazolyl or aryloxy, for example phenoxy group or substituent phenoxy.The inventor thinks that the intermediate of formula (IV-a) is new, therefore constitutes another characteristic of the present invention.The intermediate of preferred formula (IV-a) is that wherein Y is those compounds of imidazoles-1-base.
The product that reacts previously, i.e. the intermediate of formula (IV-a), need not separate usually and immediately with the amine reaction of above-mentioned formula V.Preferred amine is ammonia, but also can be ammonium salt.In the case, ammonia or ammonium salt are dissolved in the aqueous medium, at room temperature join the solution of intermediate (IV-a).
Owing to have biphasic system, use (V) to want vigorous stirring when advising in aqueous medium.After several hours, particularly after 4 hours, stop described reaction.The gained organic phase is separated products therefrom optionally separating and purifying.Wherein be dissolved with product (VI) but organic phase in follow-up reactions steps also former state use.
Step c: the preparation of carboxylamine [2-(substituted-phenyl)-2-hydroxyethyl] ester (I)
This reactions steps relates to the deprotection of hydroxy functional group and depends on the character of group P.
When P is 2-methoxyl group-2-propyl group, remove by adding suitable sour example hydrochloric acid.
In preferred embodiments, compound (VI) is dissolved in the solvent of previous step reaction and uses.Add entry and concentrated hydrochloric acid while stirring.The several minutes afterreaction is near finishing, and finished product (I) begins to settle out.The gained reaction mixture is stirred several hrs, particularly 4 hours, because finished product could filter better like this.Leach finished product and washing subsequently.
Finished product (I) can be in the solvent that is fit to (for example alcoholic solvent, as methyl alcohol) recrystallization, preferably add acidified water and carry out recrystallization.
Raw material
Raw material (II) makes by following method, it is characterized in that following steps:
The following formula amygdalic acid esterification that (d) will suitably replace:
Thereby make the corresponding ester of following formula
Wherein at (VIII) with (IX), R and R
3Define the samely, preferred R is 2-chlorine and/or preferred R
3Be methyl; And
(e) with the agent treated ester (IX) that is fit to, generate hydroxy-protective group, thereby make the intermediate of following formula:
Wherein R and P definition is the same.
With ester (IX) and the suitable reagent react that can introduce hydroxy-protective group.Preferred reagent is 2-methoxyl group propylene.
In addition, the order of above-mentioned steps can be changed, and promptly can introduce hydroxy-protective group, forms ester subsequently.
Step (d): replace the preparation of mandelate (IX)
According to this reactions steps, raw material acid (VIII) is reacted in the alcohol that generates ester (IX).Usually use C
1-4Alkanol, particular methanol, thus generate corresponding C
1-4The methyl ester of alkyl ester or preferred (XIII).
React with excessive strong acid, preferred haloid acid, for example HCl particularly uses the 1-4 molar equivalent, the dense HCl of preferred 2.5 molar equivalents.Described reaction is the sulfuric acid or the SOCl of available catalytic amount also
2Carry out.In the later case, this reaction height heat release need be taked the adequate measures control reaction temperature.
Preferred this be reflected at room temperature or the temperature that raises slightly under carry out, preferably be no more than about 30 ℃.Reaction times is usually less than about 1 hour, for example about 30 minutes.The ester (IX) that generates is generally oily compound, and this oily compound former state in follow-up reaction is used.In an embodiment preferred, ester (IX) is retained in the solvent for preparing it, follow-up former state is used.
Step (e): the preparation of the protected replacement mandelate of hydroxyl (II)
The reaction conditions of this step depends on the character of blocking group P.
In an embodiment preferred, P is by 2-methoxyl group propylene deutero-2-methoxyl group-1-propyl group.2-methoxyl group propylene is dissolved in suitable solvent, is specially the solvent that also carries out therein in other reactions steps.Gained solution is joined intermediate (IX) be dissolved in the solution that suitable caproic acid solvent forms, described acidifying particularly feeds gaseous hydrochloric acid and carries out for example by adding hydrochloric acid on gained solution.Should preferably hang down pH, for example pH 1-2.The solvent of intermediate (IX) should preferred dissolution 2-methoxyl group propylene solvent, the more preferably solvent that uses in other reactions steps.
