CN101052393A - Novel polymorphs of azabicyclohexane - Google Patents

Novel polymorphs of azabicyclohexane Download PDF

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Publication number
CN101052393A
CN101052393A CNA2005800279269A CN200580027926A CN101052393A CN 101052393 A CN101052393 A CN 101052393A CN A2005800279269 A CNA2005800279269 A CN A2005800279269A CN 200580027926 A CN200580027926 A CN 200580027926A CN 101052393 A CN101052393 A CN 101052393A
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polymorph form
polymorph
addition salts
azabicyclo
hexane
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埃里克·J·哈根
凯文·哈洛伦
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DOV Pharmaceutical Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The invention provides polymorphic crystalline forms of acid addition salts of (+)-1-(3, 4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane designated as polymorph form A, polymorph form B and polymorph form C, where polymorph form A is more thermodynamically stable than the other forms, methods for preparing and using such polymorph forms and pharmaceutical compositions containing such polymorph forms.

Description

The new polymorphic forms of azabicyclohexane
The application required submit in 2004 8 about 18 days, was changed into the priority of the U.S. Patent application 10/920,748 of provisional application.
Background technology
The salt of (+) isomer with phenyl azabicyclohexane of following formula
It is depressed to become known for treatment.As what in people's such as Lippa United States Patent (USP) 6,372,919, illustrate, be that the chemical compound of the formula I of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane has been found that to have effective antidepressant activity with the chemical name of its (+) isomeric form.
Although the azabicyclohexane of formula I, as at a lot of United States Patent (USP)s, as United States Patent (USP) 4,231,935,4,131,611,4,435,419,4,118,417 and 4,196, described in 120 like that, be produced, but these chemical compounds prepare with racemic form.In the step of people's such as Lippa United States Patent (USP) 6,372,919, prepared (+) optical antipode as the mixture of the polymorph of the multiple isomery of never being familiar with before this.The pure crystal form of (+) isomer of formula I chemical compound is a particular importance, because it can be formulated into multiple pharmaceutical formulation, for example is used for the treatment of the patient in tablet and the capsule.Known stripping, preparation, stability and the bioavailability that influences the medicinal drug product of the changes of crystal of medicinal drug material is particularly in solid oral dosage form.Therefore, importantly with (+) isomer of the pure form preparation I compound that comprises single thermodynamically stable crystal structure.
Summary of the invention
According to the present invention, have been found that as United States Patent (USP) 6 people such as Lippa, 372, (+) optical antipode of the formula I chemical compound of preparation exists with the mixture of two kinds of crystallization polymorphic structures in 919, a kind of is half hydrated form that is designated as polymorph form A, and another kind is the anhydrous form that is designated as the polymorph b form.The dehydrated form of being appointed as the polymorph form A also is found.When passing through (+) optical antipode of prior art step preparation I compound, have been found that it is that conduct is not easy to be separated into the polymorph form A of their pure polymorphous crystal forms and the mixture of polymorph form B is produced.
According to the present invention, have been found that the method that forms these polymorphs with pure independently polymorph form.In addition, the present inventor has been found that the polymorph form A of (+) optical antipode of the formula I chemical compound with its pure crystalline texture prepared in accordance with the present invention is thermodynamically stable polymorph form.Therefore, form A is the preferred crystal form of (+) optical antipode of acid-addition salts that is used for being formulated into the formula I chemical compound of medicinal drug product.
Detailed Description Of The Invention
According to the present invention, (+) optical antipode that has been found that the acid-addition salts of formula I chemical compound is present in to be appointed as in polymorph form A, polymorph form B and three kinds of the polymorph form A different crystalline polymorphs, and wherein the polymorph form A of hemihydrate form is thermodynamically stable form.
Polymorph form A can be characterized by the semihydrate of the acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane.It is acid-addition salts and semihydrate crystal form polymorph form B and other polymorph form of polymorph form A phase region A of unique sign formula I chemical compound.The polymorph form B and the polymorph form A of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane do not exist with hemihydrate form.
The polymorph of the acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane can also be characterized by their X-powder diffraction pattern (XRPD) and/or their Raman spectral peaks.About the X-ray powder diffraction, the relative intensity at the X-ray powder diffraction peak of given polymorph can change and difference according to the crystal size of the polymorph that is used for definite described pattern.This is the phenomenon of preferred orientation.Crystalline form produces preferred orientation.In this case, should in the XRPD analytic process, be used in the sample that rotates in the specimen holder and carry out the XRPD analysis to reduce the influence of preferred orientation.According to the present invention, be used for determining that sample that the XRPD of the existence of its polymorph state and character analyzes should slightly grind and/or sieve becomes to be used for about 10 to 40 microns crystal size that XRPD analyzes.
The Bragg-Brentano instrument of reporting herein that comprises the Shimadzu system that is used for the measurement of X-powder diffraction pattern, provide systemic peak-shift (all peaks can in given " ° 2 θ " angular displacement), it results from the error of sample preparation, as in people such as Chen; JPharmaceutical and Biomedical Analysis, 2001; As described in 26,63.Therefore, any " ° 2 θ " angle reading of peak value error of (±) 0.2 ° of having an appointment.
The analysis of the X-powder diffraction pattern (XRPD) of polymorph form A, B and C utilizes Cu Ka radiation to carry out with Shimadzu XRD-6000X-ray powder diffraction instrument.In this step, will be placed on the machine as crystalline powder as the chemical compound of hydrochlorate.These instrument and equipment have long microfocus X ray tube.The voltage and current intensity of this pipe is set at 40kV and 40mA respectively.Disperse with scatter slit and be set in 1 ° and receive slit and be set in 0.15mm.Diffraction radiation detects by the Nal scintillation detector.Employing 2.5 to 40 ° of 2 θ of θ-2 θ continuous sweep under 3 °/minute (0.4 second/0.02 ° steps).The silicon standard analyzed with inspection apparatus proofread and correct.With XRD-6000v.4.1 image data and analysis.
Following table 1 explanation has the peak of X-powder diffraction pattern of polymorph form A of purification that crystal size is the hydrochlorate of about 10 to 40 microns (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane.This pattern provides according to " ° 2 θ " angle with peak of as above illustrated angle error.About the relative intensity (I/I that in table 1, provides 0) percent value, I 0Expression is for all " ° 2 θ " angles, the value of the maximum peak of being determined by the XRPD of sample and the value that I is illustrated in the peak intensity of measurement given " ° 2 θ " angle under.Described angle " ° 2 θ " is the angle of diffraction, and it is the angle between incident X-ray and the diffraction X-ray.The relative intensity value at the given peak that provides with the form of percentage ratio and " ° 2 θ " angle that the position appears in described peak provide in following table 1.
Table 1
The XRPD peak of polymorph form A (° 2 θ) and relative intensity (I/I 0)
Form A
°2θ I/I 0 °2θ I/I 0
4.55 25 33.42 9
9.10 15 34.24 6
13.65 6 35.08 15
17.14 60 35.65 16
17.85 11 36.31 14
18.24 23 37.11 26
18.49 14 37.78 9
19.27 14 39.85 9
19.62 22
21.74 15
21.96 100
22.24 12
23.01 7
24.52 43
24.79 10
26.74 52
27.44 11
27.63 17
28.36 16
28.48 26
29.00 14
29.20 19
29.40 27
29.57 27
30.24 18
31.01 13
31.62 17
32.20 24
32.93 12
Following table 2 explanation has the peak of X-powder diffraction pattern of pure polymorph form B that crystal size is the hydrochlorate of about 10 to 40 microns (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane.For having crystal size is about 10 to 40 microns (+)-1-(3, the 4-Dichlorobenzene base)-and the polymorph form B of the hydrochlorate of 3-azabicyclo [3.1.0] hexane, the relative intensity value at the given peak that provides with the form of percentage ratio and " ° 2 θ " angle that the position appears in described peak provide in following table 2.
Table 2
The XRPD peak of polymorph form B (° 2 θ) and relative intensity (I/I 0)
Form B
°2θ I/I 0 °2θ I/I 0
10.50 6 32.14 10
13.34 12 32.31 7
15.58 42 32.80 7
17.12 6 32.95 6
17.36 8 33.45 44
17.52 26 33.74 12
18.21 11 35.25 10
20.40 7 35.40 12
21.35 97 35.58 9
21.61 17 36.75 8
21.93 11 37.55 18
22.64 6 39.01 15
23.04 79 39.22 7
24.09 6 39.37 7
24.52 14 39.86 11
25.43 96
26.24 53
26.36 73
26.75 11
26.88 7
27.44 6
27.94 12
28.36 20
28.54 30
29.39 10
29.72 9
30.07 7
30.58 8
30.72 100
31.07 14
31.38 12
31.55 7
31.78 12
Following table 3 explanation has the peak of X-powder diffraction pattern of pure polymorph form A that crystal size is the hydrochlorate of about 10 to 40 microns (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane.For having crystal size is about 10 to 40 microns (+)-1-(3, the 4-Dichlorobenzene base)-and the polymorph form A of the hydrochlorate of 3-azabicyclo [3.1.0] hexane, the relative intensity value at the given peak that provides with the form of percentage ratio and " ° 2 θ " angle that the position appears in described peak provide in following table 3.
