CN101565398B - Process for preparing atazanavir bisulfate and novel forms - Google Patents

Abstract

A process is provided for preparing the HIV protease inhibitor atazanavir bisulfate wherein a solution of atazanavir free base is reacted with concentrated sulfuric acid in an amount to react with less than about 15% by weight of the free base, seeds of Form A crystals of atazanavir bisulfate are added to the reaction mixture, and as crystals of the bisulfate form, additional concentrated sulfuricacid is added in multiple stages at increasing rates according to a cubic equation, to effect formation of Form A crystals of atazanavir bisulfate. A process is also provided for preparing atazanavir bisulfate as Pattern C material. A novel form of atazanavir bisulfate is also provided which is Form E3 which is a highly crystalline triethanolate solvate of the bisulfate salt from ethanol.

Description

Prepare the method for Zrivada and new form

It is that May 3, application number in 2005 are 200580022550.2, denomination of invention is dividing an application that the application of " preparing the method for Zrivada and new form " is submitted to that the application is based on the applying date.

With reference to other application

The application requires No. 60/568,043, U.S. Provisional Application of submitting on May 4th, 2004 and 60/607, No. 533 the right of priority of submitting on September 7th, 2004, and its disclosure is hereby incorporated by.

Technical field

The present invention relates to prepare the method for hiv protease inhibitor atazanavir (atazanavir) hydrosulfate and new form thereof.

Background technology

Authorize Deng United States Patent (USP) a series of azepine peptide hiv protease inhibitor (comprising Reyataz R) are disclosed for 5,849, No. 911, its structure is

Wherein

R ₁Be elementary alkoxy carbonyl,

R ₂Be the second month in a season or uncle's low alkyl group or lower alkylthio-low alkyl group,

R ₃Be the phenyl that is not substituted or is replaced by one or more lower alkoxy groups, or C ₄-C ₈Cycloalkyl,

R ₄Be phenyl or cyclohexyl, each comfortable 4-position is replaced by ring carbon atom bonded unsaturated heterocycle base, and described heterocyclic radical has 5 to 8 annular atomses, comprises 1 to 4 and is selected from nitrogen, oxygen, sulphur, sulfinyl (SO-) and alkylsulfonyl (SO ₂-) heteroatoms and be not substituted or replace by low alkyl group or by phenyl-low alkyl group,

R ₅, be independent of R ₂, have R ₂One of implication of mentioning, and

R ₆, be independent of R ₁, be elementary alkoxy carbonyl or its salt, prerequisite is to have a kind of salt forming group at least, comprises its various pharmaceutically-acceptable acid addition.

Several methods that prepare the azepine peptide are provided, comprise preparing wherein R ₁And R ₆And R ₂And R ₅Each compound of two kinds of identical groups naturally is wherein with the diamino compounds of following formula structure

Acid with the following formula structure

Or its active acid derivant condenses, wherein R ₁And R ₂Respectively as R ₁And R ₆And R ₂And R ₅Definition.

When forming Reyataz R with aforesaid method, the diamino compounds (a) with following formula structure

Be prepared as follows: make epoxide

With the diazanyl carbaminate

Coupling in the presence of Virahol forms shielded diamines

With its with hydrochloric acid solvent for example tetrahydrofuran (THF) in the presence of handle, form diamines (a)

The diamines segregation is used for next coupling step, itself and acid (b) in this step

Or its active ester reaction, wherein used coupler is for example O-(1,2-dihydro-2-oxo--1-pyridyl)-N, N, N ', N '-tetramethyl-urea-tetrafluoro-borate (TPTU).

Have found that diamines free alkali instability, the free alkali that therefore is used to prepare Reyataz R is unsatisfactory.

The United States Patent (USP) of authorizing Singh etc. discloses the hydrosulfate of the azepine peptide hiv protease inhibitor that is called Reyataz R for 6,087, No. 383, and its structure is

(being also referred to as Zrivada or Reyataz R vitriol).

The embodiment 3 of Singh etc. has described the preparation of Zrivada II N-type waferN (hydration moisture absorption crystalline form) and I N-type waferN (seemingly anhydrous/the desolvation crystalline form).

Summary of the invention

According to the present invention, the Zrivada of new form is provided, comprise C pattern (Pattern C) material and E3 shape.Preferred C pattern material.

In addition, according to the present invention, provide the method for the Zrivada (main drug) (in the embodiment 3 of No. 6,087,383, the United States Patent (USP) of authorizing Singh etc., being called the I N-type waferN) of preparation A shape crystalline form.A shape crystal by the inventive method preparation has required distribution of consistent particle size basically and consistent basically mean particle size, and is used to be converted into C pattern material (a kind of partial crystallization material), and itself and various vehicle are prepared with the preparation medicine.

The present invention prepares three crystallization techniques of Zrivada A shape crystalline method utilization improvement, wherein add sulfuric acid (as described below) with the speed that increases according to cubic equation, the step that comprises has: make solution and the first part strong sulfuric acid response of Reyataz R free alkali in organic solvent (wherein Zrivada is insoluble basically), the amount of the vitriol oil makes it and is less than about 15%, preferably be less than the Reyataz R free alkali reaction of about 12% weight, Zrivada A shape crystal crystal seed is added in the reaction mixture, when Zrivada is crystal formation, divide a plurality of stages to add the other vitriol oil according to cubic equation with the speed that increases, with effective formation A shape crystal.

In addition, according to the present invention, provide preparation to derive from and comprise Zrivada and be called the method for the Reyataz R form of C pattern material.Can by A shape crystal is suspended in water and drying obtain the C pattern.Perhaps, can be in greater than in the high relative humidity of about 95%RH (water vapour) at least 24 hours, form C pattern material by making A shape crystal.Also can form C pattern material by with the combination wet granulation of Zrivada or Zrivada and vehicle and with wet grain drying.

In preferred embodiments, for example one or more weighting agents (for example lactose), one or more disintegrating agents (for example Crospovidone) mix and wet granulation, directly the C pattern material of formation and mixed with excipients with vehicle with preparation to make A shape crystal.

According to the present invention, a kind of Zrivada (being called E3 shape) of new form also is provided, be the height crystalline form of three alcohol solvent compounds of Zrivada.

Being prepared as follows of E3 shape: form the slurry of Reyataz R free alkali in ethanol, handle slurry with the vitriol oil, heating also is seeded to the wet E3 crystal of ethanol in the solution of generation, with heptane (or other solvent for example toluene or hexane) treating mixture, filters and dry.

According to the present invention, preparation Zrivada A shape crystalline method also is provided, comprise the following steps: to prepare three amine salt (preferred HCl (3 moles) salt) of following formula structure

Three amine salt of not emanating make three amine salt and active ester, preferably have an active ester of following formula structure

React in the presence of alkali and organic solvent, form the Reyataz R free alkali, need not emanate, (cubic crystallization technique) is translated into Zrivada by three crystallization techniques of improvement described herein.

In addition,, provide new Zrivada composition, comprise Zrivada A shape crystal or C pattern material according to the present invention, and pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier can comprise weighting agent, tackiness agent, disintegrating agent, lubricant and other conventional excipients.

Available action has been various technology well known to those skilled in the art, characterizes according to various forms Zrivada of the present invention.Each crystalline form is identified and distinguished to available monocrystalline X-ray diffraction, and the monocrystalline X-ray diffraction is based on fixedly under the analysis temperature a kind of structure cell of form monocrystalline being measured.The detailed description of relevant structure cell can be consulted Stout ﹠amp; Jensen, X-Ray StructureDetermination:A Practical Guide, Macmillan Co., New York (1968), the 3rd chapter, it is hereby incorporated by.Perhaps, can characterize the unique arrangement of atom in the interior spatial relation of lattice according to the part of atoms coordinate (fractionalatomic coordinates) of actual measurement.The method of another kind of sign crystalline structure is by powder x-ray diffraction analysis, and the diffractogram of experiment or actual measurement and the mimic diagram of the pure powdered material of representative are compared, and the both carries out under the same analysis temperature, and the observed value of described form is with a series of 2 θ value representations.

Available other identified the method for crystalline form, for example solid state nmr (SSNMR), dsc (DSC) and thermogravimetric analysis (TGA).Can unite and use the described crystalline form of these parameter characterizations.

A shape crystal can characterize with following basically unit cell parameters:

Unit cell dimension:

a＝9.86(5)

b＝29.245(6)

c＝8.327(2)

α＝93.56(2)°

β＝114.77(3)°

γ＝80.49(3)°

Spacer 1

Molecule/asymmetric cell 2

Wherein crystalline form is at+22 ℃ approximately.

The part of atoms coordinate feature of A shape can be enumerated as table 3 basically, and crystal structure characteristic shows as Fig. 2 basically.

The simulation of A shape and actual measurement x-ray diffractogram of powder characterize and can show as Fig. 1 basically.

Differential scanning calorimetric (DSC) the thermogram feature of A shape can show that as Fig. 3 wherein endotherm(ic)peak is in about 165.6 ℃ of beginnings basically.

The thermogravimetric analysis of A shape (TGA) curvilinear characteristic can show at paramount about 100 ℃ to 150 ℃ negligible weight loss is arranged as Fig. 4 basically.

