CN101935305B - Method for preparing trans-4-(IR,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine and salt thereof and use as a medicament - Google Patents

Method for preparing trans-4-(IR,3S)-6-chloro-3-phenylindan-1-yl)-1,2,2-trimethylpiperazine and salt thereof and use as a medicament Download PDF

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CN101935305B
CN101935305B CN2010101632528A CN201010163252A CN101935305B CN 101935305 B CN101935305 B CN 101935305B CN 2010101632528 A CN2010101632528 A CN 2010101632528A CN 201010163252 A CN201010163252 A CN 201010163252A CN 101935305 B CN101935305 B CN 101935305B
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H·洛佩斯德迪戈
O·尼尔森
L·M·林加德
H·斯瓦纳
A·C·达尔
M·霍维尔斯
B·邦-安德森
L·O·林索
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Abstract

The invention relates to the preparation method of a compound 4-((1R,3S)-6-Chloro-3-phenylindan-1-yl)-2,2-dimethylpiperazine and its salts, and the intermediate used therein. The preparation method comprising converting the compound of fomula Va with cis configuration into the compound of fomula I.

Description

Trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2, the preparation method of 2-tri methyl piperazine and salt thereof and intermediate therefor
The application be that August 18, application number in 2004 are 200480023725.7 the applying date, denomination of invention for " trans-4-((1R; 3S)-6-chloro-3-phenyl indan-1-yl)-1; 2; the succinate of 2-tri methyl piperazine and malonate, and as the purposes of medicine " the dividing an application of application for a patent for invention.
Technical field
The present invention relates to 4-((1R, 3S)-and 6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine relates in particular to its succsinic acid hydrogen salt and bimalonate, preparation 4-((1R, 3S)-and 6-chloro-3-phenyl indan-1-yl)-1,2, the method for 2-tri methyl piperazine and salt thereof, the pharmaceutical composition and the medical usage thereof that contain these salt comprise that schizophrenia or other relate to the treatment of the disease of psychotic symptoms.
Background of invention
Compound, namely theme of the present invention [4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine] has the structure of general formula (I):
Figure GSA00000090167000011
And as described in EP638073.
EP 638073 has been contained one group of trans-isomer(ide) at the substituted 3-aryl-1-of 2-and/or 3-position (1-piperazinyl) of piperazine ring indane.It is said that these compounds are to dopamine D 1And D 2Acceptor and 5-HT 2Acceptor has high affinity and is proposed the disease that can be used for central nervous system, comprises schizoid treatment.EP 638073 is the specific enantiomeric forms of unexposed above-mentioned formula (I) compound also, and only discloses the trans-isomer(ide) of racemic modification form.
Figure GSA00000090167000012
Deng at J.Med.Chem., the enantiomer of above-mentioned formula (I) compound of fumarate form is disclosed in 1995,38, p4380～4392, consult its table 5, compound (-)-38.The document concludes: (-) of this compound-enantiomer 38 is a kind of effective D 1/ D 2Antagonist, it significantly goes out certain D external 1Selectivity and in vivo its to D 1And D 2Demonstrate the antagonistic action of equivalence.This compound also is described as a kind of effective 5-HT 2Antagonist and to α 1-adrenergic receptor has high affinity.Point out that also this compound can not cause the faintness of stiff property in rat.
Klaus P.B φ ges φ is at " Drug Hunting; the Medicinal Chemistry of 1-Piperazino-3-phenylindans and Related Compounds ", 1998, ISBN 87-88085-10-4 has also described corresponding racemoid and the fumarate of above-mentioned formula (I) compound and (has consulted the compound 69 in the table 3, p47 and table 9A, p101).
Like this, formula (I) compound is a kind of D of mixing 1/ D 2Antagonist, 5-HT 2Antagonist, and to α 1Adrenergic receptor also has affinity.Hereinafter, brief overview various disease respectively with dopamine D 1And D 2Acceptor, 5-HT 2Acceptor and α 1Relation between the adrenergic receptor.