Table 3
XRPD peak of polymorph form A (° 2 θ) and relative intensity (I/I 0)
Form A
°2θ I/I 0 °2θ I/I 0
5.46 6 27.90 54
5.66 20 28.14 8
6.37 6 28.56 32
7.26 6 28.74 17
8.75 6 29.20 6
13.34 25 29.72 6
13.94 11 29.92 26
15.65 7 30.54 13
16.26 7 30.72 19
17.01 8 30.96 31
17.38 9 31.42 7
17.64 83 31.68 11
17.92 15 31.80 15
18.23 40 31.97 6
19.08 7 32.43 21
19.38 46 33.26 12
19.86 20 33.40 15
20.07 100 33.64 25
21.16 17 33.84 18
21.32 94 34.11 15
21.64 37 34.70 11
22.42 25 35.07 8
22.70 12 35.64 11
22.97 70 35.91 8
23.31 6 36.09 21
24.09 15 37.80 12
24.86 94 38.06 6
25.24 32 38.17 6
25.38 49 39.04 6
26.12 13 39.23 8
26.32 90 39.77 7
26.87 18
27.21 39
Yet, in these X-powder diffraction pattern, there is the crucial main peaks at given angle, it is unique for each given polymorph form.These peaks are present in each to have in the XRPD pattern that crystal size is about 10 to 40 microns polymorph form.Any of these main peaks, no matter independent or in office why not with combination in, be enough to a kind of polymorph form is different from two kinds of forms in addition.For polymorph form A, " ° 2 θ " angle with as above illustrated error that characterizes these main peaks of polymorph form A is:
17.14；
19.62；
21.96；
24.52；
With
26.74。
Any of these main peaks, no matter independent or in office why not with combination in, be enough to polymorph form A is different from two kinds of polymorph forms in addition.
Equally, the crucial main peaks that in the XRPD of polymorph form B, has given angle, it is for being that the polymorph form B of about 10 to 40 microns hydrochlorate is unique as having crystal size, it typically is present in the XRPD pattern as the polymorph form B of hydrochlorate, no matter granular size how.Any of these main peaks, no matter independent or in office why not with combination in, be enough to polymorph form B is different from two kinds of polymorph forms in addition.For polymorph form B, " ° 2 θ " angle with as above illustrated error that characterizes these main peaks of polymorph form B is:
15.58；
17.52；
21.35；
23.04；
25.43；
With
30.72。
Equally, the crucial main peaks that in the XRPD of polymorph form A, has given angle, it is for being that the polymorph form A of about 10 to 40 microns hydrochlorate is unique as having crystal size, it typically is present in the XRPD pattern as the polymorph form A of hydrochlorate, no matter granular size how.Any of these main peaks, no matter independent or in office why not with combination in, be enough to the polymorph form A is different from two kinds of polymorph forms in addition.For the polymorph form A, " ° 2 θ " angle with as above illustrated error that characterizes these main peaks of polymorph form A is:
13.34；
17.64；
20.07；
21.32；
22.97；
24.86；
26.32；
With
27.90。
The another kind of method that characterizes three kinds of polymorphs of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane is to pass through Raman spectrum.The step of implementing Raman spectrum is described in Skoog and West, Principles of Instrumental Analysis (the 2nd edition); Saunders College is on the 260-275 page or leaf of Philadelphia (1980).
In brief, obtain Raman spectrum with FT-Raman 960 (or 860) spectrogrph (Thermo Nicolet) that is connected in 860 FT-IR.This spectrogrph adopts the excitation wavelength of 1064nm.The Nd:YVO of about 0.912W 4Laser power is used for excited sample.With InGaAsP (InGaAs) detectors measure Raman spectrum.Sample is pressed into bead to be used for analyzing.The scanning of 128 samples uses the Happ-Genzel apodization at about (±) 4cm altogether -1Spectral resolution under from 3600 or 3700 to 98cm -1Gather.Carry out wavelength calibration with sulfur and cyclohexane extraction.Hereinafter for polymorph form A, B and the C of the hydrochlorate of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, with wave number (cm -1) the Raman spectrum peak position that provides of form has (±) 4cm approximately -1Error.
Raman spectrum peak position for the polymorph form A of the hydrochlorate of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane provides in table 4.
Table 4
Raman peaks tabulation (peak＞400cm of polymorph form A -1)
The peak position is with wave number (cm -1) form
Form A
436 1135
479 1189
534 1229
549 1274
646 1309
691 1338
680 1366
762 1393
812 1453
836 1484
892 1557
921 1597
959 2890
982 2969
998 2982
1030 3017
1056 3046
1099 3064
1122
List in the table 5 of Raman spectral peaks position to(for) the polymorph form B of the hydrochlorate of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane.
Table 5
Raman peaks tabulation (peak＞400cm of polymorph form B -1)
The peak position is with wave number (cm -1) form
Form A
418 1245
446 1278
478 1309
533 1343
648 1380
676 1398
686 1456
767 1483
825 1557
852 1593
895 2895
964 2963
979 2993
1031 3027
1054 3066
1070
1099
1136
1189
Raman spectrum peak position for the polymorph form A of the hydrochlorate of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane provides in table 6.
Table 6
Raman peaks tabulation (peak＞the 400cm of polymorph form A -1)
The peak position is with wave number (cm -1) form
Form A
441 1246
474 1266
532 1279
648 1309
674 1343
690 1398
767 1456
811 1471
826 1557
856 1595
895 2900
970 2966
1031 2992
1059 3048
1094 3070
1122
1137
1189
1228
Table 4, table 5 and table 6 provide the complete pattern about the Raman peaks position of polymorph form A, B and C respectively.Yet, in these patterns, some crucial peaks being arranged, they all are unique in the hydrochlorate of these polymorphs each.The crucial peak of any of these, no matter independent or in office why not with combination in, be enough to a kind of polymorph form is different from two kinds of polymorph forms in addition.For the hydrochlorate of polymorph form A, these are with wave number (cm -1) peak position expressed is changed to:
For polymorph form A, with wave number (cm -1) peak position of expressing
762；
636；
921；
959；
1393；
1597；
2890；
2982；
With
3064。
The crucial peak of any of these, no matter independent or in office why not with combination in, be enough to polymorph form A is different from two kinds of polymorph forms in addition.
For the hydrochlorate of polymorph form B, with wave number (cm -1) characteristic peak positions expressed is:
For polymorph form B, with wave number (cm -1) peak position of expressing
1245；
1380；
2963；
2993；
3027；
With
3066。
The crucial peak of any of these, no matter independent or in office why not with combination in, be enough to polymorph form B is different from two kinds of polymorph forms in addition.
For the hydrochlorate of polymorph form A, with wave number (cm -1) characteristic peak positions expressed is:
For the polymorph form A, with wave number (cm -1) peak position of expressing
1059；
1094；
1266；
1343；
1595；
2900；
2966；
With
3070。
The crucial peak of any of these, no matter independent or in office why not with combination in, be enough to the polymorph form A is different from two kinds of polymorph forms in addition.
According to the present invention, each crystalline polymorph form of the acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane can not have basically its other enantiomer, how much obtain with polymorphous isomeric forms.Term " do not have basically " its other enantiomer, how much to refer to that described crystalline material is at least about 95 weight % pure with polymorphous isomeric forms because it comprises its other enantiomer of being no more than about 5 weight %, how much and polymorphous isomeric forms.
In the past, the preparation of the acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane causes the mixture of A and B polymorph form.This mixture comprises every kind of polymorph of about 50 weight % mixture that can not separate easily.In addition, have been found that be positioned over ambient temperature following time that polymorph form A and B have some enantiotropys, or when heating, this 50% mixture change forms the mixture of polymorph form A, B and C.Yet these mixture can not easily separate.Therefore, can not obtain not have basically pure isomeric forms its other enantiomer, how much and these independent polymorph forms polymorphous isomeric forms.
According to the present invention, have been found that (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, particularly as polymorph form A, B and the C of salt acid-addition salts, can prepare every kind and do not have its other enantiomer, how much and polymorphous isomeric forms basically by carrying out recrystallization according to the mixture of the A of the step preparation of prior art and B polymorph form.The concentration that depends on concrete solvent, condition and the material of the mixture that is used for recrystallization polymorph form A, B and C, optionally prepare (+)-1-(3 that wishes, the 4-Dichlorobenzene base)-and the polymorph form of 3-azabicyclo [3.1.0] hexane, it does not have its other enantiomer, how much and polymorphous isomer basically.
