CN101460459A

CN101460459A - Polymorphic and pseudopolymorphic forms of trandolaprilat, pharmaceutical compositions and methods for production and use

Info

Publication number: CN101460459A
Application number: CNA2007800204242A
Authority: CN
Inventors: T·贝德尔
Original assignee: Universitaet Zuerich; Azad Pharmaceutical Ingredients AG
Current assignee: Universitaet Zuerich; Azad Pharma AG
Priority date: 2006-04-05
Filing date: 2007-04-04
Publication date: 2009-06-17

Abstract

The present invention provides novel polymorphic and pseudopolymorphic forms of Trandolaprilat, including crystalline Trandolaprilat Form A, crystalline Trandolaprilat Form B, crystalline Trandolaprilat Form C, crystalline Trandolaprilat Form D, crystalline Trandolaprilat Form E, and mixtures thereof. The invention also provides novel methods for producing Trandolaprilat, pharmaceutically acceptable salts of Trandolaprilat, and polymorphic and pseudopolymorphic forms of Trandolaprilat, pharmaceutical compositions including one or more novel Trandolaprilat compounds and methods for treating high blood pressure and/or cardiac insufficiency using one or more novel Trandolaprilat compounds.

Description

The Trolaprilat of polymorphic and pseudopolymorphic forms, pharmaceutical composition and production and using method

Technical field

The application is non-temporary patent application, and it is applied for certainly and requires the applying date is on April 5th, 2006, and series number is 60/789,806 U.S. Provisional Application No. formerly.Series number is that 60/789,806 U.S. Provisional Application is introduced this non-temporary patent application as a reference here in full.

The present invention relates to the polymorphic of novel Trolaprilat (Trandolaprilat) and pseudopolymorphic forms and composition thereof, produce the novel method of Trolaprilat, the Trolaprilat pharmacy acceptable salt, the polymorphic of Trolaprilat and pseudopolymorphic forms, comprise the pharmaceutical composition of one or more novel Trolaprilat compounds, and the method for using one or more novel Trolaprilat compounds for treating hypertension and/or cardiac dysfunction.

Background technology

Trolaprilat (2S, 3aR, 7aS)-1-[[(2S)-2-[[(1S)-and 1-carboxyl-3-hydrocinnamyl] amino] propionyl]-octahydro-1H-Indoline-2-carboxylic acid } be the active metabolite of Trolapril (Trandolapril).Trolapril and Trolaprilat have chemical structure shown below respectively, are a kind of inhibitor that is commonly called the enzyme of angiotensin-converting enzyme (" ACE enzyme ").The ACE enzyme is a kind of peptidyl dipeptidase, and its catalysis angiotensin I is converted into Angiotensin II, and Angiotensin II is that a kind of strong peripheral blood vessel shrinks medicine, also stimulates adrenocortical aldosterone to secrete and provide the reverse feedback of renin secretion.

R=Et (Trolapril)

R=H (Trolaprilat)

As ACE inhibitor, Trolapril and Trolaprilat suppress the activity of ACE, and this causes the hypertension effect.Therefore, Trolapril can be used to reduce hypertension with Trolaprilat and treat the cardiac dysfunction medical symptom relevant with hypertension with other.As if their effects on hypertension are mainly derived from the active inhibition of ACE to circulation and tissue, reduce formation, reduction vasoconstriction, the secretion of reduction aldosterone of Angiotensin II thus and increase plasma renin.

The ketone secretion also increases plasma renin.

Trolapril is the ethyl ester prodrug of Trolaprilat, and it is angiotensin-converting enzyme (ACE) inhibitor of non-sulfydryl.Trolapril is become diacid metabolite, Trolaprilat by de-esterifying.Trolaprilat is described in the literature than the powerful about 8 times ACE activity inhibitor of Trolapril.But though for example tablet or capsule use of Trolapril through port oral dosage form, also have with dicarboxylic acid (for example Trolaprilat) form and use ACE inhibitor through skin, perhaps as pharmaceutically active salt, as U.S. Patent application U.S.2004/0052835 and the U.S. Patent number of announcing 6, described in 303,141.

Described in the U.S. Patent application U.S.2004/0052835 that is announced, because the decomposition of employed activeconstituents in the patch uses these non-stable ACE inhibitor can cause problem with transdermal patch (transdermal patch).This decomposition betides in the very short period of storage, so the restriction of product degraded has surpassed limit.Describe in this document: the salt (dicarboxylic acid) of the active metabolite by ACE inhibitor that dicarboxylic acid and strong acid (1:1) or alkali (1:2) reaction are formed is stable in fact with respect to decomposition.

As everyone knows, very disadvantageously, Trolapril and Trolapril are pulled in that it is synthetic and/or store in (cyclisation is corresponding diketopiperazine, and is as follows) all have the trend of decomposing in decomposition reaction.Trolapril be pulled in its synthetic with separates in be tending towards decomposing, this causes the pollution and the reduction output of final product.

R=Et (Trolapril) R=Et (Trolapril diketopiperazine)

R=H (Trolapril diacid=Trolaprilat) R=H (Trolaprilat diketopiperazine)

Develop different being used for and stablized the method and the composition especially for these compound formulas of Trolapril and Trolaprilat.Referring to, for example, U.S. Patent number 4,743,450 or the U.S. Patent application U.S.2004/0137054 that announced.

Problem mentioned above demonstrates, and current new, strong and preparation efficiently of development and the steady tendency of needing is in the method for the ACE inhibitor of decomposing.And, perhaps,, determined that other such methods can comprise research and the evaluation to the different crystalline form of ACE inhibitor, because they play a decisive role in these compounds stable for above-described method.

Usually, crystalline form that compound can be different and amorphous form exist.Usually, amorphous solid is called as " amorphous form ", the molecular composition that it is arranged by confusion.The different crystalline form of same compound comes from the Different Package of solid-state middle molecule, and it causes different crystal symmetries and/or unit cell parameters.These crystalline forms are called as " polymorphic forms " and/or " non-solvent form ", this means that it does not have residual organic solvents in fact.If material has been introduced the water (hydrate) of stoichiometric or nonstoichiometry quantity in its crystalline texture, or any other solvent (solvate), then be called as " pseudopolymorphic forms ".

Known a lot of compound exists with various polymorphics, pseudo-polymorphic or amorphous form.These different solid forms can have character different physics, spectroscopical and/or chemical, for example solvability and dissociate speed, fusing point, density, stability and mobile.For active compound, the solvability and the speed of dissociating may exert an influence to its bioavailability, density and flowability, and this needs to consider in prescription.And, the chemistry of these compounds and (thermodynamics) physics stability for, for example, decompose or that more unsettled on the thermodynamics (kinetics is preferential) polymorphs body is converted into more stable polymorphs body is extremely important, this can influence the biologic activity of these compounds.

The method of synthetic Trolapril discloses in for example EP 0084164 (with its corresponding U.S. Patent number 4,933,361) and WO 2005/051909.

The method for preparing Trolaprilat from Trolapril is not suitably described in the literature.Though preparation Trolaprilat diastereomer is at J.Med.Chem.30,992-998 has description in (1987), but for the separation of diacid, the mixture that needs freeze-drying to produce, and by the resulting resistates of purifying of the ion-exchange chromatography on the Amberlite IR-120.Disadvantageously, this method is not suitable for the scale operation Trolaprilat.

Another one prepares the method for Trolaprilat at U.S. Patent number 5,101, description is arranged in 039.Concrete program does not provide, and used program has several shortcomings: crystalline material is not provided; Need under vacuum, remove and anhydrate; And depend on diisopropyl ether and make solvent.Clearly crystalline material needs in separation and purifying more; Under vacuum, remove to anhydrate and expend time in very much; And diisopropyl ether forms dangerous superoxide easily.Therefore, this is not a suitable technique method.

To sum up, provide efficiently, dependable and strong mass preparation Trolaprilat, and the method for salt, polymorphs body, pseudo-polymorphic body and its mixture, and synthetic and store in have the stability of improvement the polymorphs body and the pseudo-polymorphic body of Trolaprilat be favourable.

Summary of the invention

Advantageously, the invention provides efficiently, dependable and strong mass preparation has the method for Trolaprilat and salt, polymorphs body, pseudo-polymorphic body and its mixture of high yield and purity, and compare with the Trolaprilat of non-solvent form, synthetic with store in have the different polymorphs body of stability (the carrying out cyclisation of reduction and form the trend of corresponding diketopiperazine) of improvement and the Trolaprilat of pseudo-polymorphic bodily form formula.Determined: the crystalline form of Trolaprilat is played an important role in its stabilization, and can allow to be undertaken by Trolapril efficient, strong, pure preparation.

Because unstabilized Trolaprilat has the high trend of decomposition, especially be corresponding Diketopiperazine derivative by cyclisation, the preparation of diacid and purifying (for example recrystallization under higher temperature) are very difficult, have caused production loss, and regular unacceptable low-purity.

Determine astoundingly with unexpectedly: the diacid of Trolapril (Trolaprilat) forms different pseudopolymorphic forms with alcohol and/or water, the Trolaprilat of this different pseudopolymorphic forms and non-solvent form (especially cyclisation and form corresponding diketopiperazine) is compared, the stability that in synthetic and storage, has increase, and can high yield and purity preparation.Further determine: the pseudopolymorphic forms of these Trolaprilats can be under mild conditions be converted into high yield and purity and be astable (non-solventization) form.

In one aspect, the invention provides a kind of method for preparing the crystal Trolaprilat of polymorphic or pseudopolymorphic forms, may further comprise the steps:

(a) the free amino acid form with Trolaprilat provides Trolaprilat in the solution that contains propyl carbinol and water; With

(b) from solution, remove enough water to induce the Trolaprilat crystallization.

In yet another aspect, the invention provides a kind of method for preparing Trolaprilat, may further comprise the steps:

(a) Trolapril and hydroxide compound are at least almost completely being reacted effectively carrying out under the saponified temperature and time in the saponification reaction solvent, wherein hydroxide compound is the alkylammonium oxyhydroxide of alkali metal hydroxide, alkaline earth metal hydroxides, tetraalkylammonium hydroxides or replacement, wherein Trolapril, hydroxide compound and saponification reaction solvent each all use with the amount that can effectively produce reaction mixture, this reaction mixture comprises the salt of chemical formula 3:

Wherein, M is the alkyl phosphate ion of basic metal, alkaline-earth metal, tetra-allkylammonium or replacement, and n is 1 or 2;

(b) with the reaction mixture of step (a) and the iso-electric point that reaches mixture with the pH that makes this mixture effectively and the acid of amount that Trolaprilat is provided with the free amino acid form of Trolaprilat in the iso-electric point that reaches mixture with the pH that makes this mixture effectively and provide with the free amino acid form of Trolaprilat under the temperature and time of Trolaprilat and mix; With

(c) from the reaction mixture of step (b) with the free amino acid isolated in form Trolaprilat of Trolaprilat.

In yet another aspect, the invention provides a kind of method for preparing the crystal Trolaprilat of polymorphic or pseudopolymorphic forms, may further comprise the steps:

(a) Trolapril and hydroxide compound are at least almost completely being reacted effectively carrying out in the saponification reaction solvent that is selected from water, C1-C4 alcohol or its mixture under the saponified temperature and time, wherein hydroxide compound is the alkylammonium oxyhydroxide of alkali metal hydroxide, alkaline earth metal hydroxides, tetraalkylammonium hydroxides or replacement, wherein Trolapril, hydroxide compound and saponification reaction solvent each all use with the amount that can effectively produce reaction mixture, this reaction mixture comprises the salt of chemical formula 3:

(b) if used saponification reaction solvent comprises alcohol except propyl carbinol in the step (a), then from the reaction mixture of step (a), remove this alcohol;

(c), in reaction mixture, add the water that the amount of the aqueous solution can be provided completely effectively if the reaction mixture of step (b) is not the aqueous solution;

(d) with the product of step (c) and the iso-electric point that reaches mixture with the pH that makes this mixture effectively and the acid of amount that Trolaprilat is provided with the free amino acid form of Trolaprilat in the iso-electric point that reaches mixture with the pH that makes this mixture effectively and provide with the free amino acid form of Trolaprilat under the temperature and time of Trolaprilat and mix;

(e) from the mixture of step (d), provide under the temperature of Trolaprilat with the free amino acid form of Trolaprilat in the solution that is enough to comprise effectively propyl carbinol and water and extract Trolaprilat to be enough to effectively in the solution that comprises propyl carbinol and water the propyl carbinol of amount that free amino acid form with Trolaprilat provides Trolaprilat; With

(f) from the solution of step (e), remove the water that is enough to induce the Trolaprilat crystallization and the amount of Trolaprilat is provided with polymorphic or pseudopolymorphic forms.

In yet another aspect, the invention provides the pure in fact crystalline form of a kind of production or as the method for the Trolaprilat of different crystalline form mixtures, may further comprise the steps:

Wherein, M is the alkyl phosphate ion of basic metal, alkaline-earth metal, tetra-allkylammonium or replacement, and n is 1 or 2; Wherein, if the saponification reaction solvent comprises the mixture of C1-C4 alcohol and water, then the saponified ratio exists the C1-C4 alcohol and water effectively to carry out at least almost completely;

(b) if used saponification reaction solvent comprises C4 alcohol in the step (a), then from the reaction mixture of step (a), remove this C4 alcohol;

(d) with step, (c) reaction mixture and the iso-electric point that reaches mixture with the pH that makes this mixture effectively and with pure in fact free amino acid form or the acid of amount of Trolaprilat is provided as the mixture of two kinds of different free amino acid forms at least the mixture of different free amino acid forms provides under the temperature and time of Trolaprilat and mixes in the iso-electric point that reaches mixture with the pH that makes this mixture effectively and with pure in fact free amino acid form or as at least two kinds;

(e) product with step (d) separates from supernatant liquor; With

(f) product of drying step (e) with provide pure in fact crystalline form or as the Trolaprilat of the mixture of at least two kinds of different crystalline forms.

In yet another aspect, the invention provides the pure in fact crystalline form of a kind of production or as the Trolaprilat of crystalline mixture form, may further comprise the steps:

(a) make Trolapril and at least 2.0 normal NaOH in comprising the saponification reaction solvent of second alcohol and water in about 20 ℃ of times that are enough to produce the reactant salt mixture that comprises chemical formula 3 to about 25 ℃ of reactions, the volume ratio of second alcohol and water is about 1/1 to about 1/1.5:

Wherein, M is a sodium, and n is 2;

(b) with the pH of hydrochloric acid regulating step (a) product to about 3.6 to about 4.0, provide Trolaprilat with pure in fact free amino acid form or as the mixture of at least two kinds of different free amino acid forms;

(c) product with step (b) separates from supernatant liquor; With

(d) with the product drying of step (c) with provide pure in fact crystalline form or as the Trolaprilat of the mixture of at least two kinds of different crystalline forms.

In yet another aspect, the invention provides the Trolaprilat of crystalline form, comprise the structure of chemical formula 4:

Wherein R is H or C1-C4 alkyl, and n is 0 to 2, can be stoichiometric or non-stoichiometric.

In yet another aspect, the invention provides the crystal Trolaprilat, it is Trolaprilat form A, Trolaprilat form B, the Trolaprilat form A, Trolaprilat form D or Trolaprilat form E, comprise the pharmaceutically pull-shaped formula A of crystal Trolapril of significant quantity, B, C, the pharmaceutical composition of D and/or E, and comprise and use one or more Trolaprilat forms A, B, C, the methods of treatment of D and/or E pharmaceutical composition, this pharmaceutical composition comprises at least a crystal Trolaprilat, is selected from Trolaprilat form A, Trolaprilat form B, the Trolaprilat form A, Trolaprilat form D or Trolaprilat form E.