Described reaction can be finished less than 1 hour, finished within half hour usually.
Method output high yield of the present invention and highly purified end product (I) can expand the batch process scale to.A concrete aspect of present method is the stereochemistry integrity that it has kept the asymmetric center on the carbon atom that connects hydroxy functional group, i.e. present method demonstration racemization can be ignored or not exist.
The various intermediate products of present method (comprising the step for preparing raw material) can separate, and if desired, can be further purified before next step uses.In addition, all reactions steps of present method (also comprising the step for preparing raw material if desired) can be carried out in same solvent, promptly need not separate and optional purifying intermediate product.Under latter event, it is favourable boiling off some solvents or add some solvents in one or more reactions steps.The solvent that is fit to present method single solvent embodiment is an aromatic hydrocarbon, preferred toluene.Also can in a kind of solvent, carry out the reactions steps of some amount, in another kind of solvent, carry out other reactions steps.
Carry out whole process and have special superiority in a kind of solvent, promptly whole process is greatly simplified, and can carry out quickly and needn't discard or novel solvent more, and it is all very favourable to saving cost and environment protection.
Polymorphic form
The invention still further relates to the new crystalline structure of formula (I) compound, wherein R is a 2-chlorine, R
1And R
2Be hydrogen, this is called compound (I-a) below compound.
The crystal formation of compound (I-a) can pass through the suitably recrystallization preparation in the organic solvent that is fit to of formula (I-a) compound.Can obtain crystal form A or crystal form B, depend on the method for recrystallization.
A kind of crystal formation of compound (I-a) is called ' crystal form A ', can be by compound (I-a) recrystallization in the solvent that is fit to is prepared.In this recrystallization process, temperature keeps below 60 ℃, particularly is lower than 50 ℃.The solvent that is fit to is that its Chinese style (I-a) compound dissolves under comparatively high temps, and is difficult to those solvents of dissolved at a lower temperature relatively, and described lesser temps for example is lower than 20 ℃, or is lower than 10 ℃, or even is lower than 0 ℃ or-10 ℃.The solvent that is fit to is low-level chain triacontanol, i.e. C
1-4Alkanol, particularly methyl alcohol.
In one embodiment, by heating or backflow, (I-a) is dissolved in methyl alcohol with compound, or is dissolved in low-level chain triacontanol by heating.The temperature of this mixture must not be above 60 ℃.Subsequently, with the cooling of gained solution, preferred slowly cooling is for example only put described solution cold.In about 50 ℃ of beginning crystallizations.At room temperature, in the gained mixture, add acidified water and stirring 15-20 hour.Water is preferably used the strong acid acidifying, and for example hydrochloric acid or pH value are the similar acid of about 3-4, and particularly pH about 3.5.This mixture is continued to be cooled to about 0-10 ℃,, under this temperature, continue to stir for example about 1 hour particularly approximately to 5 ℃.Then with the filtration of gained crystallization end product, drying.
More on the one hand, the present invention relates to be mainly the compound (I-a) of crystal form A.Particularly the present invention relates to the polymorphic mixture and mainly contain the compound (I-a) of crystal form A.More specifically the present invention relates to contain at least 90% or more crystal form A, particularly contain 95% or more crystal form A again, more specifically contain 99% or more crystal form A again with the compound (I-a) that the polymorphic form of mixtures occurs.
Therefore, with a kind of new crystal formation of above-mentioned formula (I-a) compound recrystallization generation (I-a), this paper is called ' crystal form A '.
Compound (I-a) crystal form A has special crystal formation, i.e. monoclinic form.