In the preparation of polymorph form A that does not have other polymorph form basically and B, adopt crystallization from the mixture of A and B usually.Yet about preparing every kind of these polymorph forms that do not have other polymorph form basically, its crystallization technique is different.At conduct (+)-1-(3, the 4-Dichlorobenzene base)-preparation of the polymorph form A of the semihydrate of the acid-addition salts of 3-azabicyclo [3.1.0] hexane in, the most handy solvent medium will comprise the solid of polymorph form A, and for example the mixture of polymorph form A and B is dissolved in the aqueous organic solvent of bag.Preferred available organic solvent comprises low-grade alkane alcohol in this step, for example methanol, butanols, ethanol or isopropyl alcohol, and other solvent, for example acetone, dichloromethane and oxolane.In the formation of the polymorph form A of the purification that does not have other polymorph form basically, when preparation is used for crystalline medium, preferably water is incorporated in these solvents.In case solid, the mixture of preferred polymorph form A and B is dissolved in this solvent, should make the evaporation for a long time at room temperature of described solvent, simultaneously described solution is exposed in the atmosphere.Room temperature can comprise from about 15 ℃ to 35 ℃ any temperature.Described evaporation can be carried out being removed until all solvent mediums always, stays the crystal of the purification of polymorph form A.Can preferably carry out evaporation process naturally, for example by slowly evaporation.The amount and the concentration thereof that depend on solution, evaporation can 3 to 15 days or the longer time under carry out, evaporate fully until described solvent, stay the drying solid crystalline residue that does not have the polymorph of other polymorph form form A basically.
Polymorph form B is the anhydrous form of the acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane.(+)-1-(3, the 4-Dichlorobenzene base)-the polymorph form B of the acid-addition salts of 3-azabicyclo [3.1.0] hexane can be from comprising the solid of polymorph form A, the mixture of polymorph form A and B for example, preferred by dissolving as the polymorph form A of hydrochlorate or the mixture of polymorph form A and B, utilize anhydrous condition and prepare.According to the preferred embodiment of the invention, this solid is a crystal form, and by using the anhydrous organic solvent recrystallization.All organic solvents of above mentioning can use with the preparation polymorph b by its anhydrous form.As mentioned above, it is important carrying out described recrystallization under anhydrous condition.In addition, preferably at elevated temperatures, promptly about 50 ℃ to 80 ℃, under anhydrous condition, remove the crystal form that desolvates with the preparation polymorph b.After the crystallization, can by filtration or incline to remove and desolvate from solvent mixture at polymorph form B, staying have the polymorph of other polymorph form form B basically.In the preparation that removes the crystallization medium before desolvating, if desired, can be at elevated temperatures, promptly be used for the formation of crystallization medium of the mixture that comprises form A and B of recrystallization under 50 ℃ to 80 ℃.
The polymorph form A can be from polymorph form A or polymorph form B or the preparation of its mixture.By loosely heating polymorph form A or polymorph form B or its mixture, be at least 50 ℃ in temperature, preferred 60 ℃ to 80 ℃ prepare the polymorph form A down.Heating can continue until does not have the polymorph of other polymorph form form A to form basically.If desired, heating can be for a long time, carries out under promptly 12 hours to 4 days or longer time, and being converted into up to the polymorph form of raw material does not have the polymorph of other polymorph form form A basically.Basically do not have the preparation of acid-addition salts of the polymorph form A of other polymorph form, not in the presence of solvent, undertaken usually by the acid-addition salts that loosely heats polymorph form A and B with crystalline texture.Preferred acid-addition salts in this preparation is a salt acid-addition salts form.
Above-mentioned technology also allows to prepare the mixture of independent polymorph form of acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane of the every kind of polymorph that comprises specified quantitative.Particularly, polymorph form A and polymorph form B or polymorph form A, the mixture of polymorph form B and polymorph form A and polymorph form A, polymorph form B and polymorph form A, the polymorph separately of available desired amount easily prepares.Such as but not limited to, comprising the polymorph form A of every kind of polymorph of desired amount and the mixture of polymorph form B can not experience the process of aforesaid preparation polymorph form B by will there being polymorph form A other polymorph form and preparation as mentioned above basically, and the lasting time is for producing the needed time of polymorph form B of desired amount.Another example, comprising the polymorph form A of every kind of polymorph of desired amount and the mixture of polymorph form A can not experience the process of aforesaid preparation polymorph form A by will there being polymorph form A other polymorph form and preparation as mentioned above basically, and the lasting time is for producing the needed time of polymorph form A of desired amount.Another example, comprising the polymorph form B of every kind of polymorph of desired amount and the mixture of polymorph form A can not experience the process of aforesaid preparation polymorph form A by will there being polymorph form B other polymorph form and preparation as mentioned above basically, and the lasting time is for producing the needed time of polymorph form A of desired amount.Another example, the polymorph form A and polymorph form B or the polymorph form A that comprise every kind of polymorph of desired amount, polymorph form B and polymorph form A, can not prepare by will there being desirable polymorph combination other polymorph form and preparation as mentioned above basically with the mixture of polymorph form A, polymorph form B and polymorph form A, with the mixture that obtains to wish.
Utilize aforesaid technology, can obtain to comprise the mixture of independent polymorph form of acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane of particular percentile.For example, can prepare that to comprise about 10% are mixture of polymorph form B and polymorph form A one or both of to about 10-20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95% with until the polymorph form A of 95-99% or higher (weight) and all the other.As another example, can prepare and comprise about 10% is mixture of polymorph form A and polymorph form A one or both of to about 10-20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95% with until the polymorph form B of 95-99% or higher (weight) and all the other.As another example, can prepare and comprise about 10% is mixture of polymorph form A and polymorph form B one or both of to about 10-20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95% with until the polymorph form A of 95-99% or higher (weight) and all the other.
In addition, many pharmaceutical active organic compound are usually with second exogenous molecules, and especially the solvent molecule crystallization is incorporated in the crystal structure of main pharmaceutically active compound to form pseudopolymorph.When described second molecule was solvent molecule, described pseudopolymorph also can be called as solvate.The other form of all these (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane falls within the scope of the present invention equally.
Polymorph form A of the present invention, B and C can be prepared into the acid-addition salts by the basic nitrogen group formation of acid and (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane.Suitable acid-addition salts is formed by the acid that forms nontoxic salts, and the example of described acid-addition salts is hydrochlorate, hydrobromate, hydriodate, sulfate, disulfate, nitrate, phosphate and hydrophosphate.The example of pharmacy acceptable addition salt comprises mineral acid and organic acid addition salt.The acceptable salt of pharmacy includes but not limited to, slaine, for example sodium salt, potassium salt, cesium salt etc.; Alkali salt, for example calcium salt, magnesium salt etc.; The salt of organic amine, for example salt of the salt of the salt of triethylamine, pyridiniujm, picoline salt, ethanolamine, triethanolamine, the salt of dicyclohexylamine, N, the salt of N '-dibenzyl-ethylenediamin etc.; Acylate, for example acetate, citrate, lactate, succinate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalates, formates etc.; Sulfonate, for example mesylate, benzene sulfonate, tosilate etc.; And amino acid salts, for example arginine salt (arginate), aspartate (asparginate), glutamate, Glu, tartrate, gluconate etc.The available salt of typical case is to form hydrochlorate with hydrochloric acid.
Above-mentioned (+)-1-(3, the 4-Dichlorobenzene base)-mode that the independent polymorph form of the acid-addition salts of 3-azabicyclo [3.1.0] hexane and the mixture of polymorph form can be identical with (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane of former form known is to the human patients administration.Be used for above-mentioned (+)-1-(3, the 4-Dichlorobenzene base)-the suitable route of administration of the independent polymorph form of the acid-addition salts of 3-azabicyclo [3.1.0] hexane and the mixture of polymorph form comprises, but be not limited to, oral, buccal, nasal cavity, pulmonary, aerosol, part, percutaneous, through mucous membrane, injection, slow release and controlled-release delivery are although multiple other known route of delivery, apparatus and method can adopt equally.Available non-intestinal delivering method includes, but not limited in the intravenous, intramuscular, intraperitoneal, spinal column, in the sheath, Intraventricular, intra-arterial and subcutaneous injection.