The solid state NMR of A shape (SSNMR) chemical shift feature can be basically as shown in Table 4, and the wave spectrum feature shows as Fig. 5 basically.

The part of atoms coordinate feature of A shape can be enumerated as table 5 basically.

The feature of the moisture sorption isotherm of A shape salt be 25 ℃ in 25 to the 75%RH scopes weight increase about 0.1%.

In one aspect of the present invention, the actual measurement x-ray diffractogram of powder feature of C pattern can show as Fig. 5 basically.

At different aspect of the present invention, the differential scanning calorimetric thermogram feature of C pattern shows as Fig. 7 basically, usually at about 76.7 to about 96.6 ℃ and about 156.8 to about 165.9 ℃ of scopes heat absorption is arranged.

At different aspect of the present invention, the thermogravimetric curve of C pattern characterizes basically and shows as Fig. 8, in about 125 ℃ of weight loss about 2.4% with in paramount about 190 ℃ of weight loss about 4.4%.

According to the present invention, the crystallographic data feature of E3 shape is as shown in Table 5, as follows basically:

a＝10.749

b＝13.450(4)

c＝9.250(2)

α＝98.33(2)°

β＝95.92(3)°

γ＝102.82(3)°

Spacer P1

Molecule/asymmetric cell 1

Wherein crystalline form is at-23 ℃ approximately.

At different aspect of the present invention, the part of atoms coordinate feature of E3 shape is enumerated as table 6 basically.

At different aspect of the present invention, the simulation of E3 shape and actual measurement x-ray diffractogram of powder feature can show as Fig. 9 basically.

At different aspect of the present invention, the differential scanning calorimetric thermogram feature of E3 shape shows to about 96.6 ℃ of scopes heat absorption is arranged about 89.4 usually as Figure 11 basically.

At different aspect of the present invention, the thermogravimetric curve feature of E3 shape basically as shown in Table 8, in about 150 ℃ of weight loss about 14.7%.

At different aspect of the present invention, the crystal structure characteristic of E3 shape shows as Figure 10 basically.

Description of drawings

Fig. 1 shows the calculating (simulation) (22 ℃) and actual measurement (in the room temperature experiment) x-ray diffractogram of powder (CuK α λ=1.5418 of A shape );

Fig. 2 shows the crystalline structure of A shape;

Fig. 3 shows differential scanning calorimetric (DSC) thermogram of A shape;

Fig. 4 shows the thermogravimetric curve (TGA) of A shape;

Fig. 5 shows the C-13 solid state NMR of A shape;

Fig. 6 shows actual measurement (in the room temperature experiment) x-ray diffractogram of powder (CuK α λ=1.5418 of C pattern );

Fig. 7 shows the differential scanning calorimetric thermogram of C pattern;

Fig. 8 shows the thermogravimetric curve of C pattern;

Fig. 9 shows the calculating (simulation) (22 ℃) and actual measurement (in the room temperature experiment) x-ray diffractogram of powder (CuK α λ=1.5418 of E3 shape

);

Figure 10 shows the crystalline structure of E3 shape; With

Figure 11 shows differential scanning calorimetric (DSC) thermogram of E3 shape, and the thermogravimetric curve of E3 shape.

Embodiment

The present invention provides the novel material of Zrivada form to small part, is called E3 shape and C pattern, particularly pharmaceutically acceptable form.Term " pharmaceutically acceptable " is meant those compounds, material, composition and/or formulation herein, it is in the rational medicine determination range, the tissue that is fit to the contact humans and animals, no overdosage toxicity, pungency, anaphylaxis or other problem complication, and have rational interests/risk-benefit risks.In some preferred embodiment, the crystalline form of free alkali I and salt thereof is pure form basically.Term " pure substantially " is meant purity herein greater than about 90% compound, for example comprises about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% and about 100% the compound of purity.

" polymorphic " is meant to have identical chemical constitution but formation crystalline molecule, atom and/or the different crystalline form of ionic spatial disposition herein.

" solvate " is meant herein and also comprises molecule, atom and/or the ionic crystalline form that is incorporated into one or more solvent molecules in the crystalline structure.Solvent molecule in the solvate can be in regularly arranged and/or lack of alignment.Solvate can comprise the solvent molecule of stoichiometry or nonstoichiometry amount.For example, the solvate that contains nonstoichiometry amount solvent molecule may be lost from the part of solvent in the solvate.

Basically the inhomogeneity crystalline form sample of pure phase can be provided, show to have the single crystalline form of advantage amount and optional a small amount of one or more other crystalline forms.The technology of available for example powder x-ray diffraction (PXRD) or solid state nmr spectral method (SSNMR) determines to exist in the sample more than one crystalline forms.Exist additional peak to point out when for example, the PXRD of measuring figure compares with simulation PXRD figure and have more than a kind of crystalline form in the sample.Simulation PXRD can use monocrystalline X ray data computation, see Smith, D.K., " A FORTRAN Program for Calculating X-Ray PowderDiffraction Patterns; " Lawrence Radiation Laboratory, Livermore, California, UCRL-7196 (in April, 1963).Preferably in the PXRD of measuring figure, be less than 10%, preferably be less than 5% and come non-existent additional peak among the comfortable simulation PXRD figure, show that crystalline form has pure phase homogeneity basically more preferably less than 2% total peak area.Most preferably have the inhomogeneity crystalline form of pure phase basically, wherein in the PXRD of measuring figure, be less than 1% total peak area and come non-existent additional peak among the comfortable simulation PXRD figure.

The step of preparation crystalline form known in the art.The prepared in various methods crystalline form be can pass through, crystallization or recrystallize, distillation for example comprised from suitable solvent, from melt growth, from another mutually solid-state conversion, crystallization and jet spraying from supercutical fluid.From solvent mixture, make the technology of crystalline form crystallization or recrystallize for example comprise evaporating solvent, reduce the solvent mixture temperature, in the over-saturation solvent mixture of molecule and/or salt, introduce crystal seed, with the solvent mixture lyophilize and will resist solvent (counter solvent) to add in the solvent mixture.

The feature description of medicine crystal, preparation method and medicine crystal that comprises polymorphic is in Solid-State Chemistry of Drugs, S.R.Byrn, R.R.Pfeiffer and J.G.Stowell, the 2nd edition, SSCI, West Lafayette, Indiana (1999).

For the crystallization technique that uses solvent, one or more choice of Solvent depend on one or more factors usually, for example the vapour pressure of the solubleness of compound, crystallization technique and solvent.Solvent can be united use, for example compound can be dissolved in first kind of solvent and obtain solution, then adds anti-solvent and reduces the solubleness of this compound in solution to form crystal.Anti-solvent is the compound low solvent of solubleness therein.Be used to prepare the crystalline suitable solvent and comprise polarity and non-polar solvent.

In a kind of preparation crystalline method, Zrivada is suspended in and/or in suitable solvent, stirs to obtain slurry, can be heated to promote dissolving.Term " slurry " is meant the saturated solution of Zrivada or its salt herein, also can comprise additional content Zrivada or its salt to obtain Zrivada or its salt and the uniform mixture of solvent under assigned temperature.Suitable in this respect solvent comprises for example mixture of polar aprotic solvent and polar aprotic solvent and two or more solvents described herein.

Crystal seed can be added any crystalline mixture to promote crystallization.Should clearly put into crystal seed as the technician as the method for the specific crystalline form growth of control or the method for control crystalline product size-grade distribution.Therefore, the average product granular size of obtainable crystal seed size and needs is depended in the calculating of required crystal seed amount, for example be described in " Programmed cooling of batchcrystallizers; " J.W.Mullin and J.Nyvlt, Chemical Engineering Science (1971) 26:369-377.Usually, need the small size crystal seed effectively to control crystalline growth in the batch of material.Can be by screening, grind or make than the macrocrystal micronization, or produce the small size crystal seed by the micro-crystallization of solution.It should be noted that crystalline grinding or micronization do not cause any variation (promptly becoming non-crystalline state or another kind of polymorphic) of required crystalline form crystallized form.

But vacuum filtration refrigerative mixture, available suitable solvent (for example cold recrystallize solvent) washs isolating solid, and drying obtains required crystalline form under nitrogen purging.Can analyze isolating solid by suitable spectral method or analytical technology (for example SSNMR, DSC, PXRD etc.), to guarantee to form the preferred crystalline form of product.Usually the crystalline form output that obtains is greater than about 70% weight of segregation output, but is preferably greater than 90% weight of the Zrivada weight that begins to be used for crystallisation step.If desired, product can be ground altogether or make the product piece separately by mesh screen.

Crystalline form can directly prepare from the whole step reaction medium of preparation Zrivada.For example, this can therefrom crystalline solvent or solvent mixture be realized by use Zrivada in whole step.Perhaps, crystalline form can obtain by distillation or solvent adding technique.The suitable solvent of realizing this purpose comprises those solvents described herein, comprises proton polar solvent (for example alcohol) and aprotic polar solvent (for example ketone).