A kind of crystal formation of compound (I-a) is called ' crystal form B ', can be by in the solvent that is fit to compound (I-a) recrystallization being prepared.In this re-crystallization step, temperature is increased to more than 60 ℃, particularly more than 70 ℃.The solvent that is fit to is that its Chinese style (I-a) compound dissolves under comparatively high temps, and not diffluent at a lower temperature those solvents, described lesser temps for example is lower than 20 ℃, or is lower than 10 ℃, or even is lower than 0 ℃ or-10 ℃.The solvent that is fit to is low-level chain triacontanol, for example C
3-4Alkanol, particularly propyl alcohol (n-propyl alcohol or 2-propyl alcohol).Other solvents that are fit to are ester, and for example ethyl acetate or similarly solvent, or itself and the mixture of lower boiling halohydrocarbon are for example with trichloromethane or methylene dichloride, the preferred mixture of methylene dichloride.In this case, preferred elder generation is dissolved in ethyl acetate with raw material, and then adds halohydrocarbon.The volume of used halohydrocarbon is about 5 times (v/v) of the volume of ethyl acetate, and preferred volume ratio is about 1: 2-1: 5 the scopes, (ethyl acetate: halohydrocarbon) that for example can be about 1: 3.The solvent of Shi Heing also has polyvalent alcohol in addition, particularly dibasic alcohol, for example ethylene glycol (preferably) or propylene glycol, butyleneglycol etc.Can add entry, particularly when polyvalent alcohol is used as solvent, add entry.If add entry, available suitable strong acid (example hydrochloric acid) is acidified to low pH, and for example pH is in the 2-5 scope, and for example pH is about pH 3.Water can various amounts add.When for example making spent glycol or similar dibasic alcohol, the volume ratio of the water of dibasic alcohol and adding is 1: about 1: 8 of 1-, or 1: 2-1: 5, for example about 1: 4 (dibasic alcohol: water, v/v).
In one embodiment, by heating or backflow, compound (I-a) is dissolved in the mixture of 2-propyl alcohol, ethyl acetate or ethyl acetate/dichloromethane, more preferably the mixture of 1: 3 ethyl acetate/dichloromethane.Subsequently gained solution is put coldly, the product crystallization that needs in this process is separated out.
Described method also can be used for changing crystal form A into crystal form B, promptly changes crystal form A into crystal form B with crystal form A alternative compounds (I-a) in aforesaid method.
In 60 minutes, crystal form A is heated to 130 ℃ (DSC experiments), can obtains highly purified crystal form B anorthic crystal.
On the other hand, the present invention relates to be mainly the compound (I-a) of crystal form B.Particularly the present invention relates to the polymorphic mixture and mainly contain the compound (I-a) of crystal form B.More specifically the present invention relates to contain at least 90% or more crystal form B, more specifically contain 95% or more crystal form B, more specifically contain 99% or more crystal form B again with compound (I-a) the polymorphic mixture that the polymorphic form of mixtures occurs.
Formula (I-a) compound new crystal can characterize by using suitable powder diffractometer to record its corresponding X-ray powder diffraction figure, particularly uses the method for general introduction in an embodiment to characterize.
Aspect another, the invention provides the crystal form A of preparation formula (I-a) compound or be mainly the method for formula (I-a) compound of crystal form A, described method comprises formula (I-a) compound is dissolved in the suitable solvent, this solvent is heated above about 50 ℃ but be lower than about 60 ℃ temperature, puts described solution cold subsequently.The solvent that is fit to is alcohols, particularly C
1-4Alkanol, particular methanol.In the specific embodiments of described method, hot solution is put cold until beginning to occur crystal, particularly this solution is put and be chilled to 50 ℃ and make and begin to occur crystal, continue to put cold subsequently, particularly time be chilled to room temperature.
On the other hand, the invention provides preparation formula (I-a) compound crystal form B or be mainly the method for formula (I-a) compound of crystal form B, described method is included in 60 ℃ or higher, particularly under 70 ℃ or higher temperature, from the solvent that is fit to compound (I-a) recrystallization.The solvent that is fit to is for example low-level chain triacontanol, for example C
3-4Alkanol, particularly propyl alcohol.Other solvents that are fit to are the mixture of ethyl acetate or itself and lower boiling halohydrocarbon such as methylene dichloride.
Following embodiment can introduce the present invention in more detail, but purpose is to set forth the present invention rather than the present invention is made restriction.