Schizoid etiology is unknown, but be formed at early stage schizoid Dopamine HCL hypothesis (Carlsson, Am.J.Psychiatry, 1978 of nineteen sixty generation, 135,164～173) for causing the biological mechanism of this disease, understanding provides a kind of theoretical frame.The simplest form of this hypothesis is, this Dopamine HCL hypothesis thinks that schizophrenia is relevant with a kind of high dopaminergic state (hyperdopaminergic state), and this viewpoint has obtained the support of the following fact: all Antipsychotic drug things of selling in market have now all been brought into play certain dopamine D 2Receptor antagonism (consulting Science and Medicine 1995,2,28～37).Yet, the dopamine D in the fringe region of brain 2The antagonistic action of acceptor this saying that plays a crucial role in the treatment of schizoid positive symptom obtains general approval, but the D in the striatum zone of brain 2The retardance of acceptor has but caused extrapyramidal symptoms (EPS).As described in EP 638073, in to schizophreniac's treatment, used the psycholeptic compound of some what is called " atypia ", particularly used the dopamine D of observing mixing in the process of leoponex 1/ D 2The roughly situation that acceptor suppresses.
Central α has also been proposed 1Antagonistic action helps to improve spiritual rejection characteristic (Millan etc., JPET, 2000,292,38～53).
In addition, D optionally 1Antagonist relevant with the treatment of somnopathy and excessive drinking (D.N.Eder, Current Opinion in Investigational Drugs, 2002,3 (2), 284～288).
Dopamine HCL also may play an important role in the etiology of affective disorder.(P.Willner, Brain.Res.Rev.1983,6,211～224,225～236 and 237～246; J.Med.Chem., 1985,28,1817～1828).
In EP 638073, described 5-HT 2Acceptor has the compound of affinity, particularly 5-HT 2Receptor antagonist, how to be proposed for the different disease for the treatment of, schizophrenia for example comprises the parkinsonism that schizophrenia, dysthymia disorders, anxiety disorder, somnopathy, migraine and the Antipsychotic drug thing of the symptom that is negative among the schizophreniac cause.5-HT is also proposed 2Receptor antagonism can reduce because the sickness rate (Balsara etc., Psychopharmacology, 1979,62,67～69) of the outer side effect of the typical caused pyramidal tract of Antipsychotic drug thing.
Brief Description Of Drawings
Fig. 1: the X-ray powder diffraction figure that has shown formula I compound succsinic acid hydrogen salt alpha-crystal form (uses copper K α 1Ray
Figure GSA00000090167000031
Obtain)
Fig. 2: shown that formula I compound succsinic acid hydrogen salt beta crystal X-ray powder diffraction figure (uses copper K α 1Ray
Figure GSA00000090167000032
Obtain)
Fig. 3: the X-ray powder diffraction figure that has shown formula I compound bimalonate (uses copper K α 1Ray
Figure GSA00000090167000033
) obtain.
Detailed Description Of The Invention
Salt of the present invention
Have now found that the succsinic acid hydrogen salt of formula (I) compound and bimalonate water-soluble is significantly higher than the water-soluble of corresponding fumarate.
" the succsinic acid hydrogen salt " of term as used herein formula (I) compound refers to 1: 1 formula (I) compound and the salt of succsinic acid.
" bimalonate " of term as used herein formula (I) compound refers to 1: 1 formula (I) compound and the salt of propanedioic acid.
Found the succsinic acid hydrogen salt than fumarate and bimalonate is more stable and be non-hygroscopic.
The bimalonate that has been found that formula I compound has the stability that is similar to fumarate when being exposed to light lower time, and more stable when being exposed to for 60 ℃/80% relative humidity (RH) lower time, but stable not as fumarate 90 ℃ of lower times.Yet 90 ℃ is a kind of state of strong stress, and needn't relate to stability under usual condition.When relative humidity rose to 95%, malonate absorbed the water up to 1% gradually, but did not have hysteresis phenomenon.Therefore, it is considered to non-hygroscopic, but has good wet characteristic, and this good wet characteristic demonstrates favourable dissolution characteristics.
The invention still further relates to crystalline salt of the present invention, this comprises dehydrate, hydrate, and the solvate of salt of the present invention for example.The term dehydrate refers to not contain the salt of the present invention of crystal combination water.Hydrate refers to comprise the salt of the present invention of the water molecules of crystal combination.Hydrate normally forms that salt prepares having under some water existence conditions.Solvate refers to comprise the salt of the present invention of crystal combination solvent molecule.Solvate prepares by form succinate under the solvent existence condition usually.Solvent molecule in the single solvent compound can have the different solvent of one or two or more.Solvate can comprise water as one of two or more organic solvents, perhaps only contains non-aqueous solvent.