Instruct as generality, reaction mixture can be filtered to remove any unwanted impurity, inorganic salt etc., then with reaction or recrystallisation solvent washing.Can be with the solution concentration that generates to remove excessive solvent or gaseous fraction.If with distillation, then the amount of the last overhead product of collecting may be different, depend on the method factor, comprise for example container size, whipping force etc.Instruct as generality, can be before carrying out solvent replacing reaction soln be distilled to { cut (1/10) } initial volume approximately.Can be according to the standard method technology with reactant sampling and analyze to determine the wt% of level of response and product.If desired, can add or remove additional reaction solvent to optimize reactant concn.Preferably final concentration is adjusted to about 50wt%, forms slurry usually at this point.

Can preferably solvent directly be added reactor and distillation reaction mixture not.The preferred solvent that realizes this purpose is the solvent of relevant with exchange of solvent as mentioned above final participation lattice.Though final concentration can be different because of required purity, the rate of recovery etc., the final concentration of free alkali I is preferably about 4% to about 7% in the solution.Reaction mixture can be stirred also simultaneously warm behind the adding solvent.As an illustration, the reaction mixture stir about can be heated to about 70 ℃ in 1 hour simultaneously.Preferably wash with the reactant heat filtering and with solvent or its combination of reaction solvent, adding.Crystal seed can be added any crystallization solution to start crystallization.

Can various forms described herein be made a distinction mutually by with various analytical technologies well known by persons skilled in the art.Such technology includes but not limited to solid state nmr (SSNMR) spectral method, X-ray powder diffraction (PXRD), differential scanning calorimetric (DSC) and/or thermogravimetric analysis (TGA).

The X-ray diffractogram that skilled person in the art will appreciate that acquisition has measuring error, and this depends on used measuring condition.Specifically, intensity can fluctuate because of measuring condition, crystalline shape or the form of using in the common known X-ray diffractogram.Should also be understood that relative intensity also can be different because of experiment condition, therefore, should not consider the accurate grade of intensity.In addition, the measuring error of the diffraction angle of conventional X-ray diffractogram is generally about 0.2% or littler, preferred about 0.1% (following discussion), and such measuring error degree should be considered as being fit to above-mentioned diffraction angle.Therefore, it should be understood that crystalline form of the present invention is not limited to provide the crystalline form of the identical X-ray diffractogram of describing with accompanying drawing disclosed herein of X-ray diffractogram.Provide with any crystalline form of the disclosed substantially the same X-ray diffractogram of accompanying drawing and all fall in the scope of the invention.Determine X-ray diffractogram basically the ability of identity in those skilled in the art's technical scope.

Term " shape " about A shape and E3 shape is meant uniform crystalline structure at this paper.

Term " pattern " about C pattern material is meant the characteristic X-ray diffractogram at this paper.

Term " Zrivada " is meant Zrivada and Reyataz R vitriol at this paper.

When enforcement the present invention prepares Zrivada A shape crystalline method, with three crystallization techniques of improvement, wherein make the Reyataz R free alkali be dissolved in Zrivada and be insoluble to basically in wherein the organic solvent (comprising acetone, acetone and N-Methyl pyrrolidone mixture, ethanol, ethanol and acetone mixture etc.), obtain the Reyataz R free alkali concentration at about 6.5 to 9.7% weight, preferred about 6.9 solution to about 8.1% weight Reyataz R free alkali.

The Reyataz R free base solution is heated under the temperature to about 50 ℃ of scopes at about 35 to about 55 ℃, preferred about 40, and (contain about 95 to about 100%H with the vitriol oil ₂SO ₄) reaction, the amount of the vitriol oil can make it and be less than about 15%, preferred about 5 to being less than about 12%, the more preferably from about 8 total Reyataz R free alkali reactions to about 10% weight.Therefore, the starting soln of Reyataz R free alkali at first will be less than used sulfuric acid total amount about 15%, preferred about 5 to about 12% weight reaction.During reaction, reaction mixture is maintained at about 35 to about 55 ℃, preferred about 40 temperature to about 50 ℃ of scopes.

Allow reaction proceed about 12 to about 60 minutes, preferred about 15 to about 30 minutes.

With Zrivada A shape crystal seeding to reaction mixture, the Zrivada weight of amount of seed in being retained in reaction mixture about 0.1 to about 80% weight, preferred about 3 to about 8% weight range, the temperature of reaction mixture is maintained at about 35 to about 55 ℃, preferred about 40 to about 50 ℃ of scopes simultaneously.

Allow reaction proceed until the beginning crystallization., according to described below cubic equation with the speed that increases divide multistage add sulfuric acid, form Zrivada, produce A shape crystal after latter's drying thereafter.

The crystal size of formed Zrivada and form depend on that vitriolic adds speed, and it determines crystallization rate." three times " crystallization technique having found to improve (press cubic equation and add acid with the speed that increases) and constant interpolation speed crystallization phases ratio provide relatively bigger, the better Zrivada crystal of determining, the narrower and expense of size range still less simultaneously.Shown that the starting acid flow rate is beneficial to crystal growth above secondary nucleation slowly.Therefore, because surface-area increases with granularity, the sour flow rate that seed bed can be accepted to increase and do not cause secondary nucleation.Initial slowly interpolation speed makes the free growth of crystal bigger, and mean sizes is increased.Three crystallizations provide compressibility less filter cake, help to make filter cake effectively dehydration and washing, and obtain than the constant interpolation speed crystalline product easier exsiccant product of lump still less.

Three times used crystallization method are temperature crystallization controls, from Mullin, " Crystallization, the 3rd edition ", and 1993, Butterworth-Heineman, Pubs, determined by following reduced equation:

$T=T_{\max -}(T_{\max }-T_{\min })x{\left[\frac{\mathrm{time}}{{\mathrm{time}}_{\mathrm{total}}}\right]}^3---\left(1\right)$

Wherein

T _Max=crystalline starting temperature

T _Min=crystalline final temperature

Time=crystalline elapsed time

Time _Total=total crystallization time

Because the crystallization of Zrivada is added rate-controlling by vitriolic, so with the temperature variable in the sour volume replacement equation (1).In this equation, removed the variable of representing minimum volume.

$V_{\mathrm{time}}=V_{\mathrm{total}}x{\left[\frac{\mathrm{time}}{{\mathrm{time}}_{\mathrm{total}}}\right]}^3---\left(2\right)$

Wherein

V _TimeThe vitriolic volume that adds in=the elapsed time

V _Total=represent the cumulative volume of the acid of 90% raw material

Time=crystalline elapsed time

Time _Total=total crystallization time

Equation (2) is called as " cubic equation ".

By with this expression formula crystallization control speed, because system keeps constant low-level hypersaturated state, so nucleogenesis can be controlled within the acceptable limit.

Identify that A shape crystalline x-ray diffractogram of powder and crystalline structure are as illustrated in figs. 1 and 2 separately.

As above the A shape crystal of the Zrivada of description preparation or C pattern material and E3 shape are final Zrivadas, can be used as medicine and deliver medicine to the patient.

The method according to this invention can be by being exposed to A shape crystal the dry then preparation C of water pattern material.

According to another kind of method of the present invention,, can form C pattern material by A shape crystal being exposed to greater than about 95%RH, preferred about 95 to the relative humidity of about 100%RH (water vapour) at least 24 hours, preferably about 24 to about 48 hours.

In another embodiment of the invention, can be by Zrivada A shape wet granulation being generated the Zrivada particle, particle drying being prepared C pattern material then.

When implementing wet granulation process, Zrivada will form particle in water, about 40 to about 80 ℃ of scopes, preferred about 50 dry under the temperature to about 60 ℃ of scopes.Drying step preferably carries out at least about 2 hours, about 20 hours at the most, preferred about 8 to about 10 hours.

Also can by with Zrivada A shape at conventional pharmaceutical excipient wet granulation in one or more weighting agents (preferred lactose), one or more disintegrating agents (preferred Crospovidone) for example, and as above describe dry to form and the C pattern material of mixed with excipients and form C pattern material.

C pattern material, A shape or E3 shape (preferred C pattern material) can be prepared and be used for administration just, to treat the disease that virus described below causes.

X-ray diffractogram of powder feature such as Fig. 3 of C pattern material show.

E3 shape is prepared as follows: make the Reyataz R free alkali form slurry in ethanol, handle slurry with the vitriol oil, used acid: the molar ratio scope of free alkali is about 1: 1 to about 1.1: 1, at about 30 solution to about 40 ℃ of heating generations, the wetting E3 crystal of the ethanol of Reyataz R vitriol is seeded in the solution, with heptane (or other solvent for example hexane or toluene) treating mixture, filter and dry, obtain Zrivada E3 shape (three alcohol solvent compounds).

The crystal seed amount that the seeding step is used will effectively form E3 crystal, for example Zrivada E-3 crystal seed: the molar ratio scope of free alkali is about 0.02: 1 to about 0.04: 1.

X-ray diffractogram of powder such as Fig. 7 of identifying E3 shape show that crystalline structure such as Fig. 6 show.