Description of drawings

Fig. 1 is the X-ray powder diffraction figure of the pull-shaped formula A of crystal Trolapril.

Fig. 2 is the crystalline structure figure that measures from the X ray of Trolaprilat form A.

Fig. 3 is the asymmetric cell figure of Trolaprilat form A, comprises a Trolaprilat molecule and two propyl carbinol molecules that are attached on the crystalline structure.

Fig. 4 has shown the powder pattern that gets from the crystal data calculating of Trolaprilat form A.

Fig. 5 is the crystalline structure figure that measures from the X ray of Trolaprilat form B.

Fig. 6 is the asymmetric cell figure of Trolaprilat form B, comprises a Trolaprilat molecule and two ethanol molecules that are attached on the crystalline structure.

Fig. 7 has shown the powder pattern that gets from the crystal data calculating of Trolaprilat form B.

Fig. 8 is the X-ray powder diffraction figure of the pull-shaped formula C of crystal Trolapril.

Fig. 9 is the X-ray powder diffraction figure of the pull-shaped formula D of crystal Trolapril.

Figure 10 has shown the synchrotron pattern of the pull-shaped formula D of crystal Trolapril.

Figure 11 is the X-ray powder diffraction figure (comprising Si as standard) of the pull-shaped formula E of crystal Trolapril.

Figure 12 is the X-ray powder diffraction figure of the mixture of pull-shaped formula B of crystal Trolapril and the pull-shaped formula E of crystal Trolapril.

Figure 13 is the X-ray powder diffraction figure of the pull-shaped formula B of crystal Trolapril.

Figure 14 is the summary of the X-ray powder diffraction pattern of the pull-shaped formula of various crystal Trolaprils that obtained according to embodiment 1 to 6.

Figure 15 has shown with white X-ray powdery diffractometry (PXRD) and has measured the pull-shaped formula B of ground sample crystal Trolapril the studied conversion to form E.

Figure 16 is the summary that shows the method for preparing the pull-shaped formula A of crystal Trolapril.

Figure 17 is the summary that shows the method for preparing the pull-shaped formula of crystal Trolapril B to E.

Detailed Description Of The Invention

The present invention can be by more easily understanding with reference to following specific descriptions to preferred embodiment and its included embodiment.

Definition

For the purpose of clear and definite, used various terms and phrase such as following mode define in this specification and the appended claims. If term or phrase used in this specification or the appended claims do not define below or in this specification, then this term or phrase should have its its ordinary meaning.

Here used phrase " use through skin " meaning be administered on the skin (normally be applied to one or more exposures or its outer surface, epidermis for example), for example, use hand, finger or various medicator (spraying, pump, brush, pad, powder puff, cotton balls, leather cue tip, patch etc.). Use and can enter or to skin or hair by for example applying, pour into, spread to cover, spray or massage, or by any other easily or suitable method.

Here used is the compound of noncrystal solid-state (namely not being crystal form) with relevant with compound phrase " amorphous form " meaning, the molecular composition that it is arranged by confusion.

Here used phrase " cardiac dysfunction " meaning is not have enough blood to flow into cardiac muscle, and causes angina pectoris.

Terminology used here " crystal " meaning is usually to have regular atomic structure (the characteristic shape and the cutting planes that are formed by the arrangement of its atom, lewis' acid, it comprises a definite pattern usually, is called " lattice ") chemical compound by solidifying the solid that forms.

Terminology used here " crystallization " meaning is to form crystal.

Terminology used here " cyclisation " meaning is to form a ring or annular compound by chain by forming new key.

Here used and compound or relevant term " effective dose " meaning of pharmaceutical composition discussed herein are can be to individuality people for example, effectively provide or strengthen heart or other healthy and/or the medically compound of benefit or amounts of pharmaceutical composition. Use information provided here and known information, those of ordinary skills can easily determine discussed herein can be effectively under multiple different medical symptom, people and many animals provided or strengthen heart or other healthy and/or one or more compounds of benefit medically and amounts of pharmaceutical composition.

Terminology used here " Et " meaning is ethyl.

Terminology used here " hyrate " meaning is to have introduced the crystal form of compound of the water of stoichiometric or non-stoichiometry quantity in its crystalline texture.

Here used abbreviation " n.d. ", for example in the table 7, the meaning is not determine.

Here used abbreviation " PXRD " meaning is powder x-ray diffraction.

Here used phrase " pharmaceutically acceptable " refers in rational medical judgment scope, be fit to contact with the mankind and/or animal and without undue toxicity, pain, allergic reaction or other problems or complication those compounds, material, composition and/or the formulation suitable with rational income/risk ratio.

Here used phrase " pharmaceutically acceptable carrier " meaning is and carries or transport chemical compound or pharmaceutical agents from the part of organ, tissue or a health to the part of another organ, tissue or health relevant pharmaceutically acceptable material, composition or medium, for example solid or liquid filler material, diluent, excipient, solvent or one-tenth capsule material. The example that can be used as the material of pharmaceutically acceptable carrier includes but not limited to, sugar is lactose, dextrose plus saccharose for example, starch for example corn forms sediment and farina, cellulose and derivative thereof, gelatin, wax, oil, other materials that water and pharmaceutical formulations known to a person of ordinary skill in the art field are used.

Here used phrase " pharmaceutically acceptable salt " refers to the avirulent salt of Trandolaprilat compound of the present invention, and it usually can be by making free alkali and suitable organic or inorganic acid reaction, and free acid and suitable alkali reaction are prepared. Those skilled in the art can determine easily which acid and/or alkali are suitable for producing the pharmaceutically acceptable salt of Trandolaprilat compound.

Here used phrase " polymorphic ", " polymorphic forms " and " non-solvent form " refer to the crystal form of a compound (its molecule is with the compound of particular crystal symmetry and/or unit cell parameters packing), it does not have in fact (that is, being less than 2%) in crystalline material: (a) water and (b) other residual and/or non-residual organic or other solvents.

Here used phrase " pseudo-polymorphic " and " pseudopolymorphic forms " refer to the crystal form of a compound (its molecule is with the compound of particular crystal symmetry and/or unit cell parameters packing), and it has been introduced in crystal structure: (a) water (hydrate) of stoichiometry or non-stoichiometry quantity or (b) a certain amount of one or more other solvent (solvate).

Terminology used here " saponification " meaning is ester hydrolysis and form pure and mild salt that should acid under alkali condition.

Terminology used here " short crystallization (the seeding) " meaning is to use the material with smallest number to start or impel crystallization.

Terminology used here " solvate " meaning is its crystal form of having introduced the compound of a certain amount of one or more solvents in crystal structure.

Here used phrase " straight or branched C1-C4 alcohol " comprises for example methyl alcohol, ethanol, normal propyl alcohol, 2-propyl alcohol, n-butanol, 2-butanols, isobutanol and the tert-butyl alcohol.

Terminology used here " individuality " comprises the human and animal.

Here the used phrase relevant with the Trandolaprilat crystal form " pure in fact " meaning is a kind of crystal form that the crystal Trandolaprilat comprises about at least 70% Trandolaprilat, a kind of crystal form that preferably comprises about at least 80% Trandolaprilat, the preferred a kind of crystal form that comprises about at least 90% Trandolaprilat, the most preferred a kind of crystal form that comprises about at least 95% Trandolaprilat.

Here used abbreviation " XRPD " meaning is X-ray powder diffraction.

General description

Since Trandolaprilat (unstabilized) its synthetic with separates in tend to decomposition, this can adversely cause the pollution of end product and the loss of output, so need to find a kind of simple, efficient and strong method, it prepares Trandolaprilat with pure in fact form and high yield, thereby avoid being present in the difficulty in other appreciable methods, for example come purifying by the desivac separating compound and with ion-exchanger, as at J.Med. Chem.30, described to the Trandolaprilat diastereoisomer among the 992-998 (1987).

Developed on a large scale, efficient, believable with strong preparation and the method for separating Trandolaprilat and salt, polymorphs body, false polymorph and its compound, it has avoided freeze-drying and with the purifying of ion-exchanger. Novel method can be used for appreciable Trandolaprilat synthetic of high yield and purity.

And, stablize the new method of Trandolaprilat by forming novel, stable crystal form and advantageously found. Compare with Trandolaprilat non-solvent (stable) form, these novel Trandolaprilat crystal forms at it synthetic and store in have the stability (be the trend of corresponding diketopiperazine than the lowland cyclisation) of improvement.

But preferably Trandolaprilat crystal form A, Trandolaprilat crystal form B, Trandolaprilat crystal form C, Trandolaprilat crystal form D and Trandolaprilat crystal form E in the New Polycrystalline type of the Trandolaprilat that the method according to this invention is produced and the pseudopolymorphic forms, with and various mixture. The important characteristic of Trandolaprilat of these forms and program and the example of preparation have been summed up hereinafter. Describe hereinafter " the first program " and " the second program " corresponding to two different synthetic methods in detail. Listed hereinafter embodiment numbering relevant in the embodiment part.

Trandolaprilat form A-E

Polymorphic or

Form For the production of program

Characteristic

Pseudo-polymorphic

Form A the first program pseudo-polymorphic

In its crystal structure in conjunction with the positive fourth of 2 equivalents

(crystallization from n-butanol/water)

Alcohol is (with two solvates of n-butanol

(disolvate))

Embodiment 1

Form B second program is (from ethanol or ethanol/pseudo-polymorphic

In the water crystallization/pulp in its crystalline structure in conjunction with 2 normal ethanol

(having alcoholic acid two solvates)

Embodiment 2, embodiment 5 (research

Embodiment 1 and 5)

Form A second program (crystallization from water) pseudo-polymorphic in its crystalline structure in conjunction with the nonstoichiometry number

The water of amount (quantity between about 5.4% to approximately

Embodiment 3 6.4%)

Form D second program (crystallization from water) pseudo-polymorphic is (single in conjunction with 1 normal water in its crystalline structure

Hydrate), it is the water of stoichiometric

Embodiment 4 (quantity is between about 4.1% to about 4.2%)

The form E second program polymorphic is removed ethanol by drying and is produced from form B

(non-solvent compound)

Embodiment 5 (research embodiment 2, has and is less than about 1.0% (non-solvent compound)

3, water 6,7) and a certain amount of according to institute in the ICH guidance

The residual solvent of the restriction that embodiment 6 describes

The preparation of Trolaprilat and separable programming

In one aspect, the invention provides a kind of novel preparation and the method for separating Trolaprilat (1):

May further comprise the steps:

(a) make Trolapril (2)

At least almost completely reacting under the saponified temperature and time effectively carrying out in the saponification reaction solvent with hydroxide compound, wherein hydroxide compound is the alkyl phosphate ion of basic metal, alkaline-earth metal, tetra-allkylammonium or replacement, wherein Trolapril, hydroxide compound and saponification reaction solvent each all use with the amount that can effectively produce reaction mixture, this reaction mixture comprises the salt of chemical formula (3):

The step of above method has specific descriptions below.

Step (a)

Hydroxide compound

Used hydroxide compound is preferably the alkyl phosphate ion of basic metal, alkaline-earth metal, tetra-allkylammonium or replacement in the step (a).The example of spendable alkali metal hydroxide comprises sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH) etc.The example of spendable alkaline earth metal hydroxides comprises manganous hydroxide, calcium hydroxide etc.The example of spendable tetraalkylammonium hydroxides preferably include wherein alkyl group between methyl to hexyl TBuA oxyhydroxide.Also can use the amino ammonium oxyhydroxide of replacement, as benzyl (trimethyl ammonium) oxyhydroxide etc.Be preferably alkali metal hydroxide, particularly sodium hydroxide in the hydroxide compound.

The saponification reaction solvent

Applicable saponification reaction solvent comprises in the step (a): (i) straight or branched C1-C4 alcohol; (ii) water; (iii) (i) and/or any mixture (ii), for example mixture of second alcohol and water.Used saponification reaction solvent is preferably the mixture of ethanol, water or second alcohol and water in the step (a), most preferably is the mixture of second alcohol and water.

When the saponification reaction solvent is that C1-C4 alcohol is for example during the mixture of second alcohol and water, the ratio of C1-C4 alcohol and water can have wide scope, be preferably about 5:1 to about 1:5 volume ratio, more preferably about 2:1 is to about 1:2 volume ratio, be more preferably about 1.5:1 again to about 1:1.5 volume ratio, most preferably be about 1:1 volume ratio.

The quantity of reactant and solvent

In the step (a) employed Trolapril, hydroxide compound and saponification reaction solvent each all use with the amount that can effectively produce reaction mixture, this reaction mixture comprises the salt of chemical formula (3), and is as indicated above.Those skilled in the art can easily determine this amount.But, be preferred between the Trolapril (weight by volume) of about 9% to 14% scope.

In a preferred embodiment of present method, the hydroxide compound of having used q.s at least is providing at least 2.0 normal oxyhydroxide in reaction mixture.In another preferred embodiment, providing hydroxide compound with the quantity that exceeds used Trolapril amount, be preferably about 3.0 equivalents, more preferably is about 2.5 equivalents, be most preferably about 2.2 equivalents, with respect to the amount of employed Trolapril.

Temperature

Step (a) with effectively carry out at least almost completely saponification (for example, about 80% or more Trolapril be converted into Trolaprilat), more preferably be enough to allow to carry out under the saponified temperature in fact completely.Conversion can be monitored by method known to those skilled in the art, for example high performance liquid chromatography (" HPLC ").This temperature is preferably between about 15 ℃ to about 25 ℃ usually between about 0 ℃ to about 40 ℃, can at room temperature carry out easily.Higher temperature may cause forming the impurity of higher amount unfriendly, and this may be that salt by chemical formula (3) causes to isomerization at the allowance below nominal size that exists of excessive hydroxide compound (alkali).Step (a) is sustainable effectively carries out at least almost completely saponified time (for example 12-20 hour), for example 20-25 ℃ following 15 hours.

The salt of chemical formula 3

In the salt of formed chemical formula (3), M can be the alkyl phosphate ion of basic metal, alkaline-earth metal, tetra-allkylammonium or replacement, as mentioned above in step (a).

Step (b)

Acid

In step (b), provide the acid of the amount of Trolaprilat to mix with the reaction mixture of step (a) and the iso-electric point that reaches mixture with the pH that can make this mixture effectively and with the free amino acid form of Trolaprilat.This pH usually between about 3.6 to about 4.0 scopes.Those of ordinary skills can easily determine the acid of such quantity.

The reaction mixture acidifying acid with in the step (a) used in the step (b) comprises, for example hydrochloric acid, Hydrogen bromide, thiosulfonic acid, alkylsulphonic acid, aryl sulfonic acid or phosphoric acid.Preferably, used acid is hydrochloric acid.

Temperature

In step (b), the acid and the reaction mixture of step (a) be preferably at the pH that is enough to make mixture reach the iso-electric point of mixture and provide Trolaprilat with the free amino acid form of Trolaprilat and do not have under the temperature of the Trolaprilat of degrading in fact and carry out.

Time

In step (b), the acid and the reaction mixture of step (a) are preferably the time that the pH that is enough to make this mixture reaches the iso-electric point of mixture and Trolaprilat is provided with the free amino acid form of Trolaprilat, for example, from about 0.5 hour to about 48 hours, be preferably from about 0.5 hour to about 6 hours.

Step (c)

In step (c), will from the mixture of step (b), come out with the Trolaprilat of the free amino acid form of Trolaprilat by extraction or precipitate and separate.Below described this isolating method, and can determine by those skilled in the art are conventional.

Purity and productive rate

The Trolaprilat that this method is produced is usually with about at least 80% productive rate production, preferably with about at least 85% productive rate production, more preferably is about at least 90% productive rate production.