Embodiment
(S)-(+)-carboxylamine-2-(2-chloro-phenyl-)-2-hydroxyl-ethyl esterThe preparation of (compound (I-a))
Embodiment 1
(S)-(+)-2-chloro methyl mandelate(intermediate 1)
At room temperature, (100.0g 535.9mmol) is dissolved in methyl alcohol (553.0g) with (S)-(+)-2-chloro amygdalic acid.After being cooled to 10 ± 5 ℃, fed hydrogen chloride gas (55.3g) 30 minutes to this solution top, temperature remains on below 20 ± 5 ℃.This reaction and follow-up each reaction are all monitored with HPLC.20 ± 5 ℃ with trimethyl orthoformate (62.6g, 589.5mmol) add described colourless to pale yellow solution, under same temperature with this solution stirring 30 minutes.(40 ± 5 ℃, 40 ± 10mbar) as far as possible except that desolvating and hydrogen chloride gas subsequently in a vacuum.Gained oily resistates removes as far as possible in a vacuum once more and desolvates with toluene (130g) dilution.Add toluene (261g), this solution is cooled to 15 ± 5 ℃.
Embodiment 2
2-methoxyl group-1-propyl group deutero-(S)-(+)-2-chloro methyl mandelate(intermediate 2)
Feed hydrogen chloride gas (0.55g, 15mmol) (the pH value is reduced to 1-2 from 3) to the solution top.In second flask, (78.0g 1081.7mmol) is dissolved in toluene (120g), intermediate 1 solution (about 30 minutes) of preparation more than 25 ± 5 ℃ of temperature add down with 2-methoxyl group-propylene under 20 ± 5 ℃.After adding finishes, mixture was stirred 30 minutes.Add triethylamine to the pale yellow solution (14.0g 138.3mmol), at room temperature stirred 5 minutes, with toluene (402g) dilution (pH 〉=8 if do not reach, add triethylamine) toward gained is colourless.This mixture water (1 * 150g), sodium bicarbonate aqueous solution (5%, 1 * 150g) and saturated sodium-chloride water solution (1 * 150g) washing.Dry with sodium sulfate (about 65g), filter, remove in a vacuum about 86g toluene, generation intermediate 2.
Embodiment 3
2-(2-chloro-phenyl-)-2-(2-(2-methoxyl group) propyl group)-ethanol(intermediate 3)
Add Venpure earlier
TMERS B (13.0g) adds Venpure again
TMERS A (13.0g), with this mixture 45 minutes internal heating to 85 ± 5 ℃.The color of this solution is become muddy slightly by clarification.With Venpure
TMERS C (73.9g, about 1239.4mmol) is added drop-wise in this solution, makes that temperature is 95 ± 5 ℃ (about 45 minutes, the generation of thermopositive reaction may postpone).Drip and finish after 15 minutes, reaction is finished, and finishing also of this reaction can be judged to grey (zinc) from the oyster white that this mixture generates in addition.If reaction is not finished, directly add Venpure again to this reaction mixture
TMERS B and Venpuretm
TMEach 7.0g of ERS A finishes whole mixture heating up until conversion.Gained solution is cooled to 15 ± 5 ℃, adds methyl alcohol (30g) (having hydrogen to emit).The dropping sodium aqueous solution (30%, 238.0g), keep temperature to be lower than 20 ℃ (about 30 minutes, occur strong foamed phenomenon when being higher than 25 ℃).After adding finishes, in 1 hour, two-phase mixture is heated to 50 ± 5 ℃, the resolution of precipitate of previous generation this moment.After being cooled to room temperature, separate each phase, water (1 * 200g) and with saturated sodium-chloride water solution (the colourless organic phase of 1 * 200g) washing.Dry with sodium sulfate (about 65g), filter, remove about 180g solvent in a vacuum, obtain the solution of intermediate 3.
Embodiment 4
Carboxylamine 2-(2-chloro-phenyl-)-2-(2-(2-methoxyl group) propyl group)-ethyl ester(intermediate 5)
In 25 ± 5 ℃ of temperature ranges, add 1,1 '-carbonyl-diimidazole (103.8g, toluene 641.4mmol) (180g) slurries in the solution that obtains toward embodiment 3 in 30 minutes.Finish conversion then to 1-imidazolyl (imodazolyl)-1 '-[2-(2-chloro-phenyl-)-2-[2-(2-methoxy-propyl]-ethoxy carbonyl (intermediate 4).Adding toluene (200g) and ammonium hydroxide aqueous solution (25%, 364g).At room temperature, will respectively be separated through after 3 hours vigorous stirring, water (1 * 200g) and saturated sodium-chloride water solution (1 * 200g) washing contains the organic phase of intermediate 5.