One embodiment of the invention relate to 1: 1 trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2, the 2-tri methyl piperazine, i.e. formula (I) compound is with the salt of the exsiccation thing form of succsinic acid.
The present inventor has been found that 2 kinds of crystalline forms (called after α and β) of the succsinic acid hydrogen salt of formula I compound.
Like this, an embodiment relates to the crystalline form of the succsinic acid hydrogen salt of formula I compound, and this form is named as α and it is characterized in that one or more in following (i)～(iii):
(i) as shown in Figure 1 X-ray powder diffraction figure;
(ii) use copper K α 1Ray
Figure GSA00000090167000041
The X-ray powder diffraction figure as shown in Table I that obtains wherein demonstrates the main peak that provides with 2 θ angles;
(iii) has DSC (dsc) trace that demonstrates at the endotherm of 139～141 ℃ of beginnings.
Another embodiment relates to the crystalline form of the succsinic acid hydrogen salt of formula I compound, and this form is named as β and it is characterized in that one or more in following (i)～(iii):
(i) as shown in Figure 2 X-ray powder diffraction figure;
(ii) use copper K α 1Ray
Figure GSA00000090167000042
The X-ray powder diffraction figure as shown in Table I that obtains wherein demonstrates the main peak that provides with 2 θ angles;
(iii) has DSC (dsc) trace that demonstrates at the endotherm of 135～138 ℃ of beginnings.
Another embodiment relates to the crystallization bimalonate of formula I compound, it is characterized in that one or more in following (i)～(ii):
(i) as shown in Figure 3 X-ray powder diffraction figure;
(ii) use copper K α 1Ray
Figure GSA00000090167000043
The X-ray powder diffraction figure as shown in Table I that obtains wherein demonstrates the main peak that provides with 2 θ angles;
Table I: use copper K α 1Ray The characteristic X-ray powder diagram of the crystal of the bimalonate α of the succsinic acid hydrogen salt of the formula I compound that obtains and beta crystal and formula I compound; Also consult Fig. 1, Fig. 2 and Fig. 3, it provides respectively the representational XRPD pattern of the malonate of the polymorphic form α of succsinic acid hydrogen salt of formula I compound and beta form and formula I compound.
Salt Feature reflection-main peak (reading by scattering angle 2 θ represents)
Succinate, α 9.36；10.23；11.81；13.45；16.21；16.57；17.49；18.89； 19.20；19.63；20.01；20.30；21.15；21.53；21.93；22.34； 24.37；25.34；27.27；29.65
Succinate, β 8.1；10.5；11.4；14.0；14.6；15.6；15.7；16.2；17.2； 17.5；17.9；18.4；18.9；19.2；20.3；21.0；21.9；22.5； 23.3；26.3
Malonate 8.3；10.6；11.5；12.8；14.2；14.5；14.7；15.8；16.5； 17.4；17.6；18.0；18.6；19.2；21.2；22.0；22.9；23.7； 24.7；28.8
The employed statement of this paper for example " is characterised in that the crystalline form such as the specific salts of the Compound I of the X-ray powder diffraction figure of figure shown in (1) " and refers to that the crystalline form of the salt of the formula I compound of discussing has the X-ray powder diffraction figure that is substantially similar to figure (1), that is, with the conditions of similarity of narrating here under or demonstrate basically such as the described X-ray powder diffraction pattern of this figure by any similar method.
Usually, all data herein are understood to be to be similar to, and are subject to the impact of normal measuring error, and this depends on the parameter of employed device for example and other influences peak position and peak intensity.
The invention still further relates to the solid succsinic acid hydrogen salt of formula I compound, the total amount of its this salt that neutralizes is compared, and this solid salt mainly is comprised of alpha-form.In one embodiment, term " mainly " refers to compare with total succsinic acid hydrogen salt of existing formula I compound, and the solid succsinic acid hydrogen salt of formula I compound comprises at least 75%, for example at least 80%, at least 90% or at least 95% alpha-crystal form.
The invention still further relates to the solid succsinic acid hydrogen salt of formula I compound, the total amount of its this salt that neutralizes is compared, and this solid salt mainly is comprised of beta form.In one embodiment, term " mainly " refers to compare with total succsinic acid hydrogen salt of existing formula I compound, and the solid succsinic acid hydrogen salt of formula I compound comprises at least 75%, for example at least 80%, at least 90% or at least 95% beta crystal.