According to the present invention; the Reyataz R of free alkali form is prepared as follows: with acid, preferred hydrochloric acid (wherein using Boc) or alkali (wherein using trifluoroacetyl group) at shielded three amine salt solutions that have the following formula structure under the existence of organic solvent (for example methylene dichloride, tetrahydrofuran (THF) or methyl alcohol, the wherein preferred methylene dichloride of solvent), about 25 to about 50 ℃, preferred about 30 Temperature Treatment to about 40 ℃ of scopes

(wherein PG represents blocking group, for example tert-butoxycarbonyl (Boc) or trifluoroacetyl group, preferably Boc), form three amino acid salts, the hydrochloride of preferred following formula structure

And three amino acid salts of not emanating, the active ester of the acid of usefulness following formula structure

The active ester of preferred following formula structure

At alkali (K for example ₂HPO ₄, diisopropylethylamine, N-methylmorpholine, yellow soda ash or salt of wormwood, preferred K ₂HPO ₄) existence under, in organic solvent (for example methylene dichloride, ethyl acetate and butylacetate mixture, acetonitrile or ethyl acetate, preferred methylene dichloride) under the existence,, forms the Reyataz R free alkali at about 25 to about 50 ℃, preferred about 30 Temperature Treatment three amino acid salts to about 40 ℃ of scopes.

Shielded triamine parent material is prepared as follows: make epoxide

PG Boc preferably wherein, N-(tert-butoxycarbonyl)-2 (S)-amino-1-phenyl-3 (R)-3 for example, 4-epoxy group(ing)-butane is with the diazanyl carbaminate of Boc preferably of PG wherein

In for example reaction in the presence of ethanol or the butanols of Virahol or other alcohol.

Zrivada can deliver medicine to warm-blooded animal (particularly people), be used for the treatment of or prevent suppressing retroviral Protease (retrovirus aspartate protease particularly, for example HIV-1 or HIV-II gag proteolytic enzyme) disease that responds, for example retroviral diseases (for example AIDS or its latent period (preliminary statge)).

Can be with Zrivada (particularly C pattern material, A shape or E3 shape, preferred C pattern material or A shape) be used for the treatment of in the method for the disease (particularly AIDS or its latent period) that virus (particularly retrovirus) causes, wherein treat significant quantity Zrivada C pattern material, A shape or E3 shape, its dosage can effectively be treated described disease, particularly warm-blooded animal for example suffers from and states the people that one of disease (particularly AIDS or its latent period) needs such treatment.To warm-blooded animal, the people of for example about 70kg body weight, preferred dosage is extremely about 1.5g of about for each person every day 3mg, and preferably about 10mg is to about 1.25g, and for example about 50mg preferably is divided into single dose 1 to 4 time to about 600mg, and described single dose can for example be identical size.Usually, children's half of dosage of accepting to be grown up.The preferred oral administration.

Zrivada C pattern material, A shape or E3 shape are used for above-mentioned pharmaceutical usage.The suitable groups compound that contains C pattern material or A shape or E3 shape that oral administration is used comprises tablet, pulvis, capsule and elixir.Acceptable solvent, carrier, vehicle, tackiness agent, sanitas, stablizer, seasonings etc. on about 10-600mg activeconstituents and the physiology are blended in the unit dosage of acceptable pharmacy practice requirement.

By activeconstituents is mixed with solid carrier, when needing then with the granulating mixture that generates, if desired or essential, after adding suitable vehicle, mixture is processed into tablet, ingot nuclear, capsule or pulvis is used for orally, can obtain the medicinal compositions of oral administration.Also activeconstituents can be added in the plastic carrier, make activeconstituents diffusion or discharge with measuring vol.

In the medicinal compositions of the present invention the content of weighting agent or filler composition weight about 0 to about 95% weight, preferred about 10 to about 85% scope.Be applicable to that the weighting agent of this paper or the example of filler include but not limited to: derivatived cellulose (for example Microcrystalline Cellulose or wood cellulose), lactose, sucrose, starch, pregelatinized starch, glucose, N.F,USP MANNITOL, fructose, Xylitol, sorbyl alcohol, W-Gum, modified corn starch, inorganic salt (for example lime carbonate, calcium phosphate, Lin Suanergai, calcium sulfate), dextrin/dextrates, Star Dri 5, sompressible sugar and other known weighting agent or filler, and/or two or more mixture wherein, preferred lactose.

Tackiness agent is optional to be present in the medicinal compositions of the present invention, its amount composition weight about 0 to about 20% weight, preferred about 1 to about 10% scope.The example that is applicable to the tackiness agent of this paper includes but not limited to: hydroxypropylcellulose, W-Gum, pregelatinized starch, modified corn starch, (molecular weight ranges is from about 5 for polyvinylpyrrolidone (PVP), 000 to about 80,000, preferred about 40,000), Vltra tears (HPMC), lactose, gum arabic, ethyl cellulose, cellulose acetate, and wax adhesive for example carnauba wax, paraffin, spermaceti, polyethylene or Microcrystalline Wax, and other conventional tackiness agent and/or two or more mixture wherein, preferred hydroxypropylcellulose.

Disintegrating agent is optional to be present in the medicinal compositions of the present invention, its amount composition weight about 0 to about 20% weight, preferred about 0.25 to about 15% scope.The example that is applicable to the disintegrating agent of this paper includes but not limited to: croscarmellose sodium, Crospovidone, yam starch, pregelatinized starch, W-Gum, Explotab, Microcrystalline Cellulose or other known disintegrating agents, preferred croscarmellose sodium.

Lubricant is optional to be present in the medicinal compositions of the present invention, its amount composition weight about 0.1 to about 4% weight, preferred about 0.2 to about 2% scope.The compressing tablet example with lubricator that is applicable to this paper includes but not limited to: Magnesium Stearate, Zinic stearas, calcium stearate, talcum powder, carnauba wax, stearic acid, palmitinic acid, sodium stearyl fumarate or hydrogenated vegetable fat, or other known compressing tablet two or more mixture with lubricator and/or wherein, preferred Magnesium Stearate.

Capsule is a hard capsule, also can be the soft seal capsule of being made by gelatin and softening agent (for example glycerine or sorbyl alcohol).Hard capsule can comprise the activeconstituents of particle form, for example with weighting agent (for example lactose), tackiness agent (for example starch, Crospovidone) and/or glidant (for example talcum powder or Magnesium Stearate), also can add stablizer if desired.In soft capsule, preferably make activeconstituents dissolving or be suspended in the suitable oiliness vehicle (for example fatty oil, paraffin oil or liquid macrogol), equally also can add stablizer and/or antiseptic-germicide.

Following examples are represented the preferred embodiments of the invention.

Embodiment 1

1-[4-(pyridine-2-yl) phenyl]-5 (S)-2,5-two { [N-(methoxycarbonyl)-uncle's L-leucyl] amino }-4-(S)-hydroxyl-6-phenyl-2-aza-hexane, hydrosulfate (A shape) (Zrivada-A shape)

(1-[4-(pyridine-2-yl) phenyl]-5 (S)-2,5-two [tert-butoxycarbonyl) amino]-4 (S)-hydroxyl-6-phenyl-2-aza-hexane .3HCl (triamine .3HCl salt))

With shielded triamine 1-[4-(pyridine-2-yl) phenyl]-5 (S)-2,5-two [tert-butoxycarbonyl) amino]-4 (S)-hydroxyl-6-phenyl-2-aza-hexane

(100g, 0.178mol) and CH ₂Cl ₂(500mL; The shielded triamine inlet amount of 5mL/g) (its preparation is described in Z.Xu etc.; Process Research and Development for an EfficientSynthesis of the HIV Protease Inhibitor BMS-232; 632; Organic ProcessResearch and Development 6, 323-328 (2002)) add and dispose in the 1000mL 3 neck round-bottomed flasks of mechanical stirrer, nitrogen inlet and temperature sensor, the slurry that generates is stirred, maintain the temperature at about 5 to about 22 ℃ simultaneously.

With concentrated hydrochloric acid (68mL, 0.82mole, 4.6eq.) so that the speed that reaction mixture temperature remains between 5 to 30 ℃ add in the reaction mixture.Reaction mixture is heated to 30 to 40 ℃ also to be stirred until finishing with the definite reaction of HPLC analysis.

Water (70-210mL, the shielded triamine inlet amount of 0.7-2.1mL/g) is added in the reaction mixture, reaction mixture was stirred 15 minutes, allow respectively be separated.The moisture oily matter of upper strata by-pass product (triamine .3HCl salt) is transferred in the addition funnel.

(N-methoxycarbonyl-L-Terleu ( ) active ester))

With N-methoxycarbonyl-L-Terleu (77.2g, 0.408mol, 2.30eq.), I-hydroxybenzotriazole (HOBT) (60.8g, 0.450mol, 2.53eq.) and the N-ethyl n '-dimethylaminopropyl carbodiimide (EDAC) (82.0g, 0.430mol 2.42eq.) adding is disposed in the 3000mL 3 neck round-bottomed flasks of mechanical stirrer, addition funnel, nitrogen inlet and temperature sensor, adds CH then ₂Cl ₂(880mL; 8.8mL/g shielded triamine inlet amount), stir the mixture, until determining that by HPLC forming of active ester finish in envrionment temperature (18-25 ℃).