Embodiment 5
The preparation of compound (I-a)
In the organic phase that contains intermediate 5 by the preparation of above-mentioned introduction method, add entry (160g) and concentrated hydrochloric acid aqueous solution (39g), make pH value＜1.0.After 5 minutes, compound (I-a) begins to settle out in stirring at room.After 4 hours, leach product, the filter cake water (3 * 75g) and toluene (3 * 44g) washing.Dry back (50 ± 5 ℃, 40 ± 10mbar), receive 96.9g compound (I-a) (purity 99.8%, HPLC measures content 99.0%, chirality HPLC measures enantiomeric excess＞99.9%, 444.8mmol, total recovery 83.0%).
Embodiment 6
The preparation of compound (I-a) crystal form A
The raw material of a last embodiment is suspended in the methyl alcohol (115g), be heated to backflow after, the solution filtered while hot with gained is cooled to room temperature, and stirs under this temperature 15-20 hour.Add the water (577g) that contains concentrated hydrochloric acid (about 13mg, the pH value of gained solution is 3.7 ± 0.2).The gained mixture is cooled to 5 ± 5 ℃, under same temperature, stirred 2 hours, filter then.Water (3 * 30g) washing gained filter cakes.Dry back (50 ± 5 ℃, 50 ± 10mbar), obtain 93.0g
Change Compound (I-a)Crystal form A (purity 100%, content 99.7%, enantiomeric excess＞99.9%, 430.0mmol, total recovery 80.2%) is colourless needle.
Embodiment 7
Measure polymorphic form with powder X-ray diffractometry
Specimen preparation
About 0.5-1g sample is pressed into the powdered sample container gently to obtain the smooth surface of sharp outline
Instrument
Adopt the powdery diffractometry instrument system APD1700 (Philips) with automatic divergent slit and secondary monochromator or similar devices of computer control.
Record condition
Copper radiation: K
α 1=0.15406; K
α 2=0.15444nm
Voltage: 40kV
Electric current: 30mA
Divergent slit: automatically
Receive slit: 0.1 °
Be used for C
U-K
α 1The graphite secondary monochromator of Xe proportional counter
Since 1.5 ° of 2 θ counting, scan until 402 θ with the amplitude of 0.02 ° of 2 θ.The gate time at every interval is 3 seconds, and the summary journal time is 2 hours 50 minutes.
Formula (I-a) compound crystal form A can characterize with its X-ray diffractogram, and described figure comprises the main peaks that is listed in the embodiment table 1.
The powder x-ray diffraction peak of table 1. crystal form A
Formula (II) compound crystal form B can characterize with its X-ray diffractogram, and described figure comprises the main peaks that is listed in the table 2.
Crystal form A
Angle d value intensity
2-θ°
pCps ％
9.217 9.58681 4610 100.0
10.506 8.41395 108 2.3
14.954 5.91952 986 21.4
17.375 5.09990 1501 32.6
18.435 4.80892 3287 71.3
20.028 4.42979 884 19.2
20.720 4.28343 286 6.2
21.045 4.21801 2535 55.0
22.205 4.00026 80.1 1.7
23.257 3.82165 1248 27.1
24.954 3.56544 494 10.7
25.715 3.46166 1776 38.5
26.093 3.41233 684 14.8
27.379 3.25489 3953 85.8
27.689 3.21908 954 20.7
29.339 3.04172 163 3.5
30.134 2.96333 517 11.2
31.480 2.83961 129 2.8
31.780 2.81347 310 6.7
32.139 2.78287 113 2.4
32.880 2.72180 318 6.9
33.097 2.70446 337 7.3
34.664 2.58570 479 10.4
35.170 2.54967 972 21.1
35.500 2.52667 464 10.1
35.995 2.49305 109 2.4
36.700 2.44679 250 5.4
36.958 2.43029 374 8.1
37.314 2.40791 1034 22.4
38.349 2.34527 408 8.9
39.222 2.29508 161 3.5
39.683 2.26945 310 6.7
Embodiment 8
The preparation of compound (I-a) crystal form B
By being heated to backflow, the crude product of 5.0g (19.0mmol) RWJ-333369 (polymorphic A) is dissolved in the 2-propyl alcohol of 4.75g.In 30 minutes, this solution is cooled to room temperature, separates out crystalline material simultaneously.Stirred 1 hour down at 4 ℃ more subsequently, leach product, under 80 ℃ and 20mbar dry 8 hours.Generate 4.0g (15.2mmol, 80%) polymorph b.