The invention still further relates to any mixture of the crystalline form of succsinic acid hydrogen salt of the present invention, for example the α of the succsinic acid hydrogen salt of formula I compound and the mixture of beta-crystalline form.
The preparation of salt of the present invention
Can process the free alkali of formula (I) compound by in inert solvent, using succsinic acid, prepare succinate of the present invention with postprecipitation, separation and optional recrystallization.If necessary, then can carry out micronization to crystalline salt by wet-milling or dry grinding or other conventional processing, perhaps prepare particle from solvent-emulsification method.
Preferably be dissolved in suitable solvent, for example acetone or the toluene by the free alkali with formula (I) compound, then with this solution and succsinic acid suspension or the solution precipitation of mixing to implement succinate of the present invention in suitable solvent, for example acetone, aqueous acetone or toluene.In one embodiment, solvent is the mixture of acetone and water, for example the mixture of major ingredient acetone and the water of, preferably approximately 5% about 2%～10% based on the weighing scale of this mixture.Can heat resulting suspension or add solvent until all succsinic acid is dissolved.Preferably after this solution of cooling, precipitate the succinate of the compounds of this invention.Optionally succinate of the present invention is carried out the one or many recrystallization, by filtering separation, use for example washing with acetone and dry.
The invention still further relates to the method for the succsinic acid hydrogen salt beta crystal of preparation I compound, the method comprises that at ambient temperature the aqueous solution to the succsinic acid hydrogen salt of formula I compound carries out slowly solvent evaporation.
Can obtain malonate by similar step.Therefore, can process the free alkali of formula (I) compound by in inert solvent, using propanedioic acid, with postprecipitation, separate and randomly recrystallization prepare malonate of the present invention.If necessary, then can carry out micronization to crystalline salt by wet-milling or dry grinding or other conventional processing, perhaps prepare particle with solvent-emulsification method.
Preferably be dissolved in suitable solvent for example in the 2-propyl alcohol by the free alkali with formula (I) compound, the precipitation of then this solution and malonate being mixed to implement malonate of the present invention at suitable solvent, suspension in for example 2-propyl alcohol or solution.Can heat until all propanedioic acid are all dissolved this suspension.Preferably after this solution of cooling, precipitate the malonate of the compounds of this invention.Optionally malonate of the present invention is carried out the one or many recrystallization, by filtering separation, for example washing and drying in the 2-propyl alcohol.
The preparation of formula (I) compound
Can pass through such as EP638073 and B φ ges φ etc., J.Med.Chem., 1995,38, the described method in p4380～4392 prepares formula (I) compound of racemic form, how to have described in the document by diastereomeric salt being carried out crystallization finishing the optical resolution of racemic compound, thereby and obtained the enantiomer of formula (I).
The present inventor has developed a kind of improved synthetic route, the enantiomer of its Chinese style (I) is via the V from enantiomer-pure, the composition sequence that is compound Va ((1S, 3S)-6-chloro-3-phenyl indan-1-alcohol sees below) beginning obtains.Therefore, in the method, by for example chiral chromatography or enzyme method split-type V intermediate, obtain the enantiomer of formula Va.Carry out the method for crystallization with the salt of above-mentioned diastereomer to the finished product I and compare, the new synthesis route of this acquisition formula (I) compound is much effective.Especially, (amount with respect to the racemize starting raw material is 45% to fractionation productive rate in this novel method, namely, the theoretical maximum productive rate is 50%) (amount with respect to the racemize starting raw material is 22% to be significantly higher than fractionation productive rate by diastereoisomeric salt being carried out the final product I of crystallization, that is, the theoretical maximum productive rate is 50%).Another advantage of the present invention is: when synthesizing according to the present invention, enantiomeric purity (I) (being higher than 99%ee) is higher than synthetic (95.4%ee) that adopts crystallization diastereo-isomerism salt.In addition, intermediate is split to replace the fractionation that the finished product carry out has been provided a kind of more effective synthesizing, owing to only in subsequent step, use needed enantiomer, obtained higher volume productivity and reagent consumption still less.
Therefore, can obtain by the method that comprises the steps the enantiomer of formula (I):
Figure GSA00000090167000071
In the presence of the potassium tert.-butoxide (t-BuOK) that alkali for example suits, at suitable solvent for example in the dme (DME), with α-tolunitrile and 2,5-dichlorophenyl cyanogen reacts, and then causes automatic ring-closure reaction and form formula (II) compound by single still reaction (one pot) with methyl chloroacetate (MCA) reaction.