Above-mentioned (+)-1-(3, the 4-Dichlorobenzene base)-suitable effective unit dosage that the independent polymorph form of the acid-addition salts of 3-azabicyclo [3.1.0] hexane and the mixture of polymorph form are used for mammalian object can be about 1 to 1200mg, 50 to 1000mg, 75 to 900mg, and 100 to 800mg or 150 to 600mg.In some embodiments, described effective unit dosage will be in close limit, and for example about 10 to 25mg, and 30 to 50mg, and 75 to 100mg, and 100 to 150mg, selects in 150 to 250mg or 250 to 500mg.These and other effective unit dosage can single dose or every day, weekly or the form administration of every month multiple dose, for example in dosage regimen, comprise every day, weekly or every month about 1 to 5, or 2 to 3 dosed administrations.In typical embodiment, about 10 to 25mg, and 30 to 50mg, and 75 to 100mg, 100 to 200mg (dose intensities of expectation) or 250 to 500mg dosage with once a day, twice, three times or four administrations.In more detailed embodiment, about 50 to 75mg, and 100 to 150mg, and 150 to 200mg, 250 to 400mg or 400 to 600mg dosage with once a day, twice or three administrations.In alternate embodiment, dosage calculates based on body weight, and can be for example to make an appointment with extremely about 30mg/kg, extremely about 15mg/kg, extremely about 10mg/kg, extremely about 20mg/kg, extremely about 10mg/kg or the extremely amount administration of about 15mg/kg of 3mg/kg every day of 2mg/kg every day of 2mg/kg every day of 1mg/kg every day of 1mg/kg every day of 0.5mg/kg every day.
Utilization is described in route of administration and method and dosage above and is described in hereinafter dosage form, and the mixture of independent polymorph form of the present invention and polymorph form can be used for preventing and treats multiple disease and situation in the people.Such as but not limited to, under the situation of depression, this the polymorph form by comprising from a kind of above-mentioned mixture that does not have other polymorph form or polymorph basically to the depressed patient's administration of suffering from of the described treatment of needs and the compositions of inert carrier or diluent are finished, and described compositions is with prevention or the administration of the depressed effectively amount of treatment.According to the present invention, with (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, perhaps there not to be the polymorph form of other polymorph form basically, perhaps, effectively measure administration with prevention or treatment depression with the mixture of polymorph form.Depressed required this of any effective dose of prevention or treatment do not have the polymorph form of other polymorph form or the mixture of polymorph form to can be used in this compositions basically.Usually, under the situation of peroral dosage form, adopt about 0.5mg/kg every day dosage of about 5.0mg/kg body weight extremely.Yet, this do not have the polymorph form of other polymorph form or the amount of mixture in treating the oral dosage of administration of polymorph form will depend on strongly fragrant symptom and patient's body weight to a great extent basically, and depend on doctor's judgement certainly.According to the present invention, the oral unit dosage form that comprises the mixture of given polymorph form that does not have other polymorph form basically or polymorph form can preferably be about 30mg to 300mg every day with dosage, more preferably every day, about 50mg was to about 200mg administration, was administered once every day or twice or with required.
The present invention includes the pharmaceutical dosage form of the mixture of the independent polymorph form of acid-addition salts of above-mentioned (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane and polymorph form.These medicine agent shapes can comprise one or more excipient or additive, include but not limited to binding agent, filler, lubricant, emulsifying agent, suspending agent, sweeting agent, flavoring agent, antiseptic, buffer agent, wetting agent, disintegrating agent, effervescent and other conventional excipients and additive.Therefore compositions of the present invention can comprise any of following reagent well known by persons skilled in the art and combination: pharmaceutically acceptable carrier or excipient; Other one or more medicinal reagents; One or more pharmaceutical agents; Adjuvant; Buffer agent; Antiseptic; Diluent; And multiple other medicines additive and reagent.Formulation additives that these are other and reagent will often be biologically inert and can not cause deleterious side effect to patient's administration and interact with active agent.
As noted earlier, polymorph form A is the thermodynamically stable polymorph of the acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane.Therefore, preferably polymorph form A is used for pharmaceutical dosage form, and does not have the existence of other how much of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, optics and polymorphic isomer.Yet polymorph b and C also can be contained in the formulation of pharmaceutical products, have less positive result about preparation and stable its.
If desired, the independent polymorph form of the present invention and the mixture of polymorph form can pass through to use slow-released carrier, and for example hydrophilic release polymer is with the controlled release forms administration.Typical in this article controlled release reagent includes, but are not limited to, hydroxypropyl emthylcellulose, and it is extremely about 100 for about 100cps that it has viscosity, 000cps.
The mixture of independent polymorph form of the present invention and polymorph form can choose wantonly with carrier or other one or more additive combinations with peroral dosage form preparation and administration.The appropriate carriers that is common in drug preparation technique comprises, but be not limited to microcrystalline Cellulose, lactose, sucrose, fructose, glucose, dextrose, other saccharide, calcium hydrogen phosphate, calcium sulfate, cellulose, methylcellulose, cellulose derivative, Kaolin, mannitol, lactose, maltose alcohol, xylitol, Sorbitol, other sugar alcohol, dried starch, dextrin, maltodextrin, other polysaccharide or its mixture.
Be used for typical oral unit dosage form of the present invention and comprise tablet, capsule, powder, solution, syrup, suspending agent and lozenge, it can be by the conventional method preparation of any preparation drug oral unit dosage forms.Oral unit dosage form, for example tablet can comprise acceptable other preparation composition of one or more conventional pharmacy, include but not limited to release-modifier, fluidizer, pressing aid agent, disintegrating agent, effervescent, lubricant, binding agent, diluent, flavoring agent, flavour enhancer, sweeting agent and antiseptic.These compositions are selected from known excipient in a variety of field of pharmaceutical preparations.The character that depends on desirable oral unit dosage form, any amount of composition can select to be used for them alone or in combination in the known application as the preparation of these dosage forms of tablet.
Proper assistant comprises stearic acid, magnesium stearate, Talcum, calcium stearate, hydrogenated vegetable oil, sodium benzoate, leucine carbowax, Stepanol MG, colloidal silica and glycerol monostearate.Suitable fluidizer comprises colloidal silica, pyrogenic silica, Silicon stone, Talcum, fumed silica, Gypsum Fibrosum and glycerol monostearate.The material that can be used for wrapping quilt comprises hydroxypropyl cellulose, titanium dioxide, Talcum, sweeting agent and coloring agent.Above-mentioned effervescent and disintegrating agent are used to form rapid disintegration tablet well known by persons skilled in the art.These tablets typically in mouth in less than 1 minute time and disintegrate in being everlasting less than the time in 30 seconds.Refer to that by effervescent organic acid is typically in conjunction with carbonate or bicarbonate.
Following embodiment illustrates embodiments more of the present invention, and should not be interpreted as limiting content of the present invention.
The specific embodiment
Embodiment 1
The purpose of present embodiment is by (+)-1-(3, the 4-Dichlorobenzene base)-free alkali of 3-azabicyclo [3.1.0] hexane preparation (+)-1-(3, the 4-Dichlorobenzene base)-hydrochlorate of 3-azabicyclo [3.1.0] hexane and the method that demonstration prepares the mixture of polymorph form A and polymorph form B.
With the free alkali of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane of about 250mg in 95: 5 (v/v) hexane/isopropyl alcohol (containing 0.05% diethylamine) that be dissolved in 400mL.This solution being set on about 70 ℃ heating stirrer, is evaporated under nitrogen current, sample concentration is become the classifying gel body.Be dissolved in this gelinite in the 50mL ethyl acetate and dry under nitrogen current, form rare, clarify to milky (yellow tone), emulsus residue.This residue is dissolved in the 7mL ether, and adds the saturated ether of 7mL HCl; The white solid piece precipitates immediately.Reclaim this solid and use the washing of 19mL ether by vacuum filtration.Filtering solid look like dried.Reclaim the hydrochlorate (162.5mg) of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, yield is 55.7%.
The two all comprises the mixture of polymorph form A and polymorph form B XRPD analysis of carrying out as mentioned above and Raman spectrum explanation raw material (free alkali) and finished product (hydrochlorate).The two all comprises every kind of polymorph of about 50% (weight) to observe raw material and finished product.In raw material and finished product only have aspect the percentage ratio of these polymorphs very little different.
Embodiment 2
Stability study to the finished product of embodiment 1
(+)-1-(3 to the mixture of polymorph form A polymorph form B preparation and that comprise 50% (weight) in embodiment 1, the 4-Dichlorobenzene base)-and the unofficial stability of the bipartite sample evaluation of the hydrochlorate of 3-azabicyclo [3.1.0] hexane, be positioned over ambient temperature and the storage in the exsiccator under 50 ℃ in program control heat block (heating bloc) with test.In a week back test sample, although and two samples all comprise the mixture of polymorph form A and polymorph form B, some conversions of observed ratio display format.Is mixture at ambient temperature observed the polymorph form B of the polymorph form A and 60% (weight) that comprises 40% (weight) (as analyzing determined by XRPD?).This result is confirmed by Raman spectrum.The XRPD to being stored in the sample under 50 ℃ in the program control heat block (heating block) subsequently analyzes and is presented at the polymorph form A that stores the polymorph form A and 50% (weight) of about 50% (weight) after 17 days.