And the Trolaprilat that this method is produced is generally pure at least in fact, preferably has about at least 85% purity, more preferably has about at least 90% purity, further preferably has about at least 95% purity.

Program-(first program) of preparation and the crystal Trolaprilat that separates polymorphic or pseudopolymorphic forms

In yet another aspect, the invention provides the novel method of a kind of preparation and the crystal Trolaprilat that separates polymorphic or pseudopolymorphic forms (comprising the pull-shaped formula A of crystal Trolapril (a kind of pseudo-polymorphic body of Trolaprilat)).

Astoundingly and unexpectedly find: it is soluble being pulled in the saturated propyl carbinol of water with the Trolapril of the free amino acid form of Trolaprilat, and to the iso-electric point of mixture, this n-butanol/water mixture can be used to extract Trolaprilat with propyl carbinol from water layer at the pH of conditioned reaction mixture.

Therefore, this aspect of the present invention is a kind of method for preparing the crystal Trolaprilat of polymorphic or pseudopolymorphic forms, may further comprise the steps:

(a) make Trolapril (2)

In the saponification reaction solvent that is selected from water, C1-C4 alcohol or its mixture, be enough to allow at least almost completely to react under the saponified temperature and time with hydroxide compound, wherein hydroxide compound is the alkylammonium oxyhydroxide of alkali metal hydroxide, alkaline earth metal hydroxides, tetraalkylammonium hydroxides or replacement, wherein Trolapril, hydroxide compound and saponification reaction solvent each all use with the amount that can effectively produce reaction mixture, this reaction mixture comprises the salt of chemical formula 3:

(b) if used saponification reaction solution comprises alcohol except propyl carbinol in the step (a), then from the reaction mixture of step (a), remove this alcohol;

(e) from the mixture of step (d) to be enough to effectively in the solution that comprises propyl carbinol and water to provide in the solution that the propyl carbinol of the amount of Trolaprilat is being enough to comprise effectively propyl carbinol and water to provide under the temperature of Trolaprilat extracting Trolaprilat with the free amino acid form with the free amino acid form; With

The step of above method has specific descriptions below.

Step (a)

Hydroxide compound

Used hydroxide compound is preferably the alkyl phosphate ion of basic metal, alkaline-earth metal, tetra-allkylammonium or replacement in the step (a).The example of these compounds with above about the preparation Trolaprilat program described in identical.Be preferably alkali metal hydroxide in the hydroxide compound, most preferably be sodium hydroxide.

The saponification reaction solvent

In the step (a) used saponification reaction solvent comprise with above about the preparation Trolaprilat program described in identical saponification reaction solvent.Used saponification reaction solvent is preferably the mixture of ethanol, water or second alcohol and water in the step (a), most preferably is the mixture of second alcohol and water.

When the saponification reaction solvent is that C1-C4 alcohol is for example during the mixture of second alcohol and water, the ratio of C1-C4 alcohol and water can have wide scope, be preferably about 5:1 to about 1:5 volume ratio, more preferably about 2:1 is to about 1:2 volume ratio, be more preferably about 1.2:1 again to about 1:1.2 volume ratio, most preferably be about 1:1 volume ratio.

The quantity of reactant and solvent

In the step (a) employed Trolapril, hydroxide compound and saponification reaction solvent each all use with the amount that can effectively produce reaction mixture, this reaction mixture comprises the salt of chemical formula (3), and is as indicated above.Those skilled in the art can easily determine this quantity.But, be preferred between the Trolapril of about 9% to 14% scope.

In a preferred embodiment of present method, the hydroxide compound of having used q.s at least is providing at least 2.0 normal oxyhydroxide in reaction mixture.In another preferred embodiment, providing hydroxide compound with the quantity that exceeds used Trolapril amount, be preferably about 3.0 equivalents, more preferably is about 2.5 equivalents, be most preferably about 2.25 equivalents, with respect to the amount of employed Trolapril.

Temperature

Step (a) is being enough to allow at least almost completely saponification, more preferably is enough to allow to carry out under the saponified temperature in fact completely.Conversion can be monitored by method known to those skilled in the art, for example HPLC.This temperature can be preferably between about 15 ℃ to about 25 ℃ between about 0 ℃ to about 40 ℃ usually, more preferably between about 20 ℃ to about 25 ℃.Higher temperature may cause forming the impurity of higher amount unfriendly, and this may be that salt by chemical formula (3) causes to isomerization at the allowance below nominal size that exists of excessive hydroxide compound (alkali).

Time

Step (a) is sustainable preferably to be enough to permission at least almost completely saponification, more preferably time that can be fully saponified.Time used in the step (a) is preferably between about 10 to about 25 hours usually between about 5 to about 30 hours.

The salt of chemical formula 3

In the salt of formed chemical formula (3), M can be the alkyl phosphate ion of basic metal, alkaline-earth metal, tetra-allkylammonium or replacement in step (a).The example of these compounds with above about the preparation Trolaprilat program described in identical.

Step (b) and (c)

If used saponification reaction solvent is the mixture of alcohol or alcohol and water in the selected step (a), and used unique pure or alcohol in mixture is the alcohol except propyl carbinol, then need to remove this alcohol, this can realize by method known to those skilled in the art, for example evaporation.Otherwise (if used unique alcohol is propyl carbinol) then do not need to remove this alcohol.If the result of step (b) is not the aqueous solution, then in reaction mixture, add the water that the amount of the aqueous solution can be provided completely effectively.

Step (d)

Acid

In step (d), provide the acid of the amount of Trolaprilat to mix with the product of step (c) and the iso-electric point that reaches mixture with the pH that makes this mixture effectively and with the free amino acid form of Trolaprilat.This pH usually between about 3.6 to about 4.0 scopes.Those of ordinary skills can easily determine the acid of such quantity.

The product acidifying acid with in the step (c) used in the step (d) comprises, for example above about described in the program of preparation Trolaprilat those.Preferably, used acid is hydrochloric acid, and this hydrochloric acid is 2N water-based hydrochloric acid.

Temperature

In step (d), acid mixed with the product of step (c) preferably at the pH that is enough to make this mixture reach the iso-electric point of mixture and provide Trolaprilat with the free amino acid form of Trolaprilat and do not have under the temperature of the Trolaprilat of degrading in fact and carry out.Such temperature is usually between about 20 ℃ to about 80 ℃, preferably between about 30 ℃ to about 70 ℃, more preferably between about 60 ℃ to about 70 ℃.

Time

In step (d), acid is mixed the time that the pH that preferably is enough to make this mixture reaches the iso-electric point of mixture and Trolaprilat is provided with the free amino acid form of Trolaprilat with the product of step (c).

Step (e)

In step (e), from the mixture of step (d), with effectively from solution or contain propyl carbinol and the biphasic mixture of water provide the propyl carbinol of amount of Trolaprilat or the azeotropic mixture of propyl carbinol and water with the free amino acid form of Trolaprilat, with effectively from solution or contain propyl carbinol and the biphasic mixture of water provide under the temperature of Trolaprilat with the free amino acid form of Trolaprilat, the form of Trolaprilat Trolaprilat with free amino acid extracted.

Extraction can be preferably between extremely about 70 ℃ of about room temperatures between the boiling point of about room temperature to the azeotropic mixture of about propyl carbinol and water, more preferably carries out to about 60 ℃ temperature between about 50 ℃.

The quantity of the azeotropic mixture of used propyl carbinol or propyl carbinol and water is preferably extremely about 1:2 between about 2:1 usually between the extremely about 1:5 of about 5:1, most preferably is about 1:1.

Step (f)

In step (f), from the solution of step (e), remove the water that is enough to induce the Trolaprilat crystallization and the amount of Trolaprilat is provided with polymorphic or pseudopolymorphic forms.Because it is insoluble that Trolapril is pulled in the anhydrous normal butyl alcohol, its crystallization from organic layer can start by removing to anhydrate, and for example, uses component distillation (so that the crystal Trolaprilat to be provided) to concentrate the n-butanol/water solution that contains Trolaprilat.

Obtain required Trolaprilat product if desired, the product of step (f) randomly can be dry under the temperature and pressure of the crystal Trolaprilat that is enough to effectively to provide false polycrystalline form, continues to be enough to effectively to provide the time of the crystal Trolaprilat of false polycrystalline form.

Purity and productive rate

The Trolaprilat that this method is produced obtains with the pure in fact crystalline form of about at least 92% productive rate usually.Obtained to surpass this Trolaprilat of 99.5% purity.Purity is measured with HPLC: use Luna C18 (150 x 4.6mm, 3 μ m; Manufacturer: Phenomenex, Torrence, CA, the U.S.) post and Symmetry C18 (2) (150 x 4.6mm, 3.5 μ m; Manufacturer: Waters Corporation, Millford, MA, the U.S.) as moving phase: mobile phase A: the trifluoroacetic acid in the 0.03%v/v water; Mobile phase B: the trifluoroacetic acid in the 0.025%v/v acetonitrile; 30 ℃ of column temperatures, flow velocity: 1.5ml/min detects: UV 206nm; Gradient:

Time [minute] %A %B

0 90 10

20.00 10.0 90.0

25.00 10.0 90.0

Determine purity with same equipment in the same way in described in the text various other experiments.

Program-(second program) of preparation and the crystal Trolaprilat that separates polymorphic or pseudopolymorphic forms

In yet another aspect, the invention provides the novel method of the crystal Trolaprilat of a kind of preparation and the mixture that comprises the pull-shaped formula B of crystal Trolapril (a kind of pseudo-polymorphic body of Trolaprilat), the pull-shaped formula C of crystal Trolapril (a kind of pseudo-polymorphic body of Trolaprilat), the pull-shaped formula D of crystal Trolapril (a kind of pseudo-polymorphic body of Trolaprilat) or at least two kinds of multi-form crystal Trolaprilats that separates polymorphic or pseudopolymorphic forms.This method starts from hydroxide compound Trolapril being carried out saponification in suitable solvent.To iso-electric point, the mixture of crystal Trolaprilat compound or crystal Trolaprilat compound is separated from reaction mixture by crystallization at the pH that regulates mixture.

The method of the mixture of the Trolaprilat that this aspect of the present invention is the pure in fact form of a kind of production (as polymorphs body or pseudo-polymorphic body) or at least two kinds of different crystal forms of conduct may further comprise the steps:

(a) make Trolapril (2)

(b) if used saponification reaction solution comprises C4 alcohol in the step (a), then from the reaction mixture of step (a), remove this C4 alcohol;

(d) with the product of step (c) and the iso-electric point that reaches mixture with the pH that makes this mixture effectively and the acid of amount that Trolaprilat is provided with pure in fact free amino acid form in the iso-electric point that reaches mixture with the pH that makes this mixture effectively and provide with pure in fact free amino acid form under the temperature and time of Trolaprilat and mix;

(e) product with step (d) separates with supernatant liquor; With

(f) product of drying step (e) with provide pure in fact crystalline form or as the Trolaprilat of at least two kinds of different crystalline mixture forms.

The step of above method has specific descriptions below.

Step (a)

Hydroxide compound

The saponification reaction solvent

In the step (a) applicable saponification reaction solvent comprise with above about the preparation Trolaprilat program described in identical saponification reaction solvent.Used saponification reaction solvent is preferably the mixture of ethanol, water or second alcohol and water in the step (a), most preferably is the mixture of second alcohol and water.

In step (a), if the saponification reaction solvent comprises C1-C4 alcohol for example during the second alcohol and water, the ratio of C1-C4 alcohol and water can have wide scope, be preferably about 5:1 to about 1:5 volume ratio, more preferably about 2:1 is to about 1:2 volume ratio, be more preferably about 1:1 again to about 1:1.5 volume ratio, most preferably be about 1:1 volume ratio.

The quantity of reactant and solvent

In the step (a) employed Trolapril, hydroxide compound and saponification reaction solvent each all use with the amount that can effectively produce reaction mixture, this reaction mixture comprises the salt of chemical formula (3), and is as indicated above.Those skilled in the art can easily determine this quantity.But, as indicated above, in reaction mixture, be to use the Trolapril parent material preferably between about 9% to 14% scope with concentration.The amount of hydroxide compound also as mentioned above.

In a preferred embodiment of present method, the hydroxide compound of using q.s at least is to provide at least 2.0 normal oxyhydroxide (quantity according to used Trolapril is calculated) in reaction mixture.In another preferred embodiment, providing hydroxide compound with the quantity that exceeds used Trolapril amount, be preferably about 3.0 equivalents, more preferably is about 2.5 equivalents, be most preferably about 2.2 equivalents, with respect to the amount of employed Trolapril.

Temperature

Step (a) is being enough to allow at least almost completely saponification, more preferably is enough to allow at least almost completely to carry out under the saponified temperature.Conversion can be monitored by method known to those skilled in the art, for example HPLC.This temperature can be preferably between about 15 ℃ to about 25 ℃ between about 0 ℃ to about 40 ℃ usually, more preferably between about 20 ℃ to about 25 ℃.Higher temperature may cause forming the impurity of comparatively high amts unfriendly, and this may be that salt by chemical formula (3) causes to isomerization at the allowance below nominal size that exists of excessive hydroxide compound (alkali).

The salt of chemical formula 3

Step (b)

If saponification reaction solvent used in the step (a) comprises C4 alcohol, preferably in step (b), from the reaction mixture of step (a), remove this C4 alcohol, be preferably by distillation and remove.

Step (c)

If the reaction mixture of step (b) is not the aqueous solution, preferably in the reaction mixture of step (b), add the water that the amount of the Trolaprilat aqueous solution can be provided completely effectively.

Step (d)

Acid

With step, (c) product and the iso-electric point that reaches mixture with the pH that makes this mixture effectively, (for example pH3.6 to 4.0) and with pure in fact free amino acid form or the acid of amount that Trolaprilat is provided as the mixture of two kinds of different free amino acid forms at least in the iso-electric point that reaches mixture with the pH that makes this mixture effectively, (for example pH3.6 to 4.0) also provides the temperature and time of Trolaprilat to mix down with pure in fact free amino acid form or as the mixture of at least two kinds of different free amino acid forms.

The acid that the used product with in the step (c) is acidified to iso-electric point in the step (d) comprises, for example above about described in the program of preparation Trolaprilat those.Preferably, used acid is hydrochloric acid, and this hydrochloric acid is 2N water-based hydrochloric acid.

Temperature

In step (d), the acid and the product of step (c) mixed preferably reach the iso-electric point of mixture and the mixture of different free amino acid forms provides under the temperature of Trolaprilat and carries out with the free amino acid form of Trolaprilat or as at least two kinds at the pH that is enough to make this mixture.Such temperature preferably between about 15 ℃ to about 25 ℃, more preferably is approximately room temperature usually between about 0 ℃ to about 40 ℃.

Time

In step (d), preferably be enough to make the pH of this mixture to reach the iso-electric point of mixture acid and the mixing of the product of step (c) and with the free amino acid form of Trolaprilat or time period of Trolaprilat is provided as the mixture of two kinds of different free amino acid forms at least.

Step (e)

The product of step (c) is separated with supernatant liquor, and it can be by filtration, centrifugal or similar approach.

Step (f)

The product of drying step (e) with provide pure in fact crystalline form or as the Trolaprilat of the mixture of at least two kinds of different crystalline forms.

Temperature

Step (e) is carried out at least under the temperature of the Trolaprilat of the mixtures crystalline form that preferably is enough to effectively provide pure in fact or two kinds of different crystalline forms of conduct.This temperature is usually between about 0 ℃ to about 40 ℃, preferably between about 10 ℃ to about 30 ℃, preferably between about 20 ℃ to about 25 ℃.Convenient is room temperature.