C.1-[4-(pyridine-2-yl) phenyl]-5 (S)-2,5-two { [N-(methoxycarbonyl)-uncle's L-leucyl] amino }-4 (S)-hydroxyl-6-phenyl-2-aza-hexane (Reyataz R free alkali)

Make anhydrous di-potassium hydrogen phosphate (K ₂HPO ₄226g, 1.30mol, the shielded triamine of 7.30eq.wrt) be dissolved in 1130mL water (the shielded amine of 11.3mL/g; 5mL/g K ₂HPO ₄).

With K ₂HPO ₄In the active ester solution that solution adding B partly prepares.With the active ester/K that the A hydrochloride aqueous solution was partly slowly added in 1.5 to 2.0 hours stirring ₂HPO ₄In the aqueous mixture, keep stirring and jar temperature simultaneously between 5 to 20 ℃.

After the interpolation of A part hydrochloride solution is finished, reaction mixture (coupled reaction) is heated to 30-40 ℃, and stirs until the definite coupled reaction of HPLC analysis and finish.

The coupling mixture is cooled to 15 to 20 ℃, lower floor's by-pass product organic phase and upper strata waste water are separated.

Use 1M NaH ₂PO ₄(880mL; PH=1.5; 8.8mL/g shielded triamine inlet amount; The shielded triamine of 5 molar equivalent wrt) washing by-pass product organic phase allows respectively be separated, and removes the waste water phase.

With washed by-pass product organic phase and 0.5N NaOH (800mL; The shielded triamine inlet amount of 8mL/g) stirs together, analyze the demonstration active ester until the HPLC of rich organic phase and be lower than 0.3I.I. separately.Allow and respectively be separated and remove the waste water phase.

Use 5%NaH ₂PO ₄(450mL, the shielded triamine inlet amount of 4.5mL/g; PH=4.3) wash rich organic phase, allow respectively be separated and remove the waste water phase.

Wash rich organic phase and remove the waste water phase with 10w/v%NaCl (475mL, the shielded triamine inlet amount of 4.75mL/g).

The concentration of title free alkali is 120-150mg/mL in the solution, and the productive rate that calculates in the process is 95-100mol%.

D. from CH ₂Cl ₂Exchange of solvent to acetone/N-Methyl pyrrolidone

With N-Methyl pyrrolidone (148mL; 1.25mL/g C part free alkali is based on quantitative analysis in the process) add in the rich C part free base solution in the 3000mL 3 neck round-bottomed flasks that dispose mechanical stirrer, temperature sensor and distiller condenser.With the jacket temperature below 70 ℃ with solution concentration to about 360mL (2.5-3.5mL/g C part free alkali); 500mL acetone (4-5mL/g C part free alkali) is added in the concentrated solution, with mixture distillation to about 400mL or volume still less.

Repeat to add acetone and distillation analysis revealed CH in process ₂Cl ₂Level has reached the target terminal point.At the crystalline volume place, is rich in the CH in the machine solution ₂Cl ₂Content is 0.77v/v%.Acetone is added spissated free base solution, obtain total solution of 16mL/g free alkali.Make bath temperature remain on 40-50 ℃ with the crystallization of prevention free alkali.Make solution pass through 10 microns or the meticulousr concise filtration of filter (polish filter), maintain the temperature at 40 to 50 ℃ simultaneously.Wash concise filter with acetone (125mL, 1.0mL/g free alkali), washing fluid is added in rich free alkali acetone/N-Methyl pyrrolidone solution, be used for next step.

E.1-[4-(pyridine-2-yl) phenyl]-5 (S)-2,5-two { [N-(methoxycarbonyl)-uncle's L-leucyl] amino }-4 (S)-hydroxyl-6-phenyl-2-aza-hexane hydrosulfate

Add down by the surface, with vitriol oil total amount (19g, 1.10e.q.) in about 10% (2g) add in the free alkali acetone/N-Methyl pyrrolidone solution of D part, maintain the temperature at 40-50 ℃ simultaneously.

Reaction mixture is inoculated with 5.0wt% (free alkali that calculates in the wrt solution) hydrosulfate.Stirred at least 30 minutes at the 40-50 ℃ of mixture with inoculation, the turbidity of mixture increases during this period, show this during hydrosulfate begin crystallization.

In the following scheme of determining according to cubic equation, divide 5 stages, add remaining sulfuric acid (17.8g) with about 5 hours, maintain the temperature at 40-50 ℃ simultaneously.

It is definite according to above-described cubic equation that each adds the speed in stage, shows as following table.

Table 1

Stage	mL/kg/h	mL(H 2SO 4)/h	g(H 2SO 4)/h	Time length (min)
					1	4.62	0.579	1.065	60
2	6.93	0.868	1.597	60
					3	16.55	2.073	3.814	60
4	30.26	3.790	6.974	60
					5	48.47	6.071	11.171	23

H ₂SO ₄Interpolation finish after, under agitation with slurry cooling at least 1 hour to 20-25 ℃.At 20-25 ℃ slurry was stirred 1 hour at least.Filter hydrosulfate, as required mother liquor recirculation is changed fully with realization.With acetone (5-10mL/g free alkali; 1200mL acetone) washing leaching cake.55 ℃ of dry hydrosulfates of NMT obtain crystalline material until LOD＜1% under vacuum.

With PXRD, DSC and TGA figure and SSNMR spectral method analysis crystallized product, discovery is title hydrosulfate (non-solventization) A shape crystal (seeing Fig. 1 to 5).

Table 2

The crystallographic data table of A shape

The temperature of T=crystallographic data (℃)