Embodiment 3
The production method of the hydrochlorate of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane
Step 1: alpha-brominated-3,4-dichlorophenylacetic acid methyl ester synthetic
With 100kg 3,4-Dichlorobenzene base acetonitrile was added in 1.25 hours in 12kg water and the 140kg 98% vitriolic mixture in batches.Exotherm figure allows to be up to 65 ℃, and reactant mixture kept 30 minutes at 60-65 ℃.After being cooled to 50 ℃, in 25-30 minute, slowly add 80kg methanol.This mixture is warmed to 92-98 ℃, under this temperature, kept other 3 hours.After being cooled to 35 ℃, with the reactant mixture cancellation in the mixture (being precooled to 0-5 ℃) of 150L ethylidene bichloride that stirs and 250L water.Reactor and pipeline wash with water in the cancellation mixture, it was stirred 5 minutes and make its layering.Organic facies below separating, water washs with 2 * 150L ethylidene bichloride.The organic facies that merges is used 100L water and is used aqueous sodium carbonate (the 3kg sodium carbonate is in 100L water) washing afterwards.The solution of thick ester causes collecting the 100L ethylidene bichloride at 60-62 ℃ of following vacuum azeotropic " drying ".Do not separate product and suppose theoretical yield, and this solution " tale quale " in following bromination reaction is used.
With rough 3, the solution (on-line filtration) and the 88kg 1 of 4-dichlorophenylacetic acid methyl ester (by last gained), 3-two bromo-1, the mixture of 3-dimethyl hydantoin (DBDMH) is warmed to 80 ℃, the solution that added the 15L ethylidene bichloride of 2.5kg VAZO 52 in 5 hour time with batch mode keeps 85-90 ℃ (under refluxing).Add other 8.8kgDBDMH then, in 2.5 hour time, added the solution of the 4L ethylidene bichloride of 0.5kg VAZO 52, keep 85-90 ℃ (under refluxing) with batch mode.Stop heating, stir adding 350L water down.Make demixing, the organic facies below separating is also used 50L ethyoxyl dichloro washing water.The organic facies that merges is washed with thiosulfuric acid saline solution (5.0kg sodium thiosulfate is in 150L water), aqueous sodium carbonate (the 2.5kg sodium carbonate is in 150L water) and dilute hydrochloric acid (5.4L 32%HCl is in 100L water).With the organic facies on-line filtration and be distilled to " doing " (vacuum to 83 ℃) in a vacuum.Residual ethylidene bichloride is driven (vacuum to 83 ℃) out of with 20kg toluene.With rough alpha-brominated-3,4-dichlorophenylacetic acid methyl ester is dissolved in the 82kg toluene, is cooled to 40 ℃, and dumps in the stainless steel cask.Not with this product separation, and " tale quale " used in step 2.Suppose that theoretical yield is used to calculate purpose.
Step 2:1-(3, the 4-Dichlorobenzene base)-1,2-cyclopropane-dimethyl dicarboxylate's is synthetic
Will from step 1 obtain rough alpha-brominated-3,4-dichlorophenylacetic acid methyl ester fully mixes with the 55.6kg acrylic acid methyl ester., then with this mixture in 5.5 hours under good the stirring and remain on＜be added to (2 ℃) 54.4kg Feldalat KM of pre-cooling in the mixture of 500L toluene (argon covering) under+10 ℃.After with brine-cooled (5 ℃) standing over night (5psig argon), the reactant mixture cancellation that this is cold is in the mixture of 250L water under good stirring the and 30kg32% hydrochloric acid.In other 30 minutes, 200L water and 2.5kg potassium carbonate joined in the mixture under good the stirring.After the layering, lower layer of water is separated, and 150L water and 1.0kg potassium carbonate are added in the organic facies.Mixture was stirred 5 minutes and layering.Separate lower floor's water and also discard, and the water washing that the emulsion between the interface and organic facies is comprised 1L 32% hydrochloric acid with 100L.Layering with separate below water after, be distilled to " doing " (65 ℃ of following vacuum) with the organic facies on-line filtration and under vacuum.In this hot residue, stir and add 70kg methanol down.With this mixture cooling (producing crystal seeds) at+10 ℃ to-5 ℃ and under this temperature, keep spending the night.The condensed suspension sucking filtration (Nutsche) that this is cold, and with 1-(3, the 4-Dichlorobenzene base)-1,2-cyclopropane-dimethyl dicarboxylate's filter cake is drained, with 2 * 20L hexane wash, drained 30 minutes and (be placed on the frame) under environmental condition air drying on the paper 2 days.
In described methanol solution, in 8 hours, under good the stirring, add the 50kg Caustic Soda Flakes in batches.In degasification with after slowly heat release (the highest 60 ℃) stops, this condensed suspension was kept 1 hour down at 50 ℃.In 10 minutes, slowly add the 100L isopropyl alcohol, mixture is slowly stirred under environmental condition spend the night then.Again make slurry with 80L methanol with this solid sucking filtration (Nutsche) and with it.With the 1-(3, the 4-Dichlorobenzene base)-1 that obtains, 2-cyclopropane-dicarboxylic acids disodium salt sucking filtration (Nutsche) with methanol (40L) washing, was drained 1 hour and (is being placed on the frame) air drying on the paper.
Step 3:1-(3, the 4-Dichlorobenzene base)-1,2-cyclopropane-dicarboxylic acids synthetic
With 42.0kg 1-(3, the 4-Dichlorobenzene base)-1, the suspension of 2-cyclopropane-dicarboxylic acids disodium salt (deriving from step 2) and 120L deionized water is warmed to 30-35 ℃, and neutralizes to precipitate described free dicarboxylic acids with this solution on-line filtration and with 30kg 32% hydrochloric acid.Add the 120kg ethyl acetate, and chemical compound is warmed to 40-50 ℃ to form solution.Separate lower floor's water and use the washing of 20kg ethyl acetate.The organic extract that merges is with saturated sodium-chloride (3kg is in 30L water) washing, is distilled to " doing " (vacuum to 70 ℃) then under vacuum.In this warm residue, add the 60kg ethylidene bichloride, and with this solution under slowly stirring-5 ℃ of cool overnight.The residual ethyl acetate of distillation (vacuum to 43 ℃) is to forming condensed suspension, then with its under vacuum at 2.5 hours internal cooling to-5 ℃, sucking filtration (Nutsche) then.With cold ethylidene bichloride (2 * 5L) and use ethylidene bichloride (4 * 5L) washing 1-(3, the 4-Dichlorobenzene base)-1, the 2-cyclopropane-dicarboxylic acids filter cake of ambient temperature subsequently.Diacid product was drained 15 minutes and (be placed on the frame) air drying on the paper.
With 31.0kg 1-(3, the 4-Dichlorobenzene base)-1,2-cyclopropane-dimethyl dicarboxylate (deriving from step 2), 40L water, the mixture of 35kg methanol and 18.0kg50% caustic soda are warmed to 70-75 ℃ (backflow) and kept 1.5 hours down at 70-75 ℃.Add 10L water then, and this mixture was kept other 2 hours down at 75-77 ℃.Remove methanol in vacuum down to 70 ℃ of slow steamings and provide condensed suspension, then this suspension is mixed with 80L water to form solution.Should also use the extracting of 100kg ethyl acetate with 31kg 32% salt Acid precipitation by free diacid.Separate the water of lower floor and use the washing of 20kg ethyl acetate.The organic facies that merges is used 50L water and is washed with saturated sodium-chloride water solution then.With vacuum 80 ℃ of following distilling under reduced pressure to producing spissated 1-(3, the 4-Dichlorobenzene base)-1,2-cyclopropane-dicarboxylic acids, it is cyclized in the step of imines " tale quale " at next step and uses.For the amount of computation purpose supposition from the diester generation.
Step 4:1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane-2, the synthetic and recrystallization of 4-diketone
With 1-(3, the 4-Dichlorobenzene base)-1, (serosity that derives from step 3) joins in warm (68 ℃) Methanamide of 45.6kg 2-cyclopropane-dicarboxylic acids, and residual ethyl acetate is distilled down at 68-73 ℃ with vacuum.In this mixture, add the 14.4kg Methanamide in addition, add the described diacid of 11.2kg subsequently and (derive from described disodium salt, step 3).Keep argon to cover this mixture to carry out following operation.This mixture is stirred down 15 minutes to be completed into solution at 73-75 ℃, then at 1 hour internal heating to 140-145 ℃ and under this temperature, kept other 2.25 hours.Stop heating, this mixture is cooled to 70 ℃ and slowly added the water that 10L comprises 20ml32%HCl in 30 minutes.Mixture produces crystal seed and begins crystallization.In this condensed suspension, in 2 hours, slowly add other 20L water.After placement is spent the night under the environmental condition, this mixture was stirred 1.25 hours at ambient temperature, then sucking filtration (Nutsche).Rough 1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane-2, the filter cake water of 4-diketone (drained 30 minutes, and (be placed on the frame) air drying on the paper 2 days under environmental condition by 3 * 20L) washings.