Then make formula (II) compound carry out acidic hydrolysis, should be by in the mixture of acetic acid, sulfuric acid and water, heating, to form formula (III) compound, then by suitable solvent for example in toluene and triethylamine or the N-Methyl pyrrolidone heating-type (III) compound carry out decarboxylation, to form formula (IV) compound.
Figure GSA00000090167000081
Then reduction-type (IV) compound suits to use NaBH 4, for example pure at solvent, in ethanol or Virahol, and preferably-30 ℃～+ 30 ℃ temperature range, for example below 30 ℃, below 20 ℃, below 10 ℃, or preferably below 5 ℃, have formula (V) compound of cis-configuration with formation:
Figure GSA00000090167000082
Split the formula V compound to realize needed enantiomer (formula Va), that is, also have cis-configuration ((1S, 3S)-6-chloro-3-phenyl indan-1-alcohol):
(V) to the fractionation of (Va) for example can be by using chiral chromatography, the preferred liquid phase chromatography, scribbling chiral polymer aptly, for example be coated on and carry out chromatography on the chirality silicagel column of modification amylose starch on the silica gel, preferred amylose starch three-(3,5-3,5-dimethylphenyl carbamate) and carry out.The suitable solvent of using in Chiral liquid chromatography has, and for example alcohol, nitrile, ether or alkane or its mixture suit to use ethanol, methyl alcohol, Virahol, acetonitrile or methyl tertiary butyl ether or its mixture, particular methanol or acetonitrile.The scale that can use suitable technology (for example simulating mobile pearl technology (SMB)) to amplify this Chiral liquid chromatography.
Perhaps, can formula (V) compound be split into compound Va by the enzyme fractionation.Having been found that can be by implementing compound Va or its acylated derivatives that enzyme enantioselectivity acidylate obtains high-optical-purity to the hydroxyl of racemic compound V.Perhaps, can also obtain by the method that comprises the steps the compound Va of enantiomer-pure: in hydroxy position racemic compound V is changed into corresponding ester, carry out subsequently enzyme enantioselectivity deacylation.Reported the compound of enzyme enantioselectivity deacylation for other.
Therefore, can be by the fractionation of selectivity enzyme acidylate realization from compound V to compound Va.Selectivity enzyme acidylate refers to that this enzyme acidylate is preferentially effective for a kind of conversion in a pair of enantiomer of formula V compound cis, and so that another cis enantiomer of compound V in this reaction mixture, remain unchanged.
Perhaps, can be by the fractionation of selectivity enzyme deacylation enforcement from compound V to compound Va.Selectivity enzyme deacylation refers to that this enzyme deacylation is preferentially effective for a kind of conversion in a pair of enantiomer of the ester of formula (V) compound, and so that another cis enantiomer of the ester of formula (V) compound in this reaction mixture, remain unchanged.
Figure GSA00000090167000091
The suitable ester (Vb) of formula (V) compound is esters such as acetic ester, propionic ester, butyric ester, valerate, capronate, benzoic ether, laurate, isobutyrate, 2-Methyl Butyric Acid ester, 3 Methylbutanoic acid ester, pivalate, 2 methyl valeric acid ester, 3 methylvaleric acid ester, 4-methylpent acid esters.
Figure GSA00000090167000101
Wherein, for example R is acetic ester, propionic ester, butyric ester, valerate, capronate, benzoic ether, laurate, isobutyrate, 2-Methyl Butyric Acid ester, 3 Methylbutanoic acid ester, pivalate, 2 methyl valeric acid ester, 3 methylvaleric acid ester, 4-methylpent acid esters.
Like this, embodiment relates to a kind of (S, S) of preparation formula V compound-or the method for (R, R)-enantiomer (namely having cis-configuration), and it comprises:
A) use acylating agent that racemic compound V is implemented the enantioselective enzymatic acidylate, or
B) racemic compound Vb is implemented the enantioselective enzymatic deacylation to form the mixture of deacylation compound Va.
The enzyme acidylate of enantioselectivity refers to that this enzyme acidylate is preferentially effective for a kind of conversion in the enantiomer of formula (V) compound, and so that another enantiomer of formula (V) compound in this reaction mixture, remain unchanged.The enzyme deacylation of enantioselectivity refers to that this enzyme deacylation is preferentially effective for a kind of conversion in the enantiomer of formula (Vb) compound, and preferential so that another enantiomer of formula (Vb) compound remains unchanged in this reaction mixture.