Purity and productive rate

The Trolaprilat that this method is produced is usually with the pure in fact crystalline form of about 〉=90% productive rate or as at least two kinds of different crystalline form mixtures acquisitions.Can obtain having the pure in fact crystalline form of about 〉=99% purity, survey as HPLC.

According to present method, in a most preferred mode for preparing Trolaprilat by Trolapril, the salts solution of about 9% to about 14% chemical formula (3) (wherein M is Na, in the ethanol/water mixture of the volume ratio about 1/1) is acidified to pH between about 3.6 to 4.0 by 2N water-based hydrochloric acid.During acidifying, after short crystallization, the crystallization of Trolaprilat starts from pH between about 4.5 to about 5.0 o'clock.

In the last period described method, the volume ratio of the mixture of second alcohol and water is important.For example, if (wherein M is Na to the salts solution of 9% chemical formula (3), in the ethanol/water mixture of volume ratio 1/ 〉=2) be acidified to pH between about 3.6 to 4.0 by 2N water-based hydrochloric acid, temperature is between about 20 ℃ to about 25 ℃, then resin or rubber precipitate the most at the beginning, can slow crystallization when it stirs under this temperature.Produce Trolaprilat at technical grade, the formation of resin or rubber can cause problem during stirring.On the contrary, if the volume ratio of second alcohol and water is 〉=1/1, precipitation can be polluted final product in the inorganic salt (forming when acidifying).

In this method, the concentration of solution that contains the salt of chemical formula (3) is important equally.If crystallization is by with more concentrated (〉 14%) the acidifying of salts solution (wherein M is Na, in the ethanol/water mixture of the volume ratio 1/1) of chemical formula (3) carry out, then can form the thick suspension that stirs with difficulty.On the contrary, if crystallization is to be undertaken by the acidifying with the salts solution (wherein M is Na, in 1/1 ethanol/water mixture) of the chemical formula (3) that more do not concentrate (＜9%), then have the loss of yield (being taken place) of final product more than not doing like this.

Another one is preferably produced pure in fact crystalline form or as the method for the Trolaprilat that comprises the pull-shaped formula B of crystal Trolapril, the pull-shaped formula C of crystal Trolapril, the pull-shaped formula D of crystal Trolapril and composition thereof of the mixture of crystalline form, being comprised:

(a) make Trolapril and at least 2.0 normal NaOH in comprising the saponification reaction solvent of second alcohol and water, the volume ratio of second alcohol and water is about 1/1 to about 1/1.5, in about 20 ℃ of times that are enough to produce the reactant salt mixture that comprises chemical formula 3 to about 25 ℃ of reactions:

Wherein, M is a sodium, and n is 2;

(b) with the pH of hydrochloric acid regulating step (a) product to about 3.6 to about 4.0, provide Trolaprilat with pure in fact free amino acid form or as at least two kinds of different free amino acid form of mixtures;

(c) product with step (b) separates with supernatant liquor; With

(d) with the product drying of step (c) with provide pure in fact crystalline form or as the Trolaprilat of at least two kinds of different crystalline mixture forms.

The step of above method (a) to (d) can be carried out with the described identical mode of above second program.

The program of preparation and isolation of crystalline Trolaprilat form E

The pull-shaped formula E of crystal Trolapril (a kind of polymorphs body of Trolaprilat) can be prepared by the following method by the pull-shaped formula B of crystal Trolapril (a kind of pseudo-polymorphic body of Trolaprilat), comprising: be enough to effectively to remove on the crystal of the pull-shaped formula B of crystal Trolapril the institute's bonded alcoholic acid time to the crystal that is enough to effectively to remove the pull-shaped formula B of crystal Trolapril of dried crystals Trolaprilat form B under institute's bonded alcoholic acid temperature and pressure.

Before dried crystals Trolaprilat form B, can be by for example grinding or grind the granularity that advantageously reduces the pull-shaped formula B of crystal Trolapril.

The Trolaprilat crystalline form

On the other hand, the invention provides the novel crystal form of Trolaprilat.

The invention provides the Trolaprilat of crystalline form, comprise the structure of chemical formula (4):

In a preferred embodiment, in chemical formula (4), R is H, and n is 1 or nonstoichiometry.The crystalline form of this Trolaprilat is called as " hydrate " (pseudo-polymorphic body).

In second preferred embodiment, in chemical formula (4), R is H, and n is greater than 1 and is nonstoichiometry.

In the 3rd preferred embodiment, in chemical formula (4), R is C1-C4 alkyl (being preferably ethyl or butyl), and n is 2.The crystalline form of this Trolaprilat is called as " solvate " (pseudo-polymorphic body).

In the 4th preferred embodiment, in chemical formula (4), n is 0.The crystalline form of this Trolaprilat is called as " non-solvent compound " (polymorphs body).

The novel crystal form of Trolaprilat of the present invention comprises the pull-shaped formula A of crystal Trolapril, the pull-shaped formula B of crystal Trolapril, the pull-shaped formula C of crystal Trolapril, the pull-shaped formula D of crystal Trolapril and the pull-shaped formula E of crystal Trolapril, as discussed above.

By experiment, astoundingly with beyond thought discovery: Trolaprilat not only can polymorphic forms exists, and also can exist by various false polycrystalline form, if particularly crystallization is from hydroxylic solvent for example water and/or alcohol.As if Trolaprilat has the high trend of being produced from various crystal pseudopolymorphic forms, if particularly crystallization is from hydroxylic solvent.

For example, obtain from the crystal Trolaprilat of hydroxylic solvent can comprise two molecule propyl carbinols in its crystal unit (the pull-shaped formula A of crystal Trolapril) crystal (pseudo-polymorphic) form according to above-described " first program " crystallization, it is preferably pure in fact.

Obtain from the hydroxylic solvent crystalline form that for example water, alcohol or water and the crystal Trolaprilat of mixture of alcohol can be different according to above-described " second program " crystallization, the for example pull-shaped formula B of crystal Trolapril, the pull-shaped formula C of crystal Trolapril and the pull-shaped formula D of crystal Trolapril, it also is pure in fact preferably, or the mixture of two or more crystalline form.The pull-shaped formula E of crystal Trolapril can be produced by the pull-shaped formula B of crystal Trolapril by above-described mode.

Pure in fact crystal Trolaprilat (also having low pure form) can obtain from pure hydroxylic solvent by crystallization usually.

The mixture of the crystalline form that two or more are different usually can be by crystallization from two or more hydroxylic solvent, and for example water and alcoholic acid mixture obtain.Because the hydroxylic solvent crystallization with different of Trolaprilat is the high trend of pseudopolymorphic forms, it is complicated more to produce such mixture.This may be interpreted as: the pseudopolymorphic forms of crystal Trolaprilat is Duoed a difference at least than polymorphic forms, therefore must consider for example composition of solvent systems of further parameter.For this reason, second method not only can pure in fact crystalline form, and the mixture that also can be used as at least two kinds of different pull-shaped formulas of crystal Trolapril transmits Trolaprilat, if solvent mixture has been used in crystallization.The Trolaprilat crystalline form of optimizing is by thermodynamic stability of dividing other Trolaprilat crystalline form and the control of the dynamic effect in the crystallisation process.In other words, if solvent mixture has been used in crystallization, the purity of the pull-shaped formula of two or more crystal Trolapril in the final product and composition depend on the ratio of solvent for use, and the difference of crystallization rate.Slower crystallization may provide thermodynamically stable crystal Trolapril pull-shaped formula, and precipitation provides the preferential crystal Trolapril of kinetics pull-shaped formula faster.Churning time when Trolaprilat crystallization or pulp, temperature and drying conditions can have further influence to the purity and the composition of the pull-shaped formula of various crystal Trolaprils.For example, if Trolaprilat is according to the mixture of " second program " crystallization from the different ratios of second alcohol and water, then isolating Trolaprilat can contain the water of different amounts, usually between about 0.63% to about 4.2% (latter is corresponding to the monohydrate form), ethanol with different amounts, usually between about 0.2% to about 19% (latter is corresponding to having alcoholic acid two solvate forms), this has shown the different Trolaprilat crystalline forms or the formation of its mixture.Aforesaid parameter, the for example churning time of the difference of the ratio of used ethanol/water, crystallization rate, whipping temp and crystallization rear suspension liquid in the crystallisation step, and drying conditions (temperature, pressure, time etc.) has material impact to the composition of the crystalline form of Trolaprilat.Use information provided here and known information, those of ordinary skills can easily change one or more these conditions with the Trolaprilat of producing needed crystalline form or the mixture of two or more these crystalline forms.

The solid form of crystal Trolaprilat of the present invention can be pure in fact the pull-shaped formula of crystal Trolapril or exist as the mixture of the pull-shaped formula of two or more crystal Trolapril, behind X-ray diffraction, each all shows himself X-ray diffraction pattern characteristic of (special), and can be identified by himself X-ray diffraction pattern characteristic of (special).

The pull-shaped formula A of crystal Trolapril

The pull-shaped formula A of crystal Trolapril is the false monocrystalline type form of Trolaprilat, comprises the 2 normal propyl carbinols (that is, it is two solvates that have propyl carbinol) that are attached in its crystalline structure.

The pull-shaped formula A of crystal Trolapril has the X ray as shown in table 1 powder diffraction data that spreads out, crystallization data and structural parameter as shown in table 2, X-ray powder diffraction pattern as shown in Figure 1 and crystalline structure as shown in Figure 2 (X ray from compound is measured).The intensity at the various X-ray powder diffractions peak that this document is described and/or shown may change because of quality or other factors, as is known to the person skilled in the art.In addition, one skilled in the art will realize that 2 θ positions in the powder pattern of particular crystalline of same substance may change in error span (usually from, for example, the mensuration accuracy of used specific X-ray diffraction meter).At last, whole peak pattern may be because the density variation of specimen preparation, sample packaging etc. have partly variation by a relatively large margin.Listed X-ray powder diffraction data are based on actual experimental result in the table that occurs in this document, and the numeral in several row is rounded up to behind the radix point one in mode easily, expects difference approximately+/-0.20.For example, can reasonably expect to have approximately+difference of/-0.20 degree 2 θ at any one or more peaks.Here all X-ray diffraction analysis of describing and/or show are and use following instrument to carry out: (producer setting=30mA 40kV), and has to have the Philips PW1800 diffractometer that xenon-ratio detection is counted

The Bruker AXS D8 Advance of detector (producer setting=40mA, 40kV): radiation: CuK α; Angular range 2 θ=2 °/3 ° to 40 °; Step-length (step size)=0.02 °; Be 1 second to 4 seconds each sweep time in step (scan step time) of measuring.

Fig. 3 has shown the asymmetric unit of the pull-shaped formula A of crystal Trolapril (propyl carbinol that contains 1 molecule Trolaprilat and 2 molecules), and Fig. 4 has shown the powder pattern as calculated (Trolaprilat two solvates that have 2 propyl carbinols) of the crystal data of the pull-shaped formula A of crystal Trolapril.

The pull-shaped formula A of crystal Trolapril can use aforesaid " first program " according to embodiment 1, produces by the Trolaprilat solution (promptly using the mixture of solvent, n-butanol and water) of component distillation from water-saturated n-butanol, and it starts its crystallization.Because it is insoluble usually that Trolapril is pulled in the anhydrous normal butyl alcohol, from solvent mixture, remove the meeting of anhydrating and start its crystallization by for example component distillation.Required product can be pure in fact the crystalline form that in its crystalline structure, contains 2 normal propyl carbinols obtain.

Table 1

The pull-shaped formula A powder x-ray diffraction of crystal Trolapril data

Pos.[° of 2Th.] highly [cts] d-distance [

] relative intensity [%]

7.7 15534 11.5 100.0

9.2 2211 9.6 14.2

11.4 325 7.7 2.1

13.2 913 6.7 5.9

13.5 421 6.6 2.7

14.3 84 6.2 0.5

15.6 1898 5.7 12.2

15.9 1087 5.6 7.0

16.4 1891 5.4 12.2

16.9 1068 5.3 6.9

17.3 1246 5.1 8.0

17.7 1481 5.0 9.5

18.2 503 4.9 3.2

18.6 4220 4.8 27.2

18.9 4715 4.7 30.4

19.8 3656 4.5 23.5

20.6 4538 4.3 29.2

21.2 1141 4.2 7.3

22.0 5420 4.0 34.9

22.2 2072 4.0 13.3

23.3 1242 3.8 8.0

23.7 731 3.8 4.7

23.9 491 3.7 3.2

24.6 1117 3.6 7.2

25.2 997 3.5 6.4

25.7 1055 3.5 6.8

26.7 1383 3.3 8.9

27.0 1773 3.3 11.4

27.5 663 3.2 4.3

28.6 645 3.1 4.2

29.0 667 3.1 4.3

29.5 264 3.0 1.7

30.0 152 3.0 0.9

30.5 828 2.9 5.3

30.9 576 2.9 3.7

31.6 707 2.8 4.6

32.0 796 2.8 5.1

32.7 893 2.8 5.8

33.0 597 2.7 3.8

33.7 1154 2.6 7.4

34.1 250 2.6 1.6

34.4 251 2.6 1.6

35.1 748 2.6 4.8

35.9 881 2.5 5.7

36.2 576 2.5 3.7

38.3 355 2.4 2.3

38.7 316 2.3 2.0

39.4 140 2.3 0.9

Table 2

Crystallization data and the structural parameter of the pull-shaped formula A of crystal Trolapril

Crystalline form H ₂O/n-BuOH

Empirical formula C ₃₀H ₅₀N ₂O ₇

Molecular weight [g mol ^-1] 550.73

Crystal color, habit is colourless, prism

Crystalline size [mm] 0.20 x 0.28 x 0.32

Temperature [K] 160 (1)

Crystal system orthorhombic

Spatial group P2

₁2 ₁2 ₁(#19)

Z 4

The reflection 3887 of raji cell assay Raji

2 θ scopes of raji cell assay Raji [°] 4-55

The unit cell parameters

10.2709 (2)

12.9233(2)

22.6409(3)

90

90

90

3005.22(8)

F(000) 1200

D _x[g cm ^-3] 1.217

μ(Mo Kα)[mm ^-1] 0.0855

Scan type

And ω

2θ _(max)[°] 55

Total reflection 45353 of being surveyed

The independent reflection 3864 of symmetry

R _int 0.051

Reflection I〉2 σ (I) 3418

Add the used reflection of detail 3858

Refinement parameter 376

Final R (F) [I〉2 σ (I) reflection] 0.0417

WR (F ²) (all data) 0.1100

Weight w=[σ ²(F _o ²)+(0.0562P) ²+ 0.8633P] ^-1P=(F wherein _o ²)+2F _c ²)/3

The goodness of fit 1.039

Secondary optical extinction coefficient 0.012 (1)

Final Δ _Max/ σ 0.001

0.46；-0.23

0.003-0.005

The pull-shaped formula B of crystal Trolapril

The pull-shaped formula B of crystal Trolapril is the false monocrystalline type form of Trolaprilat, comprises the 2 normal ethanol (that is, it is to have alcoholic acid two solvates) that are attached in its crystalline structure.It has the X ray as shown in table 10 powder diffraction data that spreads out, X-ray powder diffraction pattern as shown in figure 13, X ray diffracting data crystalline structure as illustrated in Figures 5 and 6, crystal data as shown in table 3 and structural parameter, and powder pattern as calculated as shown in Figure 7.

The pull-shaped formula B of crystal Trolapril can use aforesaid " second program ", and according to

embodiment

2 and 5, crystallization/pulp in ethanol, and slow crystallization Trolaprilat is produced from the ethanol/water mixture of dilution.Required product can be pure in fact the 2 normal alcoholic acid crystalline forms that in its crystalline structure, contain obtain.