2-θ d value intensity Rel.Int.
9.13 9.686 486.0 0.324
10.38 8.522 198.0 0.132
12.81 6.910 334.0 0.223
15.04 5.890 507.0 0.338
15.92 5.567 153.0 0.102
17.32 5.120 594.0 0.396
18.31 4.845 694.0 0.463
18.58 4.775 282.0 0.188
19.37 4.582 239.0 0.159
20.04 4.431 326.0 0.217
20.81 4.268 864.0 0.576
21.72 4.092 324.0 0.216
22.15 4.013 1500.0 1.000
23.25 3.826 661.0 0.441
24.94 3.570 416.0 0.277
25.64 3.474 516.0 0.344
27.20 3.278 1044.0 0.696
27.59 3.233 506.0 0.337
28.23 3.161 216.0 0.144
28.56 3.125 221.0 0.147
29.44 3.034 208.0 0.139
30.34 2.946 328.0 0.219
30.83 2.900 314.0 0.209
31.77 2.816 259.0 0.173
32.13 2.786 200.0 0.133
32.68 2.740 335.0 0.223
33.04 2.711 276.0 0.184
34.30 2.614 207.0 0.138
34.81 2.577 621.0 0.414
35.29 2.543 244.0 0.163
35.91 2.501 243.0 0.162
36.36 2.471 189.0 0.126
37.08 2.424 412.0 0.275
37.66 2.388 349.0 0.233
38.55 2.335 431.0 0.287
39.09 2.304 321.0 0.214
Claims (8)
1. a following formula (I-a) compound:
It is characterized in that formula (I-a) compound is a monoclinic form.
2. according to formula (I-a) compound of claim 1 definition, described compound comprises the following X-ray powder diffraction peak that obtains with following condition:
-copper radiation: K
α 1=0.15406 and K
α 2=0.15444nm
-voltage: 40kV
-electric current: 30mA
-divergent slit: automatically
-reception slit: 0.1 °
-be used for C
U-K
α 1The graphite secondary monochromator of Xe proportional counter, wherein
-since 1.5 ° of 2 θ counting, with the amplitude of 0.02 ° of 2 θ scan until 40 ° of 2 θ and
The gate time at-every interval is 3 seconds, and the summary journal time is 2 hours 50 minutes;
Angle d value intensity
2θ°
Cps ％
9.217 9.58681 4610 100.0
10.506 8.41395 108 2.3
14.954 5.91952 986 21.4
17.375 5.09990 1501 32.6
18.435 4.80892 3287 71.3
20.028 4.42979 884 19.2
20.720 4.28343 286 6.2
21.045 4.21801 2535 55.0
22.205 4.00026 80.1 1.7
23.257 3.82165 1248 27.1
24.954 3.56544 494 10.7
25.715 3.46166 1776 38.5
26.093 3.41233 684 14.8
27.379 3.25489 3953 85.8
27.689 3.21908 954 20.7
29.339 3.04172 163 3.5
30.134 2.96333 517 11.2
31.480 2.83961 129 2.8
31.780 2.81347 310 6.7
32.139 2.78287 113 2.4
32.880 2.72180 318 6.9
33.097 2.70446 337 7.3
34.664 2.58570 479 10.4
35.170 2.54967 972 21.1
35.500 2.52667 464 10.1
35.995 2.49305 109 2.4
36.700 2.44679 250 5.4
36.958 2.43029 374 8.1
37.314 2.40791 1034 22.4
38.349 2.34527 408 8.9
39.222 2.29508 161 3.5
39.683 2.26945 310 6.7 。
3. the compound of claim 1, described compound does not contain other polymorphic forms of formula (I-a) compound substantially, and the meaning of wherein said " not containing substantially " is that the purity of described compound is at least 90%.