The 1-of the humidity that 37kg is rough (3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane-2, the mixture of 4-diketone (deriving from above-mentioned steps 4) and 120L toluene are warmed to 75-80 ℃ to form solution.Behind the water of layering and separating residual (3.3kg), add 1kg Darco G-60 active carbon (American Norit Co.) (being suspended in the 5L toluene).This mixture was stirred 30 minutes down at 80 ℃, and Sparkler (use the filter aid precoating) pressure filtration by preheating then is with the pot strainer purification (polishing) of 10 μ m.Should under vacuum, under 75-80 ℃, be concentrated into 100L final volume and slowly cooling by clarifying pale yellow solution, wherein produce crystal seed at 70 ℃.Should condensed crystallization suspension be cooled to-5 ℃, under this temperature, keep 30 minutes and sucking filtration (Nutsche).This pure 1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane-2, the filter cake of 4-diketone is with cold (10 ℃) toluene of 2 * 10L and use 2 * 20L hexane wash then.After draining 30 minutes, dry (≤62 ℃) are described 2 under the vacuum, 4-diketone product.
Step 5:(±)-the synthetic and purification of 1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane hydrochloride salt
The BH3-THF complex is joined the 2L charging hopper, and (9 * 2L is then in 1 * 1.5L) and be discharged in the 50L flask.
With 1000g (±)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane-2, the 4-diketone is dissolved among the 2L THF and in 2 hours and is added drop-wise among the BH3-THF.Reactant mixture is heated to refluxes and under this temperature, keep spending the night.Then mixture is cooled to＜10 ℃, at＜20 ℃ of following dropping 1200ml 6N HCl mixture being transferred to pH is 2, and stirs at least 1 hour.
Then this reactant mixture is transferred in the 10L Buchi flask, is concentrated into the milky white paste, and transfer to once more in the 5-gallon container.This mixture transfers to 10 with the dilution of 4L cold water and with 2000mL 25% sodium hydroxide solution with pH.Keep temperature＜20 ℃.Subsequently, add 4.5L ethyl acetate and mixture stirred 15 minutes.Then this solution is filtered by 10 inches funnels that have filter cloth and with ethyl acetate washing (2 * 250mL).
Then filtrate is transferred in the 40L separatory funnel and phase-splitting.Then each is discharged into mutually in 5 gallon container separately.Water layer is turned back in the 40L separatory funnel also with ethyl acetate (2 * 2L) extractings.Merge organic facies.Water layer discarded.
In the organic facies that merges, add 250g magnesium sulfate and 250g charcoal, and this mixture is fully stirred.Then this solution is washed (2 * 250mL) by the 18.5cm funnel with the filter plate filtration and with ethyl acetate.Filtrate is transferred in the 10L Buchi flask then, and is concentrated into dried.The light yellow oil that forms is diluted with ethyl acetate (2.25mL/g).
With the HCl bubbling by the 12L flask of 10L ethyl acetate is housed, to prepare the HCl/ ethyl acetate solution of about 2.3M.This HCl/ ethyl acetate solution is added dropwise in the described grease, drips the speed filter for can keep temperature＜20 ℃ with ice-water bath.Then with solution in ice-water bath＜10 ℃ stirred at least 2 hours down.With this material frozen overnight in the cold house.
Utilize filter cloth to filter by 10 inches funnels formed solid then, and with ethyl acetate (2 * 200mL) and ether (3 * 500mL) wash.Then with this product, rough (±)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane hydrochloride salt is transferred in the Pyrex basin and dry 4 hours.
Above-mentioned rough (±)-1-of 1900g (3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane hydrochloride salt and 15.2L isopropyl alcohol are packed in the 22L flask, heat this mixture with the dissolving all substances.
Utilize filter plate to filter by the 18.5cm funnel this material then and transfer in the 22L flask.Then this solution was at room temperature stirred 1 hour.Then solution is refrigerated to 4 ℃ and stirred 3.75 hours with ice/water-bath.Then product is placed in the cold house and spends the night.
Utilize filter cloth to filter by 13 inches filters solid then, and (3 * 633mL) wash with ethyl acetate.Then with product air drying 2 hours.
With this product, pure (±)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane hydrochloride salt is transferred in the clean Pyrex basin and is dried to constant weight.
Step 6:(±)-1-(S3,4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane hydrochloride salt splits into (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane hydrochloride salt
In 50 gal reactor of 60L 15%NaOH are housed, add pure (±)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] the hexane hydrochloride salt (deriving from above-mentioned steps 5) of 13.6kg, keep temperature constant at about 20 ℃ simultaneously.In case finish (±)-1-the adding of (3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane hydrochloride salt, reactant mixture at room temperature stirred 8 hours at least.
In described reactor, add the 40L ethyl acetate, and stir this two-phase mixture until obtaining settled solution (about 2 hours).Phase-splitting also is transferred to organic layer in the 50 other gal reactor.Ethyl acetate (6 * 6L) extractings of remaining water.All organic faciess are integrated with in described 50 gal reactor.Make the dry and decolouring of organic facies by adding 4000g magnesium sulfate and 250g charcoal.Then this mixture is filtered by pot strainer.Filtrate is transferred in 50 gal reactor through pot strainer.
In dividing other 50 gal reactor, with 23,230g L-(-)-dibenzoyl tartaric acid under agitation is dissolved in (about 30 minutes) 71L methanol.Help dissolving with heating if desired.
The methanol solution of L-(-)-dibenzoyl tartaric acid is added in the reactor that described filtrate is housed in about 1 hour time by charging hopper, maintains the temperature at 15-25 ℃.Behind reinforced the finishing, with this mixture 15-25 ℃ of following stir about 16 hours.After the stirring, in this mixture, add 50L methanol and also stirred once more other 30 minutes.With formed solid filtering to plate filter.(3 * 5L) wash and press dry this solid with methanol then.Rough solid is weighed and transfer in 50 gal reactor, in this reactor, added 80L methanol.With this mixture heated to refluxing and stir about 30 minutes under refluxing.Then this mixture is cooled to 15-20 ℃ and under this temperature stir about 2 hours.The solid that forms is filled on the plate filter with the polypropylene filter cloth.(3 * 5L) wash and press dry filter cake with methanol.With this solid transfer to tarred 5 gallon container and weigh (obtain～20kg).
Then this solid is added (about 1 hour time is interior) and in the reaction vessel that 60L 15%NaOH is housed, maintain the temperature at about 20 ℃ simultaneously.In case finish described solid adding, with reactant mixture stir about 19 hours.
The 40L ethyl acetate is joined in the described reactor, maintain the temperature at simultaneously≤35 ℃, and stir two-phase mixture until obtaining settled solution (about 2 hours).Phase-splitting also is transferred to organic layer in another 50 gal reactor.Ethyl acetate (6 * 6L) extractings of remaining water.All organic faciess are integrated with in described 50 gal reactor.In organic facies, add 5000g magnesium sulfate then.Then this mixture is filtered by pot strainer.This filtrate is transferred in 50 gal reactor through pot strainer.It is 20-30L that this filtrate is concentrated into cumulative volume.
In the three neck round-bottomed flasks of 22L, the HCl gas bell is passed through the 12L ethyl acetate, to prepare the HCl/ ethyl acetate solution of about 2.3M.After the titrimetry, this solution is accurately transferred to 2.3M by adding ethyl acetate or hydrogen chloride gas.
The HCl/ ethyl acetate solution of the described 2.3M of 8.2L is added in (in about 1.5 hours time) the described filtrate (as above), maintains the temperature at≤20 ℃, and to guarantee to obtain pH be 2.In case finish adding, this mixture stirred 16 hours at 0 to-5 ℃.
With the solid that forms, rough (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane hydrochloride salt is filled on the plate filter with the polypropylene filter cloth.Then this solid with ethyl acetate (2 * 2L), acetone (2 * 2L) and ether (2 * 2L) washings are drying under vacuum also.With this substance transfer to tarred 5 gallons of polypropylene containers and weigh.
Step 6a: recrystallization (+)-1-from isopropyl alcohol (3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane hydrochloride salt
Be transferred to solid (deriving from above-mentioned steps 6) in 50 gal reactor and add isopropyl alcohol (8-10mL/g solid).This mixture is added to backflow.This solution is filled in another 50 gal reactor by pot strainer.This solution is cooled to 0 to-5 ℃, and under agitation kept this temperature about 2 hours.Formed solid is filled on the plate filter with the polypropylene filter cloth.Then this solid with ethyl acetate (2 * 2L), acetone (2 * 2L) and ether (2 * 2L) wash.This solid is dry under vacuum.