It may not be fully pure splitting this mixture that obtains by enzyme, and for example except relatively large needed enantiomer (Va), they may comprise the another kind of enantiomer of small amount.This composition mixture that obtains after according to acidylate of the present invention or deacylation depends on employed specific lytic enzyme and the condition of implementing reaction.Enzyme acidylate/deacylation of the present invention is characterised in that a kind of enantiomer of the another kind of major part of obvious ratio is converted.Like this; the acidylate of enantioselectivity of the present invention obtains a kind of (R that preferentially comprises; R)-formula (Vb) compound and the (S of form; S)-mixture of formula (Va) compound of form; perhaps preferentially comprise (S; S)-mixture of formula (Vb) compound of form and formula (Va) compound of (R, R)-form.Similarly; the enzyme deacylation of enantioselectivity can preferentially be comprised (S; S)-formula (Vb) compound of form and (R; R)-mixture of formula (V) compound of form; perhaps can preferentially be comprised (R; R)-mixture of formula (Va) compound of form and formula (Va) compound of (S, S)-form.The optical purity of the Va that obtains by optical resolution method of the present invention is at least 90%ee. usually, preferably is at least 95%ee., more preferably is at least 97%ee, and most preferably is at least 98%ee.Yet the value of lower optical purity also is acceptable.
According to the present invention, the enzyme acidylate of enantioselectivity is to carry out under the condition that basically suppresses hydrolysis.If in reactive system, there is water, then can be hydrolyzed, hydrolysis reaction is the reversed reaction of acylation reaction.Therefore, preferably at anhydrous organic solvent or almost implement the enzyme acidylate (usually needing some water with activating enzymes) of enantioselectivity in the anhydrous organic solvent.Suitable solvent comprises hydro carbons for example hexane, heptane, benzene and toluene; Ethers is ether, diisopropyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, t-butyl methyl ether and glycol dimethyl ether for example; Ketone is acetone, metacetone, butanone and methyl ethyl ketone for example; The ester class is methyl acetate, ethyl acetate, ethyl butyrate, vinyl butyrate and ethyl benzoate for example; Halogenated hydrocarbon is methylene dichloride, chloroform and 1，1，1-trichloroethane for example; Secondary alcohol and tertiary alcohols, for example trimethyl carbinol; Nitrogen-containing solvent is dimethyl formamide, ethanamide, methane amide, acetonitrile and propionitrile for example; With first proton polar solvent for example methyl-sulphoxide, N-Methyl pyrrolidone and hexamethylphosphorictriamide.Being used for the preferred organic solvent of enzyme acylation reaction is for example toluene, hexane, heptane, dioxane and tetrahydrofuran (THF) (THF) of organic solvent.
Suitable irreversible acyl group donor is acyl group donor for example for example vinyl ester, 2-propenyl ester class or 2,2,2-, three halogenated ethyl ester classes.
Preferably in water or in the mixture of water and organic solvent, suit under the condition that buffer reagent exists, to implement the enzyme deacylation of enantioselectivity.Suitable organic solvent be for example can be miscible with water solvent, for example alcohols, acetonitrile, dimethyl formamide (DMF), methyl-sulphoxide (DMSO), Isosorbide-5-Nitrae-dioxane, DME and diglyme.
Have been found that and to use Novozym 435 (Candida Antarctica lipase (mycocandida South Pole lipase) B originates from Novozymes A/S, Fluka products catalogue numbering 73940) to implement enzyme acidylate of the present invention.Usually, preferably use lipase, esterase, acyltransferase or proteolytic enzyme to implement enzyme acidylate of the present invention or deacylation.Can be used for enzyme of the present invention for implementing to the hydroxyl in the racemic compound of formula (V) enzyme of R-selectively acylating or S-selectively acylating, perhaps can implement to the acyl group in the racemic compound of formula (Vb) enzyme of R-regioselective deacylation or S-regioselective deacylation.Particularly the consolidated form of enzyme comprises that crosslinked enzyme crystal (CLEC) is useful in the present invention.A preferred embodiment relates to the enzyme that uses lipase to carry out compound V and splits.Most preferred lipase is Candida antarctica lipase (mycocandida South Pole lipase) (Fluka products catalogue numbering 62299); Pseudomonas