4. the compound of claim 2, described compound does not contain other polymorphic forms of formula (I-a) compound substantially, and wherein the meaning that " does not contain substantially " is that the purity of described compound is at least 90%.
5. formula (I-a) compound:
It is characterized in that described formula (I-a) compound is three oblique crystal formations.
6. according to formula (I-a) compound of claim 5 definition, described compound comprises the following X-ray powder diffraction peak that obtains with following condition:
-copper radiation: K
α 1=0.15406 and K
α 2=0.15444nm
-voltage: 40kV
-electric current: 30mA
-divergent slit: automatically
-reception slit: 0.1 °
-be used for C
U-K
α 1The graphite secondary monochromator of Xe proportional counter, wherein
-since 1.5 ° of 2 θ counting, with the amplitude of 0.02 ° of 2 θ scan until 40 ° of 2 θ and
The gate time at-every interval is 3 seconds, and the summary journal time is 2 hours 50 minutes;
2 θ d value intensity Rel.Int.
9.13 9.686 486.0 0.324
10.38 8.522 198.0 0.132
12.81 6.910 334.0 0.223
15.04 5.890 507.0 0.338
15.92 5.567 153.0 0.102
17.32 5.120 594.0 0.396
18.31 4.845 694.0 0.463
18.58 4.775 282.0 0.188
19.37 4.582 239.0 0.159
20.04 4.431 326.0 0.217
20.81 4.268 864.0 0.576
21.72 4.092 324.0 0.216
22.15 4.013 1500.0 1.000
23.25 3.826 661.0 0.441
24.94 3.570 416.0 0.277
25.64 3.474 516.0 0.344
27.20 3.278 1044.0 0.696
27.59 3.233 506.0 0.337
28.23 3.161 216.0 0.144
28.56 3.125 221.0 0.147
29.44 3.034 208.0 0.139
30.34 2.946 328.0 0.219
30.83 2.900 314.0 0.209
31.77 2.816 259.0 0.173
32.13 2.786 200.0 0.133
32.68 2.740 335.0 0.223
33.04 2.711 276.0 0.184
34.30 2.614 207.0 0.138
34.81 2.577 621.0 0.414
35.29 2.543 244.0 0.163
35.91 2.501 243.0 0.162
36.36 2.471 189.0 0.126
37.08 2.424 412.0 0.275
37.66 2.388 349.0 0.233
38.55 2.335 431.0 0.287
39.09 2.304 321.0 0.214 。
7. the compound of claim 5, described compound does not contain other polymorphic forms of formula (I-a) compound substantially, and wherein the meaning that " does not contain substantially " is that the purity of described compound is at least 90%.
8. the compound of claim 6, described compound does not contain other polymorphic forms of formula (I-a) compound substantially, and wherein the meaning that " does not contain substantially " is that the purity of described compound is at least 90%.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01205097 | 2001-12-21 | ||
| EP01205097.7 | 2001-12-21 | ||
| US60/418084 | 2002-10-11 |
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|---|---|---|---|
| CNB028281128A Division CN100457723C (en) | 2001-12-21 | 2002-12-19 | Process for preparing 2-(substituted phenyl) - 2 - hydroxy-ethyl carbamates |
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| US5504108A (en) * | 1990-01-12 | 1996-04-02 | The Ohio State University Research Foundation | Optically pure 4-aryl-2-hydroxytetronic acids |
| JP3010497B2 (en) * | 1990-05-31 | 2000-02-21 | チッソ株式会社 | Method for producing optically active α-hydroxyesters |
| US5698588A (en) * | 1996-01-16 | 1997-12-16 | Yukong Limited | Halogen substituted carbamate compounds from 2-phenyl-1,2-ethanediol |
| WO2001040168A1 (en) * | 1999-11-29 | 2001-06-07 | Mitsubishi Rayon Co., Ltd. | Acetalsulfonate derivative, process for producing the same, and process for producing styrene oxide derivative |
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2002
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| KR20100134082A (en) | 2010-12-22 |
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