With this product, (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane hydrochloride salt is transferred in clean tarred one or more basins.Described one or more basins are positioned in the clean vacuum drying oven.This product is dried to constant weight under 50 ℃.With this material drying at least 12 hours under＜10mm Hg.This product is the mixture of polymorph form A and polymorph form B, and wherein the amount that is present in the described mixture of every kind of polymorph is about 50 weight %.This product is as the raw material of following embodiment 4 to 8.
Embodiment 4
The mixture (54mg) of the 50 weight % of the polymorph form A of the hydrochlorate of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane and polymorph form B is dissolved in 12ml acetonitrile and the water.Half is filled in the clean bottle by 0.2:m nylon syringe filter with the pact of stock solution then.There is the aluminium foil of pin hole to cover with thorn this bottle, and places ventilating kitchen slowly evaporation under environmental condition.After solvent in making bottle carries out about four days evaporation, obtain the crystal residue, it is the pure polymorph form A of the hydrochlorate formation of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, being proved as being analyzed by above-mentioned Raman spectrum and XRPD.
Other solvent is used in the preparation that uses the same method, and for example acetone, 2-butanols, dichloromethane, ethanol, methanol, Nitrocarbol., isopropyl alcohol and oxolane also obtain identical pure crystal formation.These solvents also comprise water.
Embodiment 5:
The mixture of the 50 weight % of the polymorph form A of the hydrochlorate of 68mg (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane and polymorph form B is dissolved in the 3.4ml ether: in ethanol (1: the 1 ratio) solvent mixture.Be filled in the clean bottle by 0.2:m nylon syringe filter obtaining solution.Collect solid sample by rotation evaporating solvent under vacuum.Then at ambient temperature, dry pure polymorph form B crystal under vacuum with the hydrochlorate that produces (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane with this solid.As being proved by above-mentioned Raman spectrum and XRPD analysis.
Embodiment 6
The mixture of the 50 weight % of the polymorph form A of the hydrochlorate of 51mg (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane and polymorph form B is weighed in the bottle.This bottle has the aluminium foil of pin hole to cover with thorn, and in 80 ℃ baking oven, placed 4 days, with the pure polymorph form A of the hydrochlorate that forms (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, being proved as analyzing by above-mentioned Raman spectrum and XRPD.
Embodiment 7
The preparation of polymorph form B
(+)-1-(3 with 50 weight %, the 4-Dichlorobenzene base)-mix to produce concentration with the 0.5mL anhydrous acetonitrile be about 80-100mg/mL to the 40mg sample of the polymorph form A of the hydrochlorate of 3-azabicyclo [3.1.0] hexane and the mixture of polymorph form B, and the sample that forms stirred the different time (some under about 50 ℃ are that 4 days and 6 days and under 80 ℃ some are 1 day) under 50 ℃ to 80 ℃ the different temperatures.The sample that obtains each supernatant liquid and some solid mixture naturally.Supernatant liquid is inclined to remove, with remaining solid at ambient temperature vacuum drying 1 hour to 2 days (50 ℃ samples) or 6 days (80 ℃ samples) so that pure polymorph form B to be provided.All samples produce the pure polymorph form B crystal of the hydrochlorate of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, proving as being analyzed by above-mentioned Raman spectrum and XRPD.
Embodiment 8
The preparation of polymorph form A
The 20mg sample of the mixture of the polymorph form A of the hydrochlorate of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane of 50 weight % and polymorph form B is dissolved in the 0.5mL aquiferous ethanol.Other sample prepares by this mixture of 20mg is dissolved in the 0.5mL water.Two kinds of solution all filter through 0.2 micrometer nylon filter.Then two kinds of filtrates are all evaporated under environmental condition, some samples are partly covered, and other samples do not cover fully.After 6 days, alcoholic solution sample unlapped and that part covers has all evaporated.After 7 days, unlapped aqueous solution evaporate.After 15 days, the aqueous solution evaporate that part covers.For each sample, after solvent (perhaps aquiferous ethanol or water) evaporates fully, stay 20mg drying solid residue.Therefore the solid in all samples that produces is the pure polymorph form A crystal of the hydrochlorate of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, proving as being analyzed by above-mentioned Raman spectrum and XRPD.

Claims (65)

1. the polymorph of the acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, its crystal form do not have its other geometric isomer, optical isomer and polycrystalline isomer basically.
2. the acid-addition salts of claim 1, wherein said salt is hydrochlorate.
3. the polymorph form A of the acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, its crystal form do not have its other geometric isomer, optical isomer and polycrystalline isomer basically.
4. the polymorph form A of claim 3, wherein said acid-addition salts is a hydrochlorate.
5. the polymorph form A of claim 4, the X-powder diffraction pattern of wherein said polymorph when being when measuring under about 10 to 40 microns in crystal size, is characterized in that one or more and at the about peak of following ° 2 θ (degree) value:
17.14；
19.62；
21.96；
24.52；
With
26.74。
6. the polymorph form A of claim 4, the X-powder diffraction pattern of wherein said polymorph when being when measuring under about 10 to 40 microns in crystal size, is characterized in that all and at the about peak of following ° 2 θ (degree) value:
17.14；
19.62；
21.96；
24.52；
With
26.74。
7. the polymorph form A of claim 4, the Raman spectrum of wherein said polymorph are characterised in that one or more and at about following wave number (cm -1) the peak:
762；
836；
921；
959；
1393；
1597；
2890；
2982；
With
3064。
8. the polymorph form A of claim 4, the Raman spectrum of wherein said polymorph are characterised in that all and at about following wave number (cm -1) the peak:
762；
836；
921；
959；
1393；
1597；
2890；
2982；
With
3064。
9. the polymorph form B of the acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, its crystal form do not have its other geometric isomer, optical isomer and polycrystalline isomer basically.
10. the polymorph form B of claim 9, wherein said acid-addition salts is a hydrochlorate.
11. the polymorph form B of claim 10, the X-powder diffraction pattern of wherein said polymorph when being when measuring under about 10 to 40 microns in crystal size, is characterized in that one or more and at the about peak of following ° 2 θ (degree) value:
15.58；
17.52；
21.35；
23.04；
25.43；
With
30.72。
12. the polymorph form B of claim 10, the X-powder diffraction pattern of wherein said polymorph when being when measuring under about 10 to 40 microns in crystal size, is characterized in that all and at the about peak of following ° 2 θ (degree) value:
15.58；
17.52；
21.35；
23.04；
25.43；
With
30.72。
13. the polymorph form B of claim 10, the Raman spectrum of wherein said polymorph are characterised in that one or more and at about following wave number (cm -1) the peak:
1245；
1380；
2963；
2993；
3027；
With
3066。
14. the polymorph form B of claim 10, the Raman spectrum of wherein said polymorph are characterised in that all and at about following wave number (cm -1) the peak:
1245；
1380；
2963；
2993；
3027；
With
3066。
15. the polymorph form A of the acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane, its crystal form do not have its other geometric isomer, optical isomer and polycrystalline isomer basically.
16. the polymorph form A of claim 15, wherein said acid-addition salts are hydrochlorate.
17. the polymorph form A of claim 16, the X-powder diffraction pattern of wherein said polymorph when being when measuring under about 10 to 40 microns in crystal size, is characterized in that one or more and at the about peak of following ° 2 θ (degree) value:
13.34；
17.64；
20.07；
21.32；
22.97；
24.86；
26.32；
With
27.90。
18. the polymorph form A of claim 16, the X-powder diffraction pattern of wherein said polymorph when being when measuring under about 10 to 40 microns in crystal size, is characterized in that all and at the about peak of following ° 2 θ (degree) value:
13.34；
17.64；
20.07；
21.32；
22.97；
24.86；
26.32；
With
27.90。
19. the polymorph form A of claim 16, the Raman spectrum of wherein said polymorph are characterised in that one or more and at about following wave number (cm -1) the peak:
1059；
1094；
1266；
1343；
1595；
2966；
2900；
With
3070。
20. the polymorph form A of claim 16, the Raman spectrum of wherein said polymorph are characterised in that all and at about following wave number (cm -1) the peak:
1059；
1094；
1266；
1343；
1595；
2966；
2900；
With
3070。
(21.+)-1-(3, the 4-Dichlorobenzene base)-preparation method of the polymorph form A of the acid-addition salts of 3-azabicyclo [3.1.0] hexane, the crystal form of described polymorph form A does not have its other geometric isomer basically, optical isomer and polycrystalline isomer, described method comprises and will comprise (+)-1-(3, the 4-Dichlorobenzene base)-solid of one or more polymorphs except polymorph form A of the acid-addition salts of 3-azabicyclo [3.1.0] hexane, be dissolved in the aqueous solvent medium of bag, with also being exposed in the atmosphere under about 15 ℃ to 35 ℃ temperature simultaneously, described solvent medium evaporates, to remove the polymorph form A of described solvent medium and the described crystal form of generation.