The drug molecule number of Z '=each asymmetric cell

Table 3

The partial parameters of A shape and estimated standard deviation table thereof

Atom	x	y	z	B(A2)
					S1	0.3230(4)	0.5467(1)	0.5608(5)	8.0(1)
O100	0.431(1)	0.5060(3)	0.649(1)	11.1(3)
					O102	0.335(1)	0.5498(4)	0.383(1)	12.0(4)
O103	0.360(1)	0.5877(4)	0.655(2)	12.0(4)
					O104	0.176(1)	0.5384(4)	0.528(1)	11.8(4)
S51	0.6177(4)	0.4505(1)	0.4003(5)	7.2(1)
					O150	0.596(1)	0.4430(4)	0.564(1)	12.5(4)
O152	0.518(1)	0.4921(4)	0.317(1)	13.8(4)
					O153	0.588(1)	0.4121(3)	0.289(2)	12.2(4)
O154	0.768(1)	0.4587(4)	0.454(1)	12.1(4)
					O4	0.6985(7)	0.1753(3)	0.6456(9)	5.7(2)
O7	0.1687(8)	0.1941(3)	0.3411(9)	6.5(2)
					O11	-0.0352(7)	0.2482(3)	0.0308(8)	5.7(2)
O14	0.2280(7)	0.1769(3)	-0.233(1)	6.1(2)
					O15	0.0399(8)	0.1335(3)	-0.330(1)	6.4(2)
O17	0.6169(7)	0.2821(3)	0.963(1)	7.1(2)
					Atom	x	y	z	B(A2)
O18	0.3750(7)	0.2905(3)	0.9136(9)	6.2(2)
					N2	0.5015(9)	0.2182(3)	0.902(1)	4.5(2)
N5	0.4642(8)	0.1647(3)	0.6001(9)	4.2(2)
					N9	0.2317(9)	0.2788(3)	0.256(1)	5.1(2)
N10	0.1820(9)	0.2760(3)	0.069(1)	4.6(2)
					N13	-0.0148(8)	0.2083(3)	-0.280(1)	4.6(2)
N39	-0.087(1)	0.5265(3)	0.272(1)	6.1(3)
					C1	0.491(1)	0.2627(4)	0.924(1)	5.5(3)
C3	0.6381(9)	0.1908(3)	0.892(1)	4.0(2)
					C4	0.600(1)	0.1764(4)	0.702(1)	4.6(3)
C6	0.420(1)	0.1551(4)	0.403(1)	5.1(3)
					C7	0.295(1)	0.1936(4)	0.297(1)	5.1(3)
C8	0.357(1)	0.2400(4)	0.346(2)	5.4(3)
					C11	0.051(1)	0.2592(4)	-0.028(1)	4.9(3)
C12	0.024(1)	0.2531(4)	-0.223(1)	4.5(3)
					C14	0.094(1)	0.1732(4)	-0.280(1)	4.7(3)
C16	0.146(2)	0.0943(5)	-0.342(2)	10.9(5)
					C19	0.616(1)	0.3313(4)	0.996(2)	8.1(4)
C20	0.701(1)	0.1485(4)	1.025(1)	5.8(3)
					C21	0.842(1)	0.1219(5)	1.007(2)	7.9(4)
C22	0.583(2)	0.1160(5)	0.997(2)	8.0(4)
					C23	0.748(2)	0.1713(5)	1.215(1)	8.2(4)
C24	0.365(1)	0.1079(4)	0.356(2)	6.6(4)
					C25	0.484(1)	0.0691(4)	0.470(1)	6.5(3)
C26	0.643(2)	0.0684(5)	0.520(2)	8.4(5)
					C27	0.753(2)	0.0293(6)	0.622(2)	11.4(6)
C28	0.709(3)	-0.0044(7)	0.691(3)	15.0(9)
					C29	0.553(2)	-0.0032(5)	0.644(2)	14.2(7)
C30	0.441(2)	0.0343(5)	0.534(2)	10.8(4)
					C31	0.291(1)	0.3229(4)	0.311(2)	5.7(3)
C32	0.177(1)	0.3650(4)	0.259(1)	5.4(3)
					C33	0.224(1)	0.4064(4)	0.262(2)	6.3(3)
C34	0.122(1)	0.4487(5)	0.233(2)	6.9(4)
					C35	-0.031(1)	0.4469(4)	0.189(1)	4.8(3)
C36	-0.081(1)	0.4043(4)	0.180(1)	5.6(3)
					C37	0.019(1)	0.3629(4)	0.218(1)	5.4(3)
C38	-0.136(1)	0.4918(4)	0.170(1)	5.3(3)
					C40	-0.170(1)	0.5683(4)	0.279(2)	7.8(4)
C41	-0.318(2)	0.5736(5)	0.158(2)	9.1(5)
					C42	-0.376(2)	0.5403(5)	0.035(2)	9.0(5)
C43	-0.283(1)	0.4964(5)	0.039(2)	8.1(4)
					C44	-0.096(1)	0.2937(4)	-0.345(1)	6.2(3)
C45	-0.258(1)	0.2901(5)	-0.366(2)	8.5(4)
					C46	-0.085(2)	0.2890(6)	-0.530(2)	10.8(5)
Atom	x	y	z	B(A2)
					C47	-0.057(2)	0.3393(5)	-0.265(2)	8.9(5)
O54	0.2347(7)	0.8167(3)	0.8392(8)	5.3(2)
					O57	0.7713(8)	0.7950(3)	1.0561(9)	5.9(2)
O61	0.9725(7)	0.7436(3)	0.9141(8)	5.3(2)
					O64	0.7062(7)	0.8164(3)	0.427(1)	5.9(2)
O65	0.8911(8)	0.8598(2)	0.535(1)	6.1(2)
					O67	0.3150(8)	0.7090(3)	1.184(1)	6.4(2)
O68	0.5587(9)	0.6986(3)	1.377(1)	6.6(2)
					N52	0.4313(9)	0.7713(3)	1.271(1)	4.9(2)
N55	0.4709(8)	0.8265(3)	1.0332(9)	4.2(2)
					N60	0.7555(8)	0.7179(3)	0.728(1)	4.6(2)
N63	0.9491(8)	0.7852(3)	0.601(1)	4.4(2)
					N89	1.026(1)	0.4719(3)	0.711(1)	6.0(3)
C51	0.442(1)	0.7247(4)	1.282(1)	5.4(3)
					C53	0.296(1)	0.7996(4)	1.141(1)	5.1(3)
C54	0.3347(9)	0.8159(3)	0.989(1)	4.1(3)
					C56	0.519(1)	0.8353(4)	0.887(1)	4.7(3)
C57	0.644(1)	0.7959(4)	0.886(1)	4.5(3)
					C58	0.587(1)	0.7494(4)	0.854(1)	5.2(3)
C61	0.884(1)	0.7334(4)	0.766(1)	4.2(3)
					C62	0.914(1)	0.7392(4)	0.603(1)	4.4(3)
C64	0.839(1)	0.8196(4)	0.513(1)	4.6(3)
					C66	0.785(2)	0.8996(5)	0.433(3)	12.1(7)
C69	0.323(1)	0.6588(4)	1.202(2)	8.8(5)
					C70	0.237(1)	0.8409(4)	1.232(1)	5.6(3)
C71	0.092(1)	0.8701(5)	1.080(2)	7.6(4)
					C72	0.352(1)	0.8744(4)	1.328(2)	7.1(4)
C73	0.187(1)	0.8195(6)	1.362(1)	8.9(4)
					C74	0.570(1)	0.8825(4)	0.907(2)	6.4(3)
C75	0.450(1)	0.9206(4)	0.919(1)	6.3(3)
					C76	0.296(2)	0.9236(5)	0.813(2)	8.1(4)
C77	0.188(2)	0.9614(6)	0.826(2)	11.2(5)
					C78	0.244(2)	0.9942(6)	0.960(2)	15.2(7)
C79	0.405(3)	0.9935(6)	1.062(2)	13.9(7)
					C80	0.504(2)	0.9552(4)	1.043(2)	9.3(5)
C81	0.644(1)	0.6672(4)	0.832(2)	6.2(3)
					C82	0.762(1)	0.6266(3)	0.839(1)	4.7(3)
C83	0.723(1)	0.5934(4)	0.696(2)	6.1(3)
					C84	0.822(1)	0.5547(4)	0.695(2)	5.9(3)
C85	0.967(1)	0.5478(4)	0.828(1)	5.0(3)
					C86	1.009(1)	0.5783(4)	0.971(2)	6.6(4)
C87	0.908(1)	0.6184(4)	0.971(2)	6.4(4)
					C88	1.076(1)	0.5070(4)	0.827(1)	5.5(3)
C90	1.111(1)	0.4326(4)	0.690(2)	7.4(4)
					Atom	x	y	z	B(A2)
C91	1.258(2)	0.4262(5)	0.792(2)	7.8(4)
					C92	1.324(2)	0.4578(5)	0.918(2)	8.7(5)
C93	1.230(1)	0.4994(5)	0.936(2)	6.9(4)
					C94	1.038(1)	0.7005(4)	0.584(1)	4.8(3)
C95	1.196(1)	0.7055(4)	0.717(2)	6.7(4)
					C96	1.021(2)	0.7049(5)	0.392(2)	8.9(4)
C97	0.998(1)	0.6536(4)	0.614(2)	7.6(4)
					N59	0.7084(8)	0.7114(3)	0.866(1)	5.1(2)
H391	0.047	0.523	0.383	6.0 *
					H891	0.931	0.477	0.646	5.8 *
H15′	0.491	0.471	0.600	3.8 *
					H15″	0.440	0.512	0.322	4.6 *

Omitted most of hydrogen; Include only the hydrogen in N9 and the acid.

The refining atom of anisotropy adopts the form of isotropy equivalent displacement parameter (isotropicequivalent displacement parameter) to provide, be defined as: [a2*B (1 for (4/3) *, 1)+b2*B (2,2)+c2*B (3,3)+ab (cos γ) * B (1,2) x+ac (cos β) * B (1,3)+bc (cos α) * B (2,3)].

Differential scanning calorimetric thermogram feature such as Fig. 3 of A shape show to about 200.9 ℃ of scopes heat absorption is arranged at about 165.6 ℃ usually.

The thermogravimetric curve feature of A shape is to have located negligible weight loss at paramount about 100 to 150 ℃.

Compare with the crystal that obtains with constant interpolation speed crystallization, add H with the speed that increases according to above-described cubic equation ₂SO ₄The crystal that three times crystallization produced relatively large and better determine, and have narrower size range and expense (fines) is lower.

The filter cake that obtains with three crystallization techniques is than littler with the filter cake compressibility of constant interpolation speed crystallization acquisition, helps effectively to dewater and wash and obtain even product for filter cake.

Table 4

The A shape of measuring is with respect to carbon-13SSNMR chemical shift of TMS (tetramethylsilane)

δ/ppm
	26.9
27.5
	33.9
37.7
	49.2
53.5
	62.7
63.3
	66.0
69.2
	69.5
122.6
	123.7
125.3
	126.1
127.6
	128.5
129.4
	131.1
134.4
	138.8
139.7
	140.6
143.2
	143.9
149.9
	150.3
153.9
	159.3
172.0

Embodiment 2

Zrivada-C pattern material

Method A:

Zrivada A shape crystal (describing preparation by embodiment 1) (25.33g) is suspended in the 200mL water, and the mechanical stirring mixture obtains viscous gel, is dried.

Obtain C pattern material with spatula mill-drying mixture.X-ray diffractogram of powder such as Fig. 6 of C pattern material show.

Method B:

With enough water (about 40%w/w) in suitable mixing tank-nodulizer with Zrivada A shape crystal wet granulation.Dry wet agglomerate in baking oven.With suitable screen cloth the product screening is a certain size (size).The C pattern material that the X-ray diffractogram of products therefrom and Fig. 6 show consistent.

Differential scanning calorimetric thermogram feature such as Fig. 7 of C pattern show, usually at about 76.7 to about 96.6 ℃ and about 156.8 heat absorption is arranged to about 165.9 ℃ of scopes.

Thermogravimetric curve feature such as Fig. 8 of C pattern show, in about 125 ℃ of weight loss about 2.4% and in about 190 ℃ of weight loss about 4.4%.

Embodiment 3

Zrivada-E3 shape (three alcohol solvent compounds)

In disposing the 100mL3 neck round-bottomed flask of mechanical stirrer, temperature sensor and pressure equilibrium addition funnel, make Reyataz R free alkali (partly preparing) (3.0g by C among the embodiment 1,4.26mmol) in dry 200 regulation (proof) ethanol (20.25mL, 6.75mL/g free alkali), make slurry.