The pull-shaped formula B powder x-ray diffraction of table 10 crystal Trolapril data

Pos.[° of 2Th.] [cts] d-distance highly Relative intensity [%]

8.1 485321 10.9 100

9.6 251491 9.2 51.8

10.6 22079 8.3 4.5

11.3 49787 7.9 10.3

11.9 38231 7.4 7.9

13.8 110823 6.4 22.8

14.8 41587 6.0 8.6

15.9 39706 5.6 8.2

16.6 50332 5.3 10.4

17.4 178820 5.1 36.8

18.1 211405 4.9 43.6

18.4 140642 4.8 29.0

19.3 430165 4.6 88.6

20.5 241048 4.3 49.7

21.2 108775 4.2 22.4

21.6 99472 4.1 20.5

22.4 103529 4.0 21.3

22.9 256485 3.9 52.8

23.9 94042 3.7 19.4

24.4 70724 3.6 14.6

24.8 60099 3.6 12.4

25.5 99950 3.5 20.6

26.0 95754 3.4 19.7

26.5 111361 3.4 22.9

27.5 75690 3.3 15.6

27.7 81574 3.2 16.8

28.6 68696 3.1 14.2

29.4 53969 3.0 11.1

30.0 91367 3.0 18.8

30.6 70719 2.9 14.6

32.1 92500 2.8 19.1

33.9 90615 2.6 18.7

34.9 63904 2.6 13.2

36.3 77597 2.5 16.0

36.7 83061 2.5 17.1

37.7 62646 2.4 12.9

38.6 60200 2.3 12.4

39.7 61743 2.3 12.7

Table 3

Crystallization data and the structural parameter of the pull-shaped formula B of crystal Trolapril

Crystalline form H ₂O/EtOH/i-PrOH 3.7:1:0.02

Empirical formula C ₂₆H ₄₂N ₂O ₇

Molecular weight [g mol ^-1] 494.62

Crystal color, habit is colourless, prism

Crystalline size [mm] 0.15 x 0.17 x 0.30

Temperature [K] 160 (1)

Crystal system orthorhombic

Spatial group P2

₁2 ₁2 ₁(#19)

Z 4

The reflection 2764 of raji cell assay Raji

2 θ scopes of raji cell assay Raji [°] 4-50

The unit cell parameters 10.0301 (2)

12.2874(2)

22.2267(3)

90

90

90

2739.30(9)

F(000) 1072

D _x[gcm ^-3] 1.199

μ(Mo Kα)[mm ^-1] 0.0863

Scan type

And ω

2θ _(max)[°] 50

Total reflection 33853 of being surveyed

The independent reflection 2746 of symmetry

R _int 0.057

Reflection I〉2 σ (I) 2405

Add the used reflection of detail 2743

Refinement parameter 340

Final R (F) [I〉2 σ (I) reflection] 0.0414

WR (F ²) (all data) 0.1116

Weight w=[σ ²(F _o ²)+(0.0699P) ²+ 0.3841P] ^-1P=(F wherein _o ²)+2F _c ²)/3

The goodness of fit 1.053

Secondary optical extinction coefficient 0.015 (2)

Final Δ _Max/ σ 0.001

0.32；-0.19

0.004-0.006

Below under the discussion of the pull-shaped formula E of crystal Trolapril, the method that another one (from the pull-shaped formula A of crystal Trolapril, form A and/or form D) is produced the pull-shaped formula B of crystal Trolapril has been described.

The pull-shaped formula C of crystal Trolapril

The pull-shaped formula C of crystal Trolapril is the false monocrystalline type form of Trolaprilat, comprises the water of the nonstoichiometry quantity that is attached in its crystalline structure.The water yield is usually between about 5.4% to about 6.4%.It has X-ray powder diffraction data as shown in table 4 and X-ray powder diffraction pattern as shown in Figure 8.

The pull-shaped formula C of crystal Trolapril can use aforesaid " second program ", and according to embodiment 3, the solution of the salt by the chemical formula in the acidified water (3) is about 3.6 to about 4.0 (iso-electric points) to pH, and the crystallization Trolaprilat is produced from water then.The initial rubber that forms is by the crystallization lentamente that stirs the mixture, usually between about 20 ℃ to about 25 ℃ temperature, continue to be preferably about at least 16 hours time, the pull-shaped formula C of the crystal Trolapril water of nonstoichiometry quantity (in its crystalline structure in conjunction with) forms thus.The pull-shaped formula C of crystal Trolapril can be pure in fact crystalline form obtain.

Table 4

The pull-shaped formula C powder x-ray diffraction of crystal Trolapril data

Pos.[° of 2Th.] [cts] d-distance highly

Relative intensity [%]

4.8 68 18.2 0.9

6.2 7234 14.2 100.0

8.4 88 10.5 1.2

10.4 911 8.5 12.6

11.1 368 8.0 5.1

11.6 247 7.6 3.4

12.1 128 7.3 1.8

12.5 1025 7.1 14.2

12.8 611 6.9 8.5

13.3 664 6.7 9.2

14.0 1452 6.3 20.1

14.6 550 6.1 7.6

15.7 1664 5.7 23.0

16.2 636 5.5 8.8

16.9 393 5.2 5.4

18.0 899 4.9 12.4

18.8 1700 4.7 23.5

19.3 830 4.6 11.5

19.5 581 4.5 8.0

20.1 203 4.4 2.8

20.8 2400 4.3 33.2

21.7 366 4.1 5.1

22.5 601 4.0 8.3

24.2 731 3.7 10.1

25.3 236 3.5 3.3

26.5 129 3.4 1.8

27.5 733 3.2 10.1

27.9 904 3.2 12.5

29.9 223 3.0 3.1

30.2 211 3.0 2.9

31.6 718 2.8 9.8

32.3 338 2.8 4.7

36.1 93 2.5 1.3

38.3 264 2.4 3.7

The crystalline form D of Trolaprilat can be by acidifying chemical formula 3 compound solution to pH most between 3.6 and 4.0 (iso-electric points) then crystallization obtain.The initial rubber that forms is by stirring the mixture 20 ℃ to 25 ℃ crystallizations lentamente, and the form D with 4.1% to 4.2% water (corresponding to monohydrate) of stoichiometric can obtain by stir this mixture between 20 to 25 ℃ temperature in 3 to 5 days.

The pull-shaped formula D of crystal Trolapril

The pull-shaped formula D of crystal Trolapril is the false monocrystalline type form of Trolaprilat, comprises the water that is attached to the stoichiometric in its crystalline structure (in its crystalline structure in conjunction with 1 normal water (monohydrate)).The water yield is usually between about 4.1% to about 4.2%.It has X-ray powder diffraction data as shown in table 5, X-ray powder diffraction pattern as shown in Figure 9 and synchrotron pattern as shown in figure 10.

The pull-shaped formula D of crystal Trolapril can use aforesaid " second program ", and according to embodiment 4, the solution of the salt by the chemical formula in the acidified water (3) is about 3.6 to about 4.0 (iso-electric points) to pH, and the crystallization Trolaprilat is produced from water then.The initial rubber that forms is by the crystallization lentamente that stirs the mixture, usually between about 20 ℃ to about 25 ℃ temperature, continue usually between about 3 to about 5 days time, the pull-shaped formula D of the crystal Trolapril water of stoichiometric (in its crystalline structure in conjunction with) forms thus.The pull-shaped formula D of crystal Trolapril can be pure in fact crystalline form obtain.

Table 5

The pull-shaped formula D powder x-ray diffraction of crystal Trolapril data

Pos.[° of 2Th.] [cts] d-distance highly

Relative intensity [%]

6.2 50 4.3 0.4

8.4 1899 10.6 14.3

10.5 874 8.4 6.6

11.5 461 7.7 3.5

12.0 1183 7.4 8.9

12.5 1748 7.1 13.2

13.6 1252 6.5 9.5

14.4 3036 6.1 22.9

15.2 969 5.8 7.3

16.4 13246 5.4 100.0

17.2 8374 5.2 63.2

17.5 710 5.1 5.4

18.8 2385 4.7 18.0

19.2 4452 4.6 33.6

19.9 3709 4.5 28.0

20.2 634 4.4 4.8

21.1 549 4.2 4.1

22.2 4817 4.0 36.4

22.5 1818 4.0 13.7

22.7 1501 3.9 11.3

23.0 933 3.9 7.1

23.6 1001 3.8 7.6

23.9 367 3.7 2.8

24.6 1037 3.6 7.8

25.2 3240 3.5 24.5

25.8 659 3.5 5.0

26.6 948 3.4 7.2

27.1 1656 3.3 12.5

27.5 5696 3.2 43.0

28.5 2383 3.1 18.0

29.4 2130 3.0 16.1

30.0 1600 3.0 12.1

30.8 995 2.9 7.5

31.7 1694 2.8 12.8

32.5 1471 2.8 11.1

33.3 714 2.7 5.4

33.7 1102 2.7 8.3

34.2 1568 2.6 11.8

34.8 1262 2.6 9.5

35.3 1447 2.5 10.9

36.2 1249 2.5 9.4

37.7 1121 2.4 8.5

38.5 1619 2.3 12.2

39.0 1491 2.3 11.3

The preparation of the form A of crystal Trolaprilat and to the conversion of the form D of crystal Trolaprilat

To be pulled in pulp in the water by the Trolapril that " second program " obtains according to embodiment 4 program B.Table 6 has shown the Trolaprilat crystalline form C (water-content: 5.4-6.4%) to monohydrate (the pull-shaped formula D of crystal Trolapril, water-content: conversion 4.2%) of initial formation.After transforming, this is accompanied by the mensuration of controlling water-content in (in process control) (filtration of mud sample) and wet product drying (as vacuum-drying) the back sample in the common technology.Be preferably at present not being higher than about 60 ℃ temperature and carry out drying.

Table 6

The formation of monohydrate

Sample number into spectrum 1234

Churning time (hour) 22 50 73 97

Water-content (%) 5.4-6.4 5.9 4.5 4.2

The form E of crystal Trolaprilat

The pull-shaped formula E of crystal Trolapril is the polymorphic non-solvent compound form of Trolaprilat.It has X-ray powder diffraction data shown in the table 8 and X-ray powder diffraction pattern as shown in figure 11.

The pull-shaped formula E of crystal Trolapril and its production method have been developed at the needs of producing the Trolaprilat that can satisfy following specification: (i) water-content≤1.0%; (ii) instruct the residual solvent of the restriction described in (available from www.ich.org) according to ICH; And the (iii) degradation impurity of some amount " Trolaprilat diketopiperazine ", its≤1.0%, survey as HPLC.The pull-shaped formula E of crystal Trolapril has each of these characteristics.

As mentioned above, find that when from hydroxylic solvent for example water, alcohol or its mixture during crystallization, Trolaprilat formation comprises the water of stoichiometry or nonstoichiometry quantity and/or the different pseudopolymorphic forms of other solvents.The final amt of solvent depends in the Trolaprilat: (i) solvent composition; (ii) selected crystallization condition.

But, when with hydroxylic solvent for example alcohol or water or any isolating crystal pseudopolymorphic forms of its mixture process for example when form A, form B, form A or form D, observe on the crystal in conjunction with the exchange (being converted into another kind of pseudopolymorphic forms) of solvent from a kind of pseudopolymorphic forms.For example, when these crystalline forms in ethanol during pulp, among the pull-shaped formula A of crystal Trolapril on the crystal can be removed by ethanol in conjunction with the water among butanols or the pull-shaped formula D of crystal Trolapril.This result shows that Trolaprilat for example has the high trend that forms different pseudopolymorphic forms during crystallization alcohol and/or the water from hydroxylic solvent, and this causes existing these solvents of the amount of the specification that has exceeded needs in final product.

But one or more discoveries of removing the stabilising method of unnecessary solvent or water from Trolapril crystal pulling pseudopolymorphic forms have caused some different difficulties.Find: if as the Trolaprilat pulp that exists with above-mentioned any crystalline form or its mixture from or crystallization from one or more non-hydroxyl solvents, for example toluene, MTBE, methyl ethyl ketone, acetone, ethyl acetate, THF etc., or its mixture, then observe the Trolaprilat product and be degraded to impurity (degraded product) " Trolaprilat diketopiperazine " (promptly obtaining relatively poor result) unfriendly.The discovery degradation rate depends on: (i) used temperature; (ii) used type of solvent.For example, the crystal Trolapril that is dissolved in THF is pulled in and shows at least per hour 0.2% degraded under the room temperature, when this solution when reflux temperature is heated, this degraded product almost completely forms in a few hours.And crystallization and precipitation can provide a unworkable resin usually from non-hydroxyl solvent.

Find astoundingly and unexpectedly: if, in crystal unit (the pull-shaped formula B-pseudopolymorphic forms of crystal Trolapril), contain alcoholic acid Trolaprilat two solvates and can under mild conditions, easily be converted into Trolaprilat non-solvent compound form (the pull-shaped formula E-polymorphic forms of crystal Trolapril) in that operation (is discussed in following table 7) under the specific drying conditions.Only be found to a spot of degraded product Trolaprilat diketopiperazine, and can almost completely remove and desolvate by (ethanol), this makes product reach specification described above.Find that the speed that transforms depends on: (i) granularity of the pull-shaped formula B of crystal Trolapril; (ii) drying temperature; (iii) vacuum condition; (iv) time of drying.The pull-shaped formula B of crystal Trolapril is preferably between about 20 ℃ to about 60 ℃, be preferably about 40 ℃ to about 60 ℃ temperature range, randomly under vacuum, carry out drying.The pull-shaped formula B of crystal Trolapril can reduce size by for example milling or grinding.

In addition, the pull-shaped formula A of crystal Trolapril, C or D or its mixture can change into the pure in fact pull-shaped formula B of crystal Trolapril by stirring usually in ethanol, and the solvent that is combined in thus in the crystal can be removed with ethanol, as described in the preceding paragraph.The pulp temperature usually between about 0 ℃ to reflux temperature, be preferably between about 10 ℃ to about 60 ℃, most preferably be between about 20 ℃ to about 45 ℃.About 20 ℃ to about 45 ℃ temperature range, between the conversion of usually enough crystalline forms of about 10 to about 15 hours time.Short churning time at a lower temperature can cause incomplete conversion unfriendly.On the contrary, the long churning time under comparatively high temps can produce a large amount of degraded product " Trolaprilat diketopiperazine " unfriendly.The pull-shaped formula B of crystal Trolapril that is obtained then can be above-mentioned and the described mode drying of table 7 to provide the crystal Trolapril pull-shaped formula E.

The experimental result that the pull-shaped formula B of crystal Trolapril is converted into the pull-shaped formula E of crystal Trolapril that (the dry wet pull-shaped formula B of crystal Trolapril that pulp obtained in by ethanol) carries out under different drying conditionss is summarized in following table 7.Displays temperature as a result in the table 7 is high more, and the vacuum tightness of perhaps certain drying conditions is low more, easy more the pull-shaped formula B of crystal Trolapril is converted into the pull-shaped formula E of crystal Trolapril (non-solvent compound) and almost completely removes ethanol.But, the formation of the degraded product Trolaprilat diketopiperazine that also can cause comparatively high amts time of drying that comparatively high temps prolongs down.

Table 8

The pull-shaped formula E powder x-ray diffraction of crystal Trolapril data

Pos.[° of 2Th.] [cts] d-distance highly Relative intensity [%]

9.4 1501 9.4 27.9

9.8 2865 9.0 53.3

12.2 393 7.3 7.3

12.9 592 6.9 11.0

14.9 1214 6.0 22.6

17.4 5380 5.1 100.0

17.7 2818 5.0 52.4

19.2 963 4.6 17.9

20.2 1049 4.4 19.5

21.0 1838 4.2 34.2

22.1 403 4.0 7.5

23.1 759 3.9 14.1

24.8 998 3.6 18.6

26.1 679 3.4 12.6

28.4 2449 3.1 45.5

31.1 757 2.9 14.1

31.9 463 2.8 8.6

34.5 325 2.6 6.0

35.5 361 2.5 6.7

37.2 539 2.4 10.0

Figure 12 has shown the X-ray powder diffraction pattern of the mixture of pull-shaped formula B of crystal Trolapril and the pull-shaped formula E of crystal Trolapril, the pull-shaped formula E of this crystal Trolapril is by the pull-shaped formula B of crystal Trolapril pulp from ethanol, obtains after dry about 15 hours at vacuum (about 1 to the about 5mbar) product that will wet down at about 40 ℃.

The package stability of the Trolaprilat of crystalline form

Table 9 provides the package stability of the different crystalline form of Trolaprilat.As if this table shows, compares with other forms, have the higher trend that resolves into corresponding degraded product Trolaprilat diketopiperazine as the Trolaprilat (the pull-shaped formula E of crystal Trolapril) of non-solvent compound, storage temperature is high more then decompose many more.As if the trend that pull-shaped formula C of crystal Trolapril (its crystalline structure is combined with the water of nonstoichiometry quantity) and the pull-shaped formula B of crystal Trolapril (its crystalline structure is combined with 2 normal ethanol) are decomposed into corresponding degraded product is obviously lower, but still can determine degraded.On the contrary, pull-shaped formula A of crystal Trolapril (containing 2 normal butanols in its crystal unit) and the pull-shaped formula D of crystal Trolapril (containing 1 normal water in its crystal unit) stablize Trolaprilat significantly, only observe the degraded product of very few number after 4 months at room temperature storage.

Table 9

The package stability of different Trolaprilat crystalline forms

The Trolaprilat crystalline form	The amount [% passes through HPLC] of Trolaprilat diketopiperazine behind separation and the dry wet product	Storage temperature	Period of storage [moon]	Store the amount [% passes through HPLC] of back Trolaprilat diketopiperazine
The Trolaprilat crystalline form		Storage temperature	Period of storage [moon]		Form A	Do not detect	20-25	4	0.02
Form B ¹	Do not detect	20-25	4	0.20	Form A	Do not detect	20-25	4	0.02
Form B ¹	Do not detect	20-25	4	0.20	Form A	Do not detect	20-25	4	0.26
Form D	Do not detect	20-25	4	0.03	Form A	Do not detect	20-25	4	0.26
Form D	Do not detect	20-25	4	0.03	Form E	0.34	4-8	3	0.75
Form E	0.19	20-25	3	0.92	Form E	0.34	4-8	3	0.75

1-is stored in the sealed vial according to the crystal that embodiment 2 obtains.

Pharmaceutical composition

The present invention also provides pharmaceutical composition, and it comprises pharmaceutically Trolaprilat compound at least a of the present invention (as activeconstituents) and one or more pharmaceutically acceptable carriers of significant quantity.Randomly, pharmaceutical composition can comprise one or more other compound, medicine or the material compatible with carrier with the Trolaprilat compound that can easily be determined by those skilled in the art, includes but not limited to tinting material, separant, coating-forming agent, sweeting agent and/or seasonings, tackiness agent, spices, sanitas and/or antioxidant.

In a preferred embodiment, pharmaceutical composition of the present invention comprises the pull-shaped formula A of crystal Trolapril, the pull-shaped formula B of crystal Trolapril, the pull-shaped formula C of crystal Trolapril, the pull-shaped formula D of crystal Trolapril or the pull-shaped formula E of crystal Trolapril, or any its combination.

In another preferred embodiment, pharmaceutical composition of the present invention comprises and comprises the have chemical formula Trolaprilat compound of crystalline form of structure (wherein R is the C1-C4 alkyl) of (4), wherein the amount of the alcohol that exists in the pharmaceutical composition is no more than about 5000ppm, if condition is the C1 alkyl for R, then the amount of the alcohol that exists in the pharmaceutical composition is no more than about 3000ppm.

In another preferred embodiment, pharmaceutical composition of the present invention comprises and comprises the have chemical formula Trolaprilat compound of crystalline form of structure (wherein n=0) of (4) that wherein the amount of the water that exists in the pharmaceutical composition is no more than about 1.0%.

Pharmaceutical composition possibility of the present invention for example, is made solid or liquid form especially for orally using, and perhaps makes through skin and uses.

The preparation of the present invention that is fit to orally use can be capsule, cachet, pill, tablet, lozenge, powder, particulate form, as solution in water or the on-aqueous liquid or suspension, as milk sap, as elixir or syrup etc.The solid dosage of pharmaceutical composition of the present invention optional by one or more intestines or field of pharmaceutical preparations in other coatings of knowing come indentation (scored) or bag quilt.Also can prepare activeconstituents that they are comprised to provide wherein slowly or the release of control.

The preparation of the present invention that is fit to use through skin can be powder, sprays, ointment, stickup, face cream, lotion, gel, solution and patch.Transdermal patch has provides the attendant advantages of Trolaprilat compound controlled delivery of the present invention to health.

The method for preparing pharmaceutical composition of the present invention generally includes one or more Trolaprilat compounds of the present invention and one or more solid support materials and randomly, with a kind of multiple ancillary component blended step is arranged.

For the preparation oral dosage form, pharmaceutical composition of the present invention can be by for example balancedly and nearly mixing one or more Trolaprilat compounds with solid carrier one or more liquid or that fine separate, then, if necessary or desired, product is carried out moulding (by compression, casting etc.) or forms capsule be prepared.The method that production is suitable for the pharmaceutical preparation that the mankind and/or animal orally use is well known by persons skilled in the art, at for example " pharmaceutical Capsules " (ISBN 0-85369-568-7, Pharmaceutical Press, 2004) and " handbook of Pharmaceutical ManufacturingFormulations " (ISBN 0-84931-7479, CRC Press, 1999) describe to some extent in.

Endermic formulation can be by for example preparing by one or more Trolaprilats are dissolved or are dispersed in the suitable media.Can use absorption enhancer to strengthen the compound skin of flowing through.For example can be by rate controlling membranes being provided or compound being dispersed to the speed of polymer matrix or gel controlling flow warp.Producing the method for medicinal transdermal patch knows on pharmaceutical industry.These methods, for example, at laid-open U.S. Patents application number U.S.2004/0052835, at U.S. Patent number U.S.5,290,561 and 6,303,141 and at Russell O.Potts and Richard.H.Guy ＂ Mechanisms of Transdermal Drug Delivery, Drugs andPharmaceutical Sciences:a Series of Textbooks and Monographs ＂ (ISBN0-8247-9863-5,1997) and Kenneth A.Walters, ＂ Dermatological and TransdermalFormulations, describe to some extent among the Drugs and the Pharmaceutical Sciences:a Series of Textbooks andMonographs ＂ (ISBN 0-8247-9889-9,2002).

Pharmaceutical composition of the present invention usually will be under doctor's guidance, and with suitable type of service, the dosage of selecting suitably with the corresponding to method of conventional medical science, veterinary science and pharmacy practice uses.

No matter the use approach of selecting, Trolaprilat compound of the present invention and pharmaceutical composition can be made pharmaceutically acceptable formulation by ordinary method well known by persons skilled in the art.

The actual dose level of used activeconstituents can change in the pharmaceutical composition of the present invention, patient is not caused the amount of toxic activeconstituents with the composition that obtains to reach effectively the needed therapeutic response of given patient, use and pattern.

Selected dosage level depends on the numerous factors known to those skilled in the art, the severity of the discharge rate of the activity of for example used specific Trolaprilat compound or its salt, use approach, duration of service, used specific Trolaprilat compound, the medical science symptom of being treated, the time that treatment continues, other drug, age, sex, body weight, symptom, general health and the medical history of uniting the compound of use and/or material, the patient that treats with the Trolaprilat compound, and the similar factor of knowing in medical science, veterinary science and the pharmacy.

Have that the doctor of ordinary skill or animal doctor can be easy to determine and the significant quantity of the pharmaceutical composition of the present invention that the medical problem of predetermined treatment given patient is required.For example, doctor or animal doctor can begin by the required dosage of result of treatment that reaches required that be lower than of used Trolaprilat compound of the present invention from pharmaceutical composition, increase dosage then gradually until reaching required effect.

Usually, Trolaprilat compound of the present invention, suitable dosage every day of pharmaceutical composition that perhaps contains one or more Trolaprilat compounds of the present invention is the lowest dose level that can access required result of treatment, and it depends on one or more factors discussed above usually.This dosage can reasonably determined in medical science or the veterinary science determination range by doctor who cures mainly or animal doctor.

If desired, effective every day of the dosage of active Trolaprilat compound can use respectively in the suitable interval in one day by the sub-doses more than 2,3,4,5,6 or 6, was chosen as unit dosage.

Methods of treatment

Trolaprilat compound of the present invention and pharmaceutical composition can be used for the human and animal and go up generation hypertension effect.Therefore the present invention also provides the method for treatment hypertension, cardiac dysfunction or other medical science symptom relevant with hypertension, comprises the pharmaceutical composition of the present invention that uses significant quantity to the individuality of this treatment of needs.This area general doctor or animal doctor can determine easily whether body needs this treatment one by one.

In a preferred embodiment, method pharmaceutical compositions for use of the present invention comprises the pull-shaped formula A of crystal Trolapril, the pull-shaped formula B of crystal Trolapril, the pull-shaped formula C of crystal Trolapril, the pull-shaped formula D of crystal Trolapril, the pull-shaped formula E of crystal Trolapril or any its combination.

Following embodiment describes and has explained the crystalline form of Trolaprilat and the method in the present invention, and it only is in order to explain the present invention, rather than limits its scope or intension.Those skilled in the art can easily understand, and the used condition of program and/or certain change of step can be used to prepare these crystalline forms described in the embodiment.All output that calculates is proofreaied and correct through identifying.

Embodiment 1

The preparation of the pull-shaped formula A of crystal Trolapril

The pull-shaped formula A of crystal Trolapril prepares by above-described first program.

With NaOH (6.5g, 153.6mmol; Mensuration=94.52%), water (157ml), ethanol (157ml, technical grade contain～5% 2-propyl alcohol) and Trolapril (31.5g, 72.94mmol; Mensuration=99.7%) solution was stirring 15 hours to about 25 ℃ medium temperature between about 20 ℃.After control showed almost completely saponification (passing through HPLC) in technology, the solution of concentrating clarifying added propyl carbinol (160ml) to 167.05g in enriched product in a vacuum.Heat this mixture between about 60 ℃ to about 70 ℃ medium temperature, add 2N water-based hydrochloric acid (150.4mmol), pH reduces to 3.66 from 12.09 thus.Organic layer is separated 66 ℃ medium temperature, extracts with propyl carbinol (80ml) 65 ℃ medium temperatures.Between about 63 ℃ to about 65 ℃ medium temperatures with twice of water washing mixings organic layer (40ml at every turn).Then in the organic layers that vacuum concentration obtained (306.4g altogether) between about 50 ℃ of extremely about 60 ℃ temperature, white solid precipitation after being concentrated into the quantity of 190g thus.Further concentrated suspension liquid adds 80mlMTBE to precipitate fully to the quantity of 75.1g in a vacuum.Between about 20 ℃ to about 25 ℃ medium temperature stirred suspensions 3.5 hours.After the filtration, with twice of the wet product of MTBE washing (each 80ml), then 40 ℃ of vacuum-dryings 15 hours so that Trolaprilat (output: 36.51g, 66.67mmol, 91.4% of the two solvent thing forms that have propyl carbinol to be provided; Measure (0.1N HClO ₄)=73.5%; HPLC purity=100%).

Embodiment 2

From reaction mixture, separate Trolaprilat and form B crystallization as single crystal

Trolaprilat comes crystallization and separates by above-described second program.

With NaOH (0.96g, 22.68mmol; Mensuration=94.52%), water (22ml) ethanol (22ml, technical grade contain～the 5%2-propyl alcohol) and Trolapril (4.5g, 10.42mmol; Mensuration=99.7%) solution was stirring 19 hours to about 25 ℃ medium temperature between about 20 ℃.After control shows almost completely saponification (passing through HPLC) in technology, be 3.8 (22.8mmol with 2N water-based hydrochloric acid clear aqueous solution being acidified to pH to about 25 ℃ temperature between about 20 ℃; Solution is by short crystallization in acidifying, and crystallization starts from pH=4.6).Between about 20 ℃ of stirred suspensions to about 25 ℃ temperature (under the situation behind this adjusting pH, churning time is 47 hours, and pH is adjusted to 3.82 by adding a 2N water-based NaOH solution from 3.71); Usually 5-6 hour maximum churning time is enough under this pH), filter then.Water (30ml) washs wet product and descends dry 15 hours so that Trolaprilat (output: 4.0g, 9.06mmol, 86.9% to be provided in 40 ℃ in vacuum (1-5mbar); Measure=91.15%; Water-content: 1.02-1.12%, ethanol content: 7.52-8.44%, 2-propyl alcohol content: 0.26-0.29%, chloride content=do not detect).

As discussed above, the solvent in the end product can change according to used condition.

The crystallization of the Trolaprilat crystalline form B that measures for X ray

The blended filtrate was being stored slowly crystallization of Trolaprilat thus 12 days between about 20 ℃ of extremely about 25 ℃ temperature.Collect crystal and 30 ℃ vacuum-drying 14.5 hours.X ray is measured and is shown the existence that has pure Trolaprilat two solvates of 2 equivalent alcoholic acid.

Note: common short crystallization procedure

Stop after pH reaches about 4.5 to about 5.0 with 2N water-based HCl acidifying mixture.Then with the short crystalline mixture of Trolaprilat crystalline form B, and stirring to about 25 ℃ temperature until can clearly observing crystallization (in about 15 minutes about 10 between about 20 ℃; PH raises in stirring and crystallisation process).Then, continue to add 2N water-based HCl (dropwise) and reach iso-electric point until pH.

Embodiment 3

The preparation of the pull-shaped formula C of crystal Trolapril

The pull-shaped formula C of crystal Trolapril prepares by above-described second program.

With NaOH (1.84g, 43.48mmol; Mensuration=94.52%), water (45ml), ethanol (45ml, technical grade contain～the 5%2-propyl alcohol) and Trolapril (9.0g, 20.78mmol; Mensuration=99.4%) solution was stirring 14 hours to about 25 ℃ medium temperature between about 20 ℃.Control shows (passing through HPLC) after the almost completely saponification in technology, and concentrated reaction mixture is to the quantity of 64.64g in a vacuum.

Use half of spissated reaction mixture, by adding 2N water-based hydrochloric acid (21.61mmol) and several 2N water-based NaOH solution with pH regulator to 3.8.In initial acidifying, be to observe sticking ulotrichy precipitation at 6 o'clock at pH, continue to form after the acidifying and contain tenderly white look solid suspension.Between about 20 ℃ of stirred suspensions 16 hours and filtering to about 25 ℃ temperature.With the wet product of water (30ml) and acetone (30ml) washing and in vacuum (1-5mbar) 40 ℃ dry 24 hours down, following 24 hours of room temperature is to provide the pull-shaped formula C of crystal Trolapril (output: 3.18g, 7.45mmol, 71.7% (deduction); Measure (0.1N HClO ₄)=94.35%; HPLC purity=100%; Water-content=5.67%, chloride content=0.16%).

Embodiment 4

The preparation of the pull-shaped formula D of crystal Trolapril

The pull-shaped formula D of crystal Trolapril prepares by two kinds of different modes, (program A and program B) as described below.

Program A

In program A, the pull-shaped formula D of crystal Trolapril prepares by above-described second program.

With NaOH (0.92g, 21.74mmol; Mensuration=94.52%), water (22ml), ethanol (22ml, technical grade contain～the 5%2-propyl alcohol) and Trolapril (4.5g, 10.39mmol; Mensuration=99.4%) solution was stirring 19 hours to about 25 ℃ medium temperature between about 20 ℃.Control shows (passing through HPLC) after the almost completely saponification in technology, and concentrated reaction mixture is to the quantity of 24.42g in a vacuum.Between about 20 ℃ to about 25 ℃ temperature, in 1 hour time, this settled solution (pH=13) is slowly joined in the mixture of 2N water-based hydrochloric acid (25.22mmol) and water (12ml).In adition process, observe sticking ulotrichy precipitation.Then, the pH of mixture is adjusted to 3.84 from 2.74, to about 25 ℃ temperature, was stirring the mixture 4 days between about 20 ℃ by adding several 2N water-based NaOH solution.Filtering suspension liquid washs wet product with water (15ml) then, and at 40 ℃ of down dry 15 hours Trolaprilat (output: 4.07g, 9.54mmol, 91.8% so that crystalline form D to be provided of vacuum (1-5mbar); Measure (0.1N HClO ₄)=96%; HPLC purity=99.82%; Water-content=4.13%, chloride content=0.15%).

Program B

With NaOH (6.70g, 158.3mmol; Mensuration=94.52%), water (98ml) ethanol (98ml, technical grade contain～the 5%2-propyl alcohol) and Trolapril (31.5g, 72.94mmol; Mensuration=99.7%) solution was stirring 21 hours to about 25 ℃ medium temperature between about 20 ℃.Control shows (passing through HPLC) after the almost completely saponification in technology, is 3.8 (159mmol with 2N water-based hydrochloric acid clear aqueous solution being acidified to pH to about 25 ℃ temperature between about 20 ℃; Stop to add 2N water-based HCl when pH=4.67, short crystallization solution slowly begins crystallization thus; After about 10 minutes, continue to add 2N water-based HCl).Between about 20 ℃ to about 25 ℃ temperature stirred suspension filtered then in 22 hours so that 42.12g to be provided the product that wets.

40 ℃ in vacuum (1-5mbar) down the wet product 15 hours of dry 2.7g so that Trolaprilat (output: 1.84g, 4.31mmol, 5.9% to be provided; Measure=94.18%; Water-content: 1.42-1.47%, ethanol content: 4.17-4.26%, 2-propyl alcohol content: 0.19%, chloride content=do not detect).

Wet product mud in the remainder water (230ml) is heated to 55 ℃ medium temperature, is cooled to then between about 20 ℃ to stir 4 days altogether to about 25 ℃ medium temperatures and under this temperature.From suspension, (in technology, control) and take out sample at interval to measure water-content.

21.5 after hour, take out a sample, filter, water (10ml) washs and descends dry 15 hours so that Trolaprilat (output: 1.2g, 2.81mmol, 3.86% to be provided in 40 ℃ in vacuum (1-5mbar); Measure=94.4%; Water-content: 5.35-6.4%, ethanol content: do not detect 2-propyl alcohol content: do not detect; Chloride content=do not detect).

After extra 28 hours, take out a sample, filter, water (10ml) washs and descends dry 15 hours so that Trolaprilat (output: 1.04g, 2.43mmol, 3.33% to be provided in 40 ℃ in vacuum (1-5mbar); Water-content: 5.92%).

After extra 23 hours, take out a sample, filter, water (10ml) washs and descends dry 15 hours so that Trolaprilat (output: 1.48g, 3.51mmol, 4.81% to be provided in 40 ℃ in vacuum (1-5mbar); Water-content: 4.52%).

After extra 24 hours, with remaining suspension filtered, the wet product of water (100ml) washing descends dry 18 hours so that Trolaprilat (output: 21.04g, 50.04mmol, 68.61%, overall yield: 86% to be provided in 40 ℃ in vacuum (1-5mbar); Measure (0.1N HClO ₄=95.73%; HPLC purity: 99.98%; Water-content: 4.18%, ethanol content: do not detect 2-propyl alcohol content: do not detect; Chloride content: do not detect).

Embodiment 5

Method and its conversion of preparing the pull-shaped formula B of crystal Trolapril to crystalline form E

From saponification mixture crystallization with separate wet product of Trolaprilat and X-ray powder diffraction (PXRD) research

With NaOH (10.8g, 255mmol; Mensuration=94.5%), water (158ml), ethanol (158ml) and Trolapril (50g, 115mmol; Mensuration=99.4%) solution was stirring 16.5 hours to about 25 ℃ medium temperature between about 20 ℃.Control shows (passing through HPLC) after the almost completely saponification in technology, (short crystallization solution during at pH=4.6 is according to common short crystallization procedure (referring to embodiment 2) by adding 2N water-based hydrochloric acid the pH of clear aqueous solution being transferred to 3.8 between about 20 ℃ to about 25 ℃ temperature; In this case, begin at 10 minutes intercrystallines, pH rises to 5.55 in crystallization, continues acidifying then until reaching pH=3.8).After pH=3.8 stirs 5 minutes, take out a sample of suspension and analyze.((1/1, v/v) washing is to provide the first wet product of 1.4g with about 0.5ml EtOH/ water for filtering sample; To the X-ray powder diffraction (PXRD) of this sample measure show have pure Trolaprilat polymorphic forms B).

Stirring remaining suspension 5 hours to about 25 ℃ temperature between about 20 ℃, filter then, with water (160ml) and the wet product of ethanol (160ml) washing with second of Trolaprilat that pure crystalline form B of containing of 63.5g the is provided product that wets.

Use the research of the second wet product:

Research embodiment 1

7.6g the second wet product in crystallizing dish room temperature (standard atmosphere pressure) down and in the slight air-flow dry 18 hours, be mainly crystalline form B to provide, the Trolaprilat (output: 7.4g that has a small amount of form E to pollute; Measure (0.1N HClO ₄)=81.91%; HPLC purity=99.96%; Trolaprilat diketopiperazine: do not detect; Water-content=0.55%, ethanol content=17.9%). Note: can avoid transforming short time of drying under this condition, and under the same temperature the long amount that may increase form E time of drying until transforming point (also referring to research embodiment 7) completely.

Usually form B depends on drying temperature, vacuum and granularity to the transformation efficiency of form E.Conversion can be quickened by grinding or grind under wet product and/or the identical or higher in a vacuum temperature drying, for

example research embodiment

2 and 3 or table 7 described in.Prolong extensive other transformation time of level according to drying means and/or equipment used (for example when using pallet layer, the thickness of substrate layer).

Research embodiment 2:

Second wet 15 hours Trolaprilat (output: 3.8g of product at 50 ℃ of following dry 5g of vacuum (1-5mbar) so that crystalline form E to be provided; Measure (0.1N HClO ₄)=99.41%; HPLC purity=99.57%; Trolaprilat diketopiperazine: 0.40%; Water-content: 0.34%, ethanol content: 0.10%).

Research embodiment 3:

In vacuum (＜1mbar) 50 ℃ of following second wet 25 hours Trolaprilat (output: 3.7g of product of dry 5g so that crystalline form E to be provided; Measure (0.1N HClO ₄)=98.9%; HPLC purity=99.48%; Trolaprilat diketopiperazine: 0.51%; Water-content: 0.27%, ethanol content: 0.09%).

Research embodiment 4:

Under about 40 ℃ temperature, stir the suspension 16 hours of the second wet product of 32.4g in the ethanol (200ml), stirring 2 hours to about 25 ℃ temperature between about 20 ℃ then.After the filtration, with the three wet product of the wet product of ethanol (80ml) washing with pure crystalline form B that 31.4g is provided.

Use the research of the 3rd wet product:

Research embodiment 5:

Second half of the 3rd wet product in crystallizing dish room temperature (standard atmosphere pressure) down and in the slight air-flow dry 21.5 hours, with the Trolaprilat (output: 13.6g that crystalline form B is provided; Measure (0.1N HClO ₄)=81.57%; HPLC purity=99.97%; Trolaprilat diketopiperazine: do not detect; Water-content: 0.56%, ethanol content=18.49%).Attention: referring to research embodiment 1.

Research embodiment 6:

In vacuum (＜1mbar) 50 ℃ of down dry the 3rd only about half of wet 21.5 hours Trolaprilat (output: 11.2g of product so that crystalline form E to be provided; Measure (0.1N HClO ₄)=99.04%; HPLC purity=99.52%; Trolaprilat diketopiperazine: 0.45%; Water-content: 0.30%, ethanol content=0.06%).

Research embodiment 7:

A sample of the 3rd wet product pulverized and be filtered to the PXRD specimen holder.Trolaprilat crystalline form B pure under room temperature and the standard atmosphere pressure follows continuous P XRD determining (seeing Figure 15) after form E transforms.In 19 hours, finish first 18 mensuration.The 19th is determined at other storage and carries out (biased sample also was filtered to specimen holder once more before in the end mensuration was carried out) after 35 hours under same condition.

Embodiment 6

The program that increases in proportion of the pull-shaped formula E of preparation crystal Trolapril

The pull-shaped formula E of crystal Trolapril prepares in following mode.

With NaOH (144.8g, 3.42mol; Mensuration=94.5%), water (2573ml), ethanol (2187ml) and Trolapril (680g, 1.58mol; Mensuration=99.81%) solution was stirring 18 hours to about 25 ℃ medium temperature between about 20 ℃.Control shows (passing through HPLC) after the almost completely saponification in technology, by adding 2N water-based hydrochloric acid the pH of clear aqueous solution is being transferred to 3.8 to about 25 ℃ temperature (according to common short crystallization procedure with the short crystallization of solution, referring to embodiment 2) between about 20 ℃.Between about 20 ℃ of stirred suspensions 5.5 hours to about 25 ℃ temperature, filter then, with water (2149ml) and ethanol (2198ml) the washing product that wets.Then, the suspension that stirs the wet product in the ethanol (6046ml) to about 43 ℃ temperature between about 38 ℃ 14 hours, stirring 2 hours to about 25 ℃ temperature between about 20 ℃ then.After the filtration, with the wet product of ethanol (2224ml) washing, vacuum (＜1mbar) 40 ℃ dry down until Trolaprilat (output: 582g, 1.44mol, 91.3% of ethanol content＜0.5% (4 days) so that crystalline form E to be provided; Measure (NaOH)=99.74%; HPLC purity=99.33%; Trolaprilat diketopiperazine: 0.52%; Water-content: 0.54%, ethanol content: 955ppm; Chloride content=do not detect).

Though the present invention is described with singularity, and with reference to its specific embodiment, one of skill in the art will recognize that it as described and fall into various variants, modification and the replacement of scope of the present invention and intension here.All such modifications and variant be considered to fall into herein as described with desired scope of the present invention in, the present invention is only limited by the scope of following claims, these claims should make an explanation with as far as possible reasonable wide scope.

Run through and quoted disclosing of various books, patent, magazine article, webpage and other in this document.The disclosing and all be incorporated herein by reference in full here of these books, patent, magazine article, webpage and other.

Claims

1, a kind of method for preparing Trolaprilat may further comprise the steps:

(a) Trolapril and hydroxide compound are at least almost completely being reacted effectively carrying out in the saponification reaction solvent under the saponified temperature and time, wherein hydroxide compound is the alkylammonium oxyhydroxide of alkali metal hydroxide, alkaline earth metal hydroxides, tetraalkylammonium hydroxides or replacement, wherein Trolapril, hydroxide compound and saponification reaction solvent each all use with the amount of effective generation reaction mixture, this reaction mixture comprises the salt of chemical formula 3:

(b) acid of amount that makes the reaction mixture of step (a) and the iso-electric point that reaches mixture with the pH that makes mixture effectively and Trolaprilat is provided with the free amino acid form of Trolaprilat is in the iso-electric point that reaches mixture with the pH that makes mixture effectively and provide with the free amino acid form of Trolaprilat under the temperature and time of Trolaprilat and mix; With

2, method according to claim 1, wherein hydroxide compound is to be enough to the providing amount of at least 2.0 normal oxyhydroxide to exist in the reaction mixture of step (a).

3, method according to claim 1, wherein the saponification reaction solvent is C1-C4 alcohol or water, or its any mixture.

4, method according to claim 3, wherein the saponification reaction solvent is the mixture of second alcohol and water.

5, method according to claim 1, wherein the temperature of reaction of step (a) is between about 0 ℃ to about 40 ℃.

6, method according to claim 1, wherein the pH of the reaction mixture of step (b) is between about 3.6 to about 4.0.

7, method according to claim 1, wherein the used acid of step (b) is hydrochloric acid, Hydrogen bromide, thiosulfonic acid, alkylsulphonic acid, aryl sulfonic acid or phosphoric acid.

8, method according to claim 7, wherein the used acid of step (b) is hydrochloric acid.

9, a kind of method for preparing the crystal Trolaprilat of polymorphic or pseudopolymorphic forms may further comprise the steps:

(a) Trolapril and hydroxide compound are at least almost completely being reacted effectively carrying out in the saponification reaction solvent that is selected from water, C1-C4 alcohol or its mixture under the saponified temperature and time, wherein hydroxide compound is the alkylammonium oxyhydroxide of alkali metal hydroxide, alkaline earth metal hydroxides, tetraalkylammonium hydroxides or replacement, wherein Trolapril, hydroxide compound and saponification reaction solvent each all use with the amount of effective generation reaction mixture, this reaction mixture comprises the salt of chemical formula 3:

(c), in reaction mixture, add the water of the amount that the aqueous solution effectively is provided if the reaction mixture of step (b) is not the aqueous solution;

(d) with the product of step (c) and the iso-electric point that reaches mixture with the pH that makes mixture effectively and the acid of amount that Trolaprilat is provided with the free amino acid form of Trolaprilat in the iso-electric point that reaches mixture with the pH that makes mixture effectively and provide with the free amino acid form of Trolaprilat under the temperature and time of Trolaprilat and mix;

(e) from the mixture of step (d), provide under the temperature of Trolaprilat with the free amino acid form of Trolaprilat in the solution that is comprising propyl carbinol and water effectively and extract Trolaprilat in order to the propyl carbinol of amount that in the solution that comprises propyl carbinol and water, provides Trolaprilat effectively with the free amino acid form of Trolaprilat; With

10, method according to claim 9, wherein hydroxide compound is an alkali metal hydroxide.

11, method according to claim 10, wherein alkali metal compound is lithium hydroxide, sodium hydroxide or potassium hydroxide.

12, method according to claim 11, wherein hydroxide compound is to be enough to the providing amount of at least 2.0 normal oxyhydroxide to exist in the reaction mixture of step (a).

13, method according to claim 9, wherein the saponification reaction solvent is C1-C4 alcohol or water, or its any mixture.

14, method according to claim 13, wherein the saponification reaction solvent is the mixture of second alcohol and water.

15, method according to claim 9, wherein the used temperature of reaction of step (a) is between about 0 ℃ to about 40 ℃.

16, method according to claim 9, wherein the pH of the reaction mixture of step (d) is between about 3.6 to about 4.0.

17, method according to claim 9, wherein the used acid of step (d) is hydrochloric acid, Hydrogen bromide, thiosulfonic acid, alkylsulphonic acid, aryl sulfonic acid or phosphoric acid.

18, method according to claim 17, wherein the used acid of step (d) is hydrochloric acid.

19, method according to claim 9, wherein the used temperature of step (e) between about room temperature to the about boiling point of the azeotropic mixture of propyl carbinol and water.

20, method according to claim 19, wherein the used temperature of step (e) between about room temperature to about 70 ℃.

21, method according to claim 9, the crystal Trolaprilat that is wherein provided is pure in fact.

22, method according to claim 21, the crystal Trolaprilat that is wherein provided are the pull-shaped formula A of crystal Trolapril.

23, the pure in fact crystalline form of a kind of production or as the method for the Trolaprilat of the mixture of different crystal form may further comprise the steps:

(c), in reaction mixture, add water with the amount that the aqueous solution is provided effectively if the reaction mixture of step (b) is not the aqueous solution;

(d) make the product of step (c) and the iso-electric point that reaches mixture with the pH that makes mixture effectively and with pure in fact free amino acid form or the acid of amount of Trolaprilat is provided as the mixture of two kinds of different free amino acid forms at least the mixture of different free amino acid forms provides under the temperature and time of Trolaprilat and mixes in the iso-electric point that reaches mixture with the pH that makes mixture effectively and with pure in fact free amino acid form or as at least two kinds;

(e) product with step (d) separates from supernatant liquor; With

(f) product of drying step (e) with provide pure in fact crystalline form or as the Trolaprilat of the mixture of at least two kinds of different crystal forms.

24, method according to claim 23, wherein hydroxide compound is an alkali metal hydroxide.

25, method according to claim 24, wherein alkali metal compound is lithium hydroxide, sodium hydroxide or potassium hydroxide.

26, method according to claim 25, wherein hydroxide compound is to be enough to the providing amount of at least 2.0 normal oxyhydroxide to exist in the reaction mixture of step (a).

27, method according to claim 23, wherein the used temperature of reaction of step (a) is between about 0 ℃ to about 40 ℃.

28, method according to claim 23, wherein the used temperature of reaction of step (d) is between about 20 ℃ to about 25 ℃.

29, method according to claim 23, wherein the pH of the reaction mixture of step (d) is between about 3.6 to about 4.0.

30, method according to claim 23, wherein the used acid of step (d) is hydrochloric acid, Hydrogen bromide, thiosulfonic acid, alkylsulphonic acid, aryl sulfonic acid or phosphoric acid.

31, method according to claim 30, wherein said acid are hydrochloric acid.

32, method according to claim 23, wherein the saponification reaction solvent is the mixture of second alcohol and water.

33, method according to claim 23 is included in effective preparation has the aqueous mixture pulp that makes step (d) under the temperature and time of Trolaprilat of water of stoichiometry or nonstoichiometry quantity in the crystalline structure of Trolaprilat.

34, method according to claim 33, wherein the used temperature of step (d) is between about 20 ℃ to about 25 ℃.

35, the pure in fact crystalline form of a kind of production or as the method for the Trolaprilat of the mixture of crystalline form may further comprise the steps:

(a) make Trolapril and at least 2.0 normal NaOH in comprising the saponification reaction solvent of second alcohol and water about 20 ℃ to about 25 ℃ of times that reaction is enough to produce the reaction mixture of the salt that comprises chemical formula 3, the volume ratio of second alcohol and water is about 1/1 to about 1/1.5:

Wherein, M is a sodium, and n is 2;

(c) product with step (b) separates from supernatant liquor; With

36, method according to claim 35, wherein Trolaprilat is with pure in fact crystalline form production.

37, method according to claim 35, wherein the Trolaprilat of being produced is the pull-shaped formula B of crystal Trolapril.

38, method according to claim 35, wherein the Trolaprilat of being produced is the pull-shaped formula C of crystal Trolapril.

39, method according to claim 35, wherein the Trolaprilat of being produced is the pull-shaped formula D of crystal Trolapril.

40, a kind of method of producing the pull-shaped formula E of crystal Trolapril is included in and effectively removes crystalline alcoholic acid temperature, pressure and the dried crystals Trolaprilat form B under time of drying that is bonded among the pull-shaped formula B of crystal Trolapril.

41, the Trolaprilat of crystalline form that comprises the structure of chemical formula 4:

Wherein R is H or C1-C4 alkyl, and n is 0-2, can be stoichiometry or non-stoichiometric.

42, according to the described Trolaprilat of claim 41, wherein R is H, and n is 1.

43, according to the described Trolaprilat of claim 41, wherein R is H, and n is greater than 1 and be non-stoichiometric.

44, according to the described Trolaprilat of claim 41, wherein R is the C1-C4 alkyl, and n is 2.

45, according to the described Trolaprilat of claim 44, wherein R is the C2 alkyl.

46, according to the described Trolaprilat of claim 44, wherein R is a normal-butyl.

47, according to the described Trolaprilat of claim 41, wherein n is 0.

48, a kind of pseudopolymorphic forms that comprises the Trolaprilat of the pull-shaped formula A of crystal Trolapril.

49, according to the pseudopolymorphic forms of the described Trolaprilat of claim 48, it has in fact as table 1 and X-ray diffraction pattern shown in Figure 1.

50, according to the pseudopolymorphic forms of the described Trolaprilat of claim 48, it is pure in fact.

51, a kind of pseudopolymorphic forms that comprises the Trolaprilat of the pull-shaped formula B of crystal Trolapril.

52, according to the pseudopolymorphic forms of the described Trolaprilat of claim 51, it has X-ray powder diffraction peak in fact as shown in figure 13.

53, according to the pseudopolymorphic forms of the described Trolaprilat of claim 51, it has following X-ray powder diffraction peak at 2 θ degree: 8.1,9.6,13.8,17.4,18.1,18.4,19.3,20.5 and 22.9.

54, according to the pseudopolymorphic forms of the described Trolaprilat of claim 51, it is pure in fact.

55, a kind of pseudopolymorphic forms that comprises the Trolaprilat of the pull-shaped formula C of crystal Trolapril.

56, according to the pseudopolymorphic forms of the described Trolaprilat of claim 55, it has in fact as table 4 and X-ray diffraction pattern shown in Figure 8.

57, according to the pseudopolymorphic forms of the described Trolaprilat of claim 55, it is pure in fact.

58, a kind of pseudopolymorphic forms that comprises the Trolaprilat of the pull-shaped formula D of crystal Trolapril.

59, according to the pseudopolymorphic forms of the described Trolaprilat of claim 58, it has in fact as table 5 and X-ray diffraction pattern shown in Figure 9.

60, according to the pseudopolymorphic forms of the described Trolaprilat of claim 58, it is pure in fact.

61, a kind of polymorphic forms that comprises the Trolaprilat of the pull-shaped formula E of crystal Trolapril.

62, according to the polymorphic forms of the described Trolaprilat of claim 61, it has in fact as table 8 and X-ray diffraction pattern shown in Figure 11.

63, according to the polymorphic forms of the described Trolaprilat of claim 61, it is pure in fact.

64, according to the polymorphic forms of the described Trolaprilat of claim 61, wherein Trolaprilat does not contain the water of about 1% the amount of surpassing.

65, according to the polymorphic forms of the described Trolaprilat of claim 61, wherein Trolaprilat does not contain one or more residual solvents of the combined amount that exceeds present pharmaceutically acceptable restriction.

66, a kind of pharmaceutical composition, it comprises compound at least a as claimed in claim 41 and pharmaceutically acceptable carrier that significant quantity is gone up in treatment.

67, a kind of pharmaceutical composition, it comprises at least a Trolaprilat compound and pharmaceutically acceptable carrier that significant quantity is gone up in treatment, and wherein the Trolaprilat compound is the pull-shaped formula A of crystal Trolapril, the pull-shaped formula B of crystal Trolapril, the pull-shaped formula C of crystal Trolapril, the pull-shaped formula D of crystal Trolapril, the pull-shaped formula E of crystal Trolapril or its any combination.

68, according to the described pharmaceutical composition of claim 67, wherein pharmaceutical composition is oral dosage form or can uses through skin.

69, according to the described pharmaceutical composition of claim 68, wherein pharmaceutical composition is the form of tablet or capsular form or transdermal patch.

70, a kind of method for the treatment of hypertension or cardiac dysfunction comprises the described pharmaceutical composition of claim 67 that uses significant quantity to the individuality of this treatment of needs.

71, a kind of method for preparing the crystal Trolaprilat of polymorphic or pseudopolymorphic forms may further comprise the steps:

72, method according to claim 9, wherein Trolaprilat provides by the method that comprises following steps:

(a) Trolapril and hydroxide compound are being reacted in the saponification reaction solvent that is selected from water, C1-C4 alcohol or its mixture under the saponified temperature and time to reach at least almost completely, wherein hydroxide compound is the alkylammonium oxyhydroxide of alkali metal hydroxide, alkaline earth metal hydroxides, tetraalkylammonium hydroxides or replacement, wherein Trolapril, hydroxide compound and saponification reaction solvent each all use with the amount that can effectively produce reaction mixture, this reaction mixture comprises the salt of chemical formula 3:

(b) if the used saponification reaction solvent of step (a) comprises the alcohol except propyl carbinol, then from the reaction mixture of step (a), evaporate this alcohol;

(d) with the product of step (c) with to provide the acid of the amount of Trolaprilat under with the temperature and time that Trolaprilat is provided with the free amino acid form of Trolaprilat effectively, to mix with the free amino acid form of Trolaprilat effectively;

(e) from the mixture of step (d), provide under the temperature of Trolaprilat with the free amino acid form of Trolaprilat in the solution that is comprising n-butanol/water effectively and extract Trolaprilat with the propyl carbinol of amount that in comprising the solution of n-butanol/water, provides Trolaprilat effectively with the free amino acid form of Trolaprilat; With

(f) from the solution of step (e), remove the water that is enough to induce Trolaprilat crystalline amount.

73, the pure in fact crystalline form of a kind of production or as the method for the Trolaprilat of the mixture of different crystalline forms may further comprise the steps:

(b) if reaction solvent comprises C4 alcohol, remove this C4 alcohol, and if necessary, the water that adds sufficient amount is with the uniform solution of the compound of salt that chemical formula (3) is provided;

(c) product of step (b) is mixed under with the temperature and time that precipitates Trolaprilat effectively with acid with the amount that precipitates Trolaprilat effectively;

(d) the sedimentary Trolaprilat of separating step (c).

74, according to the described method of claim 73, further may further comprise the steps:

(a) with the sedimentary Trolaprilat drying of step (d).

75, according to the described method of claim 73, further comprise make step (c) sedimentary Trolapril be pulled in effectively to be provided at and have stoichiometry or pulp in water under the temperature and time of the crystal Trolaprilat of the water of dose quantity non-chemically in the crystalline structure.

76, the pure in fact crystalline form of a kind of production or as the method for the Trolaprilat of the mixture of crystalline form may further comprise the steps:

(a) make to the ethanol/water reaction solvent of about 1/1.5 volume ratio Trolaprilat and at least 2.0 normal NaOH between 20 ℃ to 25 ℃ temperature be enough to produce saponification under time of reaction mixture of the salt that comprises chemical formula 3 having about 1/1:

Wherein, M is a sodium, and n is 2;

(b) regulate pH so that the Trolaprilat of free amino acid form to be provided with hydrochloric acid; With

(c) the sedimentary Trolaprilat of separating step (b) from reaction mixture.

77,, comprise that further the sedimentary Trolaprilat of drying step (c) institute is to provide the crystal Trolaprilat according to the described method of claim 76.

78, a kind of method that produces the pull-shaped formula E of crystal Trolapril is included in to remove effectively and is bonded to crystalline alcoholic acid temperature, pressure and the dried crystals Trolaprilat form B under time of drying that is present among the pull-shaped formula B of crystal Trolapril.

79, the crystal Trolaprilat that has the structure of chemical formula 4:

Wherein ROH is a stoichiometry or non-stoichiometric; N is 0 to 2; R is H or C1-C4 alkyl.

80, according to the described crystal Trolaprilat of claim 41, wherein R is H, and n is 1.

81, according to the described crystal Trolaprilat of claim 41, wherein R is H, and n is greater than 1 and be non-stoichiometric.

82, according to the described crystal Trolaprilat of claim 41, wherein R is the C1-C4 alkyl, and n is 2.

83, according to the described crystal Trolaprilat of claim 44, wherein R is an ethyl.

84, according to the described crystal Trolaprilat of claim 44, wherein R is a normal-butyl.

85, according to the described crystal Trolaprilat of claim 41, wherein n is 0.

86, the pull-shaped formula A of crystal Trolapril, it has following X-ray powder diffraction peak at 2 θ degree in Cu K α rank: 7.7,18.6,18.9,19.8,20.6 and 22.0.

87, according to the pull-shaped formula A of the described crystal Trolapril of claim 48, it has X-ray powder diffraction pattern in fact as shown in Figure 1.

88, according to the pull-shaped formula A of the described crystal Trolapril of claim 48, it is pure in fact.

89, the pull-shaped formula B of crystal Trolapril, its 2 θ degree that obtain on Cu K α rank have following X-ray powder diffraction peak: 8.1,9.6,13.8,17.4,18.1,18.4,19.3,20.5 and 22.9.

90, according to the pull-shaped formula B of the described crystal Trolapril of claim 51, it has X-ray powder diffraction pattern in fact as shown in figure 13.

91, according to the pull-shaped formula B of the described crystal Trolapril of claim 51, it is pure in fact.

92, the pull-shaped formula C of crystal Trolapril, its 2 θ degree that obtain on Cu K α rank have following X-ray powder diffraction peak: 6.2,14.0,15.7,18.8 and 20.8.

93, according to the pull-shaped formula C of the described crystal Trolapril of claim 55, it has X-ray powder diffraction pattern in fact as shown in Figure 8.

94, according to the pull-shaped formula C of the described crystal Trolapril of claim 55, it is pure in fact.

95, the pull-shaped formula D of crystal Trolapril, its 2 θ degree that obtain on Cu K α rank have following X-ray powder diffraction peak: 14.4,16.4,17.2,19.2,19.9,22.2,25.2 and 27.5.

96, according to the pull-shaped formula D of the described crystal Trolapril of claim 55, it has X-ray powder diffraction pattern in fact as shown in Figure 9.

97, according to the pull-shaped formula D of the described crystal Trolapril of claim 55, it is pure in fact.

98, the pull-shaped formula E of crystal Trolapril, its 2 θ degree that obtain on Cu K α rank have following X-ray powder diffraction peak: 9.4,9.8,17.4,17.7,21.0 and 28.4.

99, according to the pull-shaped formula E of the described crystal Trolapril of claim 55, it has X-ray powder diffraction pattern in fact as shown in figure 11.

100, according to the pull-shaped formula E of the described crystal Trolapril of claim 55, it is pure in fact.

101, according to the pull-shaped formula E of the described crystal Trolapril of claim 61, it has about 1% or the water of less amount.

102, according to the pull-shaped formula E of the described crystal Trolapril of claim 61, it has 3% or the residual solvent of less amount.

103, a kind of pharmaceutical composition, it comprises at least a crystal Trolaprilat, and this crystal Trolaprilat is selected from the pull-shaped formula A of crystal Trolapril, the pull-shaped formula B of crystal Trolapril, the pull-shaped formula C of crystal Trolapril, the pull-shaped formula D of crystal Trolapril or the pull-shaped formula E of crystal Trolapril.

104, according to the described pharmaceutical composition of claim 66, wherein the form of pharmaceutical composition is selected from oral dosage form or through the skin form.

105, according to the described pharmaceutical composition of claim 67, wherein pharmaceutical composition is the form of tablet, capsule or transdermal patch.

106, a kind of method for the treatment of hypertension or cardiac dysfunction, comprise to the individuality of this treatment of needs use significant quantity as the described pharmaceutical composition of claim 66.