22. the method for claim 21, wherein said solid are the polymorph form A of acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane and the mixture of B.
23. the method for claim 22, wherein said acid-addition salts are hydrochlorate.
24. the method for claim 21, wherein said solvent medium comprises low-grade alkane alcohol.
25. the method for claim 21, the time that wherein said evaporation is carried out arrived until described solvent medium evaporation at least 4 hours.
26. polymorph form A according to the crystal form of the method for claim 21 preparation.
(27.+)-1-(3, the 4-Dichlorobenzene base)-preparation method of the polymorph form B of the acid-addition salts of 3-azabicyclo [3.1.0] hexane, the crystal form of described polymorph form B does not have its other geometric isomer basically, optical isomer and polycrystalline isomer, described method comprises and will comprise (+)-1-(3, the 4-Dichlorobenzene base)-solid of one or more polymorphs except polymorph form B of the acid-addition salts of 3-azabicyclo [3.1.0] hexane, be dissolved in the anhydrous organic solvent and under about 50 ℃ to 85 ℃ anhydrous condition from described solvent the polymorph form B of the described crystal form of crystallization.
28. the method for claim 27, wherein said acid-addition salts are hydrochlorate.
29. the method for claim 27, wherein said solid are the polymorph form A of acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane and the mixture of B.
30. polymorph form B according to the crystal form of the method for claim 27 preparation.
(31.+)-1-(3, the 4-Dichlorobenzene base)-preparation method of the polymorph form A of the acid-addition salts of 3-azabicyclo [3.1.0] hexane, the crystal form of described polymorph form A does not have its other geometric isomer, optical isomer and polycrystalline isomer basically, described method comprises and will comprise (+)-1-(3, the 4-Dichlorobenzene base)-and the solid of one or more polymorphs except the polymorph form A of the acid-addition salts of 3-azabicyclo [3.1.0] hexane, the temperature that is heated at least 50 ℃ is until the polymorph form A that generates described crystal form.
32. the method for claim 31, wherein said acid-addition salts are hydrochlorate.
33. the method for claim 31, wherein said solid are the polymorph form A of acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane and the mixture of B.
34. the method for claim 31, wherein said solid are polymorph form A, the B of acid-addition salts of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane and the mixture of C.
35. polymorph form A according to the crystal form of the method for claim 31 preparation.
36. the pharmaceutical composition of oral unit dosage form form, it comprises (+)-1-(3, the 4-Dichlorobenzene base)-the solid polymorph form A of the acceptable acid-addition salts of pharmacy of 3-azabicyclo [3.1.0] hexane, with inert pharmaceutically acceptable carrier or diluent, the crystal form of described polymorph form A does not have its other geometric isomer, optical isomer and polycrystalline isomer basically.
37. the pharmaceutical composition of claim 36, the acceptable acid-addition salts of wherein said pharmacy is a hydrochlorate.
38. the oral unit dosage form of claim 37, the polymorph form A of wherein said crystal form is present in the described oral unit dosage form to the amount of about 300mg with about 25mg.
39. the pharmaceutical composition of claim 38, wherein said oral unit dosage form are tablet or capsule.
40. the pharmaceutical composition of oral unit dosage form form, it comprises (+)-1-(3, the 4-Dichlorobenzene base)-the solid polymorph form B of the acceptable acid-addition salts of pharmacy of 3-azabicyclo [3.1.0] hexane, with inert pharmaceutically acceptable carrier or diluent, the crystal form of described polymorph form B does not have its other geometric isomer, optical isomer and polycrystalline isomer basically.
41. the pharmaceutical composition of claim 40, the acceptable acid-addition salts of wherein said pharmacy is a hydrochlorate.
42. the oral unit dosage form of claim 41, the polymorph form B of wherein said crystal form is present in the described oral unit dosage form to the amount of about 200mg with about 50mg.
43. the pharmaceutical composition of claim 42, wherein said oral unit dosage form are tablet or capsule.
44. the pharmaceutical composition of oral unit dosage form form, it comprises (+)-1-(3, the 4-Dichlorobenzene base)-the solid polymorph form A of the acceptable acid-addition salts of pharmacy of 3-azabicyclo [3.1.0] hexane, with inertia pharmaceutically acceptable carrier or diluent, the crystal form of described polymorph form A does not have its other geometric isomer, optical isomer and polycrystalline isomer basically.
45. the pharmaceutical composition of claim 44, the acceptable acid-addition salts of wherein said pharmacy is a hydrochlorate.
46. the pharmaceutical composition of claim 45, wherein said oral unit dosage form are tablet or capsule.
47. prevention or the depressed method of treatment in the patient of needs treatment, it comprises described patient's administration composition, described compositions comprises (+)-1-(3, the 4-Dichlorobenzene base)-solid polymorph form A and the inert carrier or the diluent of the acceptable acid-addition salts of pharmacy of 3-azabicyclo [3.1.0] hexane, the crystal form of described polymorph form A does not have its other geometric isomer, optical isomer and polycrystalline isomer basically, described compositions with effective prevention or the amount for the treatment of described depression by administration.
48. the method for claim 47, the acceptable salt of wherein said pharmacy is hydrochlorate.
49. the method for claim 48, wherein said polymorph form A with every day about 0.5mg/kg body weight to the oral dose of about 5.0mg/kg body weight to patient's administration.
50. prevention or the depressed method of treatment in the patient of needs treatment, it comprises described patient's administration composition, described compositions comprises (+)-1-(3, the 4-Dichlorobenzene base)-solid polymorph form B and the inert carrier or the diluent of the acceptable acid-addition salts of pharmacy of 3-azabicyclo [3.1.0] hexane, the crystal form of described polymorph form B does not have its other geometric isomer, optical isomer and polycrystalline isomer basically, described compositions with effective prevention or the amount for the treatment of described depression by administration.
51. the method for claim 50, the acceptable salt of wherein said pharmacy is hydrochlorate.
52. the method for claim 51, wherein said polymorph form B with every day about 0.5mg/kg body weight to the oral dose of about 5.0mg/kg body weight to patient's administration.
53. prevention or the depressed method of treatment in the patient of needs treatment, it comprises described patient's administration composition, described compositions comprises (+)-1-(3, the 4-Dichlorobenzene base)-solid polymorph form A and the inert carrier or the diluent of the acceptable acid-addition salts of pharmacy of 3-azabicyclo [3.1.0] hexane, the crystal form of described polymorph form A does not have its other geometric isomer, optical isomer and polycrystalline isomer basically, described compositions with effective prevention or the amount for the treatment of described depression by administration.
54. the method for claim 53, the acceptable salt of wherein said pharmacy is hydrochlorate.
55. the method for claim 54, wherein said polymorph form A with every day about 0.5mg/kg body weight to the oral dose of about 5.0mg/kg body weight to patient's administration.
56. pharmaceutical composition, it comprises the polymorph form A of the acceptable acid-addition salts of pharmacy of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane and the mixture of polymorph form B and polymorph form A one or both of.
57. the pharmaceutical composition of claim 56, wherein the amount of polymorph form A is that about 10 weight % are to about 20 weight %.
58. the pharmaceutical composition of claim 56, wherein the amount of polymorph form A is that about 20 weight % are to about 35 weight %.
59. the pharmaceutical composition of claim 56, wherein the amount of polymorph form A is that about 35 weight % are to about 50 weight %.
60. the pharmaceutical composition of claim 56, wherein the amount of polymorph form A is that about 50 weight % are to about 70 weight %.
61. the pharmaceutical composition of claim 56, wherein the amount of polymorph form A is that about 70 weight % are to about 85 weight %.
62. the pharmaceutical composition of claim 56, wherein the amount of polymorph form A is that about 85 weight % are to about 95 weight %.
63. the pharmaceutical composition of claim 56, wherein the amount of polymorph form A is that about 95 weight % are to about 99 weight %.
64. pharmaceutical composition, it comprises the polymorph form B of the acceptable acid-addition salts of pharmacy of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane and the mixture of polymorph form A and polymorph form A one or both of.
65. pharmaceutical composition, it comprises the polymorph form A of the acceptable acid-addition salts of pharmacy of (+)-1-(3, the 4-Dichlorobenzene base)-3-azabicyclo [3.1.0] hexane and the mixture of polymorph form A and polymorph form B one or both of.
CNA2005800279269A 2004-08-18 2005-08-17 Novel polymorphs of azabicyclohexane Pending CN101052393A (en)

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US20080045725A1 (en) * 2006-04-28 2008-02-21 Murry Jerry A Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane
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