With dense H ₂SO ₄(4.69mmol 1.1eq.) adds in the Reyataz R free alkali slurry that remains on 20-25 ℃ for 0.25mL, 0.46g.(Whatman#1 paper) is filtered in solution (KF 0.2 to the 1.0% water) polishing that generates,, washing fluid is added in the filtering solution with 2.25mL dehydrated alcohol flushing filter.Solution is heated to 37 ℃, derived from E3 shape crystalline non-crystalline state Zrivada (by E3 shape crystal is exposed to envrionment temperature) inoculation, mixture was stirred 15 minutes with 10mg.With 1 hour adding heptane (380mL, 8.25mL/g free alkali).At 15-25 ℃ the crystalline mixture that generates was stirred 8 hours.The Zrivada of filtering for crystallizing on Buchner funnel.With 1: 1 ethanol of 184mL (4mL/g free alkali): heptane wash product cake.With 46mL (1mL/g free alkali) heptane wash product cake.At the product of 40-50 ℃ of vacuum-drying generation, until its LOD=0.97%.Product output is 47.7g (0.0594mol, 74.3mol%) Zrivada E3 shape (three alcohol solvent compounds), HPLC HI=100.0 (seeing Fig. 9 and 10).

Table 5

E3 shape crystallographic data table

The temperature of T=crystallographic data (℃)

The drug molecule number of Z '=each asymmetric cell

Table 6

The partial parameters of E3 shape and estimated standard deviation table thereof

Atom	x	y	z	B(A2)	Occupancy (occupany) (if being not equal to 1)
						S99	0.5568(1)	0.0760(1)	0.5936(1)	3.45(2)
O1	0.4200(5)	0.5541(4)	0.8496(5)	6.9(1)
						O2	0.2889(5)	0.6016(4)	1.0066(6)	8.1(1)
O4	0.7004(4)	0.4509(3)	1.0233(4)	4.23(8)
						O8	0.2913(4)	0.2932(3)	1.1074(4)	4.23(8)
O12	0.1057(4)	0.1088(3)	0.9299(4)	4.16(8)
						O15′	0.329(1)	-0.0602(9)	1.064(1)	4.8(3) *	.3
O15″	0.324(2)	-0.156(1)	1.003(2)	3.2(3) *	.17
						Atom	x	y	z	B(A2)	Occupancy (if being not equal to 1)
O15	0.3312(7)	-0.1150(6)	1.0380(8)	4.9(1) *	.53
						O16	0.1810(5)	-0.1433(3)	1.1819(4)	5.7(1)
O86	0.391(1)	0.6646(7)	0.6196(9)	11.5(4)
						O89	0.3714(7)	0.5646(5)	0.3408(6)	6.5(2)
O90	0.7502(4)	0.2721(3)	0.8957(5)	4.99(9)
						O95	0.4984(4)	0.0446(3)	0.7188(4)	4.50(8)
O96	0.6644(4)	0.0315(3)	0.5660(4)	4.83(8)
						O97	0.4651(4)	0.0667(3)	0.4636(4)	5.08(9)
O98	0.6112(5)	0.1957(3)	0.6332(5)	5.9(1)
						N2	0.4938(5)	0.6229(3)	1.0921(5)	4.8(1)
N5	0.5365(4)	0.4385(3)	1.1609(4)	3.16(8)
						N10	0.2952(4)	0.2239(3)	0.8056(4)	3.17(8)
N11	0.2716(4)	0.1163(3)	0.7961(4)	3.08(8)
						N14	0.1336(5)	-0.0874(4)	0.9743(5)	4.9(1)
N38	-0.2764(4)	0.0574(3)	0.2878(4)	3.24(8)
						C1	0.4011(6)	0.5893(4)	0.9712(7)	5.3(1)
C3	0.6225(5)	0.6026(4)	1.0813(5)	3.9(1)
						C4	0.6231(5)	0.4896(3)	1.0873(5)	3.19(9)
C6	0.5220(5)	0.3284(3)	1.1691(5)	3.14(9)
						C8	0.4026(5)	0.2632(3)	1.0653(5)	3.21(9)
C9	0.4165(5)	0.2747(4)	0.9050(5)	3.6(1)
						C12	0.1740(5)	0.0661(4)	0.8596(5)	3.4(1)
C13	0.1592(5)	-0.0523(4)	0.8367(5)	3.8(1)
						C15	0.2248(6)	-0.1124(5)	1.0627(6)	4.6(1)
C17	0.2720(9)	-0.1732(6)	1.2842(7)	7.3(2)
						C18	0.1818(9)	0.5715(9)	0.894(1)	11.2(3)
C19	0.7292(7)	0.6818(4)	1.1928(7)	5.8(2)
						C20	0.725(1)	0.7914(6)	1.169(1)	10.7(3)
C21	0.8613(9)	0.6645(8)	1.165(1)	10.5(3)
						C22	0.710(1)	0.6694(7)	1.3507(8)	10.2(3)
C23	0.5158(5)	0.3135(4)	1.3298(5)	3.8(1)
						C24	0.6305(6)	0.3765(4)	1.4359(5)	4.0(1)
C25	0.7519(7)	0.3708(6)	1.4192(7)	6.1(2)
						C26	0.8581(7)	0.4279(7)	1.5213(9)	7.9(2)
C27	0.8398(8)	0.4935(6)	1.6375(8)	8.6(2)
						C28	0.715(1)	0.5002(6)	1.6576(7)	8.0(2)
C29	0.6112(8)	0.4430(5)	1.5589(6)	6.0(2)
						C30	0.3043(5)	0.2519(4)	0.6582(5)	3.6(1)
C31	0.1813(5)	0.2051(4)	0.5532(5)	3.4(1)
						C32	0.0645(5)	0.2123(4)	0.5934(5)	3.9(1)
C33	-0.0489(5)	0.1725(4)	0.4957(5)	3.8(1)
						C34	-0.0441(5)	0.1243(4)	0.3503(5)	3.16(9)
C35	0.0756(5)	0.1176(4)	0.3097(5)	3.9(1)
						Atom	x	y	z	B(A2)	Occupancy (if being not equal to 1)
C36	0.1867(5)	0.1568(4)	0.4095(5)	3.9(1)
						C37	-0.1615(5)	0.0853(4)	0.2417(4)	3.11(9)
C39	-0.3885(5)	0.0247(4)	0.1969(5)	3.9(1)
						C40	-0.3891(5)	0.0200(4)	0.0470(5)	4.2(1)
C41	-0.2737(6)	0.0469(4)	-0.0057(5)	4.1(1)
						C42	-0.1596(5)	0.0781(4)	0.0890(5)	3.7(1)
C43	0.0488(6)	-0.1114(4)	0.7094(6)	4.6(1)
						C44	-0.0819(7)	-0.0958(6)	0.7378(9)	6.8(2)
C45	0.0496(9)	-0.2266(5)	0.6929(9)	7.8(2)
						C46	0.0797(8)	-0.0738(5)	0.5667(7)	6.2(2)
C84	0.569(1)	0.7880(9)	0.725(1)	6.3(3)
						C85	0.448(1)	0.7726(9)	0.673(2)	8.4(4)
C87	0.204(1)	0.449(1)	0.405(2)	10.6(4)
						C88	0.240(1)	0.517(1)	0.316(1)	8.6(3)
C91	0.8826(7)	0.2919(5)	0.8896(8)	5.8(2)
						C92	0.9613(7)	0.3439(6)	1.035(1)	7.8(2)
H381	-0.275	0.053	0.403	3.2
						H891	0.397	0.602	0.446	6.6
H981	0.658	0.219	0.717	6.6

Omitted most of hydrogen; Include only the hydrogen in N9 and the acid.

The refining atom of anisotropy adopts the form of the equivalent displacement of isotropy parameter to provide, and is defined as: (4/3) * [a2*B (1,1)+b2*B (2,2)+c2*B (3,3)+ab (cos γ) * B (1,2) x+ac (cos β) * B (1,3)+bc (cos α) * B (2,3)].

Differential scanning calorimetric thermogram feature such as Figure 11 of E3 shape show to about 96.6 scopes heat absorption is arranged about 89.4 usually.

Thermogravimetric curve feature such as Figure 11 of E3 shape show, in about 150 ℃ of weight loss about 14.7%.

Embodiment 4

Zrivada C pattern capsule preparations preparation as described below with following composition.

Composition	Feed particles a (％w/w)	50mg capsule (mg/ capsule)	100mg capsule (mg/ capsule)	200mg capsule (mg/ capsule)
					Zrivada	63.2	56.84 b	113.67 b	227.34 b
Lactose, monohydrate, NF	30.4	27.33 c	54.69 c	109.35 c
					Crospovidone, NF	6.0	5.39	10.79	21.58
Magnesium Stearate, NF	0.4	0.36 d	0.72 d	1.44 d
					Pure water, USP or water for injection, USP	q.s. e	q.s. e	q.s. e	q.s. e
The #4 capsule	-	Each is 1 years old	-	-
					The #2 capsule	-	-	Each is 1 years old	-
The #0 capsule	-	-	-	Each is 1 years old
					Total filling weight	100.0	89.9	179.9	359.7

^aCapsular Zrivada feed particles (stock granulation) (55.5%w/w free alkali) is used to prepare 50mg, 100mg and 200mg capsule.

^bThis amount is represented with the Zrivada of 100% usefulness, equals the 55.5%w/w free alkali.

^cLactose, hydration level will change with the different of Magnesium Stearate consumption with Zrivada purity.

^dThe consumption of Magnesium Stearate can change from 0.4%w/w to 0.8%w/w.

^eThis is used for operation and removes by dry.

The feed particles of Zrivada is prepared as follows, and therefrom forms C pattern material.

In planetary-type mixer, Zrivada A shape, lactose hydrate and a part of Crospovidone (accounting for 3% total Crospovidone weight) are mixed.With pure water with the mixture wet granulation that generates A shape is converted into C pattern material.Dry wet particle and make a certain size (size) in tray dryer with hammer mill.Remaining Crospovidone is added the particle that grinds and in PK V-mixing tank, mixture is mixed.Add Magnesium Stearate, stir the mixture until forming basically feed particles uniformly.

An amount of feed particles is inserted in the capsule, obtained containing 50mg, 100mg and the 200mg capsule of Zrivada.

Embodiment 5

The Zrivada A shape material powder that is used for oral preparations with following composition is prepared as follows.

Composition	Amount (%w/w)
		Zrivada A shape	3.79
Aspartame, NF	10.00
		Sucrose, NF	81.21
The orange vanilla flavor	5.00

In suitable blender, Zrivada A shape is mixed with aspartame, orange vanilla flavor and sucrose.Use the hammer mill grinding mixture, carry out then mixing the second time to obtain uniform mixture.Product is inserted in the high-density polyethylene bottle.

Claims (18)

1. a method for preparing Zrivada C pattern material comprises

(a) Zrivada A shape crystal is suspended in water and with the suspension drying, form C pattern material; Or

(b) make Zrivada A shape crystal stand to form C pattern material greater than the high relative humidity of 95%RH at least 24 hours; Or

(d) make A shape crystal and one or more preparation mixed with excipients,, directly form C pattern material with mixed with excipients with the mixture wet granulation that generates;

Wherein Zrivada C pattern material have specification sheets x-ray diffractogram of powder shown in Figure 6 and

Zrivada A shape crystal has specification sheets x-ray diffractogram of powder shown in Figure 1.

2. a method for preparing Zrivada C pattern material comprises

(a) make solution and the first part strong sulfuric acid response of Reyataz R free alkali in the organic solvent of the mixture of the mixture that is selected from acetone, acetone and N-Methyl pyrrolidone, ethanol or ethanol and acetone, wherein the add-on of the vitriol oil and the Reyataz R free alkali reaction that is less than 15% weight; Zrivada A shape crystal crystal seed is added in the reaction mixture, when Zrivada is crystal formation, divides a plurality of stages to add the other vitriol oil according to cubic equation with the speed that increases, with effective formation A shape crystal;

Wherein

V _TimeThe vitriolic volume that adds in=the elapsed time

V _Total=represent the cumulative volume of the acid of 90% raw material

Time=crystalline elapsed time

Time _Total=total crystallization time

(b) the Zrivada A shape crystal of step (a) is suspended in water and, form C pattern material the suspension drying; Or

(c) make the Zrivada A shape crystal of step (a) stand to form C pattern material greater than the high relative humidity of 95%RH at least 24 hours; Or

(d) form C pattern material with the Zrivada wet granulation of step (a) and with wet grain drying; Or

(e) make the A shape crystal of step (a) and one or more preparation mixed with excipients, with the mixture wet granulation that generates, the direct C pattern material of formation and mixed with excipients;

Wherein Zrivada C pattern material have specification sheets x-ray diffractogram of powder shown in Figure 6 and

Zrivada A shape crystal has specification sheets x-ray diffractogram of powder shown in Figure 1.

3. the described method of claim 2, the wherein initial sulfuric acid that reacts with the Reyataz R free base solution accounts for 5 to 15% weight of total consumption.

4. the described method of claim 2, the wherein initial sulfuric acid that reacts with the Reyataz R free base solution accounts for 8 to 12% weight of total consumption.

5. the described method of claim 2, wherein Reyataz R free alkali and the first part's sulfuric acid thermotonus in 35 to 55 ℃ of scopes.

6. the described method of claim 2, wherein the Reyataz R free base solution with sulfuric acid reaction before be heated to 35 to 55 ℃ of temperature in the scope.

7. the described method of claim 2, wherein 0.1 to 80% weight A shape crystal with Reyataz R free alkali weight is seeded in Reyataz R free alkali and the vitriolic reaction mixture.

8. the described method of claim 2, wherein the heating of the temperature in 35 to 55 ℃ of scopes is through the reaction mixture of inoculation.

9. the described method of claim 2, the organic solvent that wherein is used for the Reyataz R free alkali is the mixture of acetone or acetone and N-Methyl pyrrolidone.

10. method for preparing Zrivada C pattern material, it comprises: make Zrivada A shape crystal stand the high relative humidity at least 24 hours of 95%RH at least;

Wherein Zrivada C pattern material have specification sheets x-ray diffractogram of powder shown in Figure 6 and

Zrivada A shape crystal has specification sheets x-ray diffractogram of powder shown in Figure 1.

11. Zrivada for preparing C pattern material form

Method, comprise;

(a) three amine salt of preparation following formula structure

Three amine salt that need not to emanate make the acid of three amine salt and following formula structure

Active ester and alkali in the presence of organic solvent, react, form the Reyataz R free base solution of following formula structure

Be converted into corresponding hydrosulfate with free alkali is following: with N-Methyl pyrrolidone and the solution of acetone treatment free alkali in methylene dichloride, the heating said mixture is to remove methylene dichloride, Zrivada A shape crystal is seeded in the mixture of free alkali, acetone and N-Methyl pyrrolidone, handle said mixture to form the hydrosulfate of free alkali with the vitriol oil, wherein add sulfuric acid with the speed that increases according to following equation

Wherein

V _TimeThe vitriolic volume that adds in=the elapsed time

V _Total=represent the cumulative volume of the acid of 90% raw material

Time=crystalline elapsed time

Time _TotalTotal interpolation time of=total crystallization time or acid,

To form Zrivada A shape crystal;

(b) the Zrivada A shape crystal of step (a) is suspended in water and, form C pattern material the suspension drying; Or

(c) make the Zrivada A shape crystal of step (a) stand to form C pattern material greater than the high relative humidity of 95%RH at least 24 hours; Or

(d) form C pattern material with the Zrivada wet granulation of step (a) and with wet grain drying; Or

(e) make the A shape crystal of step (a) and one or more preparation mixed with excipients, with the mixture wet granulation that generates, the direct C pattern material of formation and mixed with excipients;

Wherein Zrivada C pattern material have specification sheets powder X-ray x ray diffration pattern x shown in Figure 6 and

Zrivada A shape crystal has specification sheets x-ray diffractogram of powder shown in Figure 1.

12. the described method of claim 11, wherein three amine salt are hydrochlorides of following formula

13. the described method of claim 11, wherein Suan active ester has the following formula structure

14. the described method of claim 11, wherein alkali is alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal phosphate, alkali earth metal phosphate or organic bases.

15. the described method of claim 11, wherein alkali is NaOH, KOH, Mg (OH) ₂, K ₂HPO ₄, MgCO ₃, Na ₂CO ₃, K ₂CO ₃, triethylamine, diisopropylethylamine or N-methylmorpholine, organic solvent is methylene dichloride, ethyl acetate, ethylene dichloride, tetrahydrofuran (THF), acetonitrile or N, dinethylformamide.

16. the described method of claim 11, wherein three amine salt and the active ester thermotonus in 30 to 40 ℃ of scopes.

17. the described method of claim 16, wherein there are K in three amine salt and active ester ₂HPO ₄React under the situation as solvent as alkali and methylene dichloride.

18. Zrivada for preparing C pattern material form

Method, comprise

(a) three amine hydrochlorates of preparation following formula structure

Make the active ester of three amine hydrochlorates and following formula structure

And K ₂HPO ₄In the presence of methylene dichloride, react, form the free alkali of following formula structure

Solution in methylene dichloride is converted into corresponding hydrosulfate by three crystallization techniques with free alkali, wherein adds sulfuric acid according to following equation stage by stage with the speed that increases

Wherein

V _TimeThe vitriolic volume that adds in=the elapsed time

V _Total=represent the cumulative volume of the acid of 90% raw material

Time=crystalline elapsed time

Time _TotalTotal interpolation time of=total crystallization time or acid,

To form Zrivada A shape crystal;

(b) the Zrivada A shape crystal of step (a) is suspended in water and, form C pattern material the suspension drying; Or

(c) make the Zrivada A shape crystal of step (a) stand to form C pattern material greater than the high relative humidity of 95%RH at least 24 hours; Or

(d) form C pattern material with the Zrivada A shape crystal wet granulation of step (a) and with wet grain drying; Or

(e) make the A shape crystal of step (a) and one or more preparation mixed with excipients, with the mixture wet granulation that generates, the direct C pattern material of formation and mixed with excipients;

Wherein Zrivada C pattern material have specification sheets x-ray diffractogram of powder shown in Figure 6 and

Zrivada A shape crystal has specification sheets x-ray diffractogram of powder shown in Figure 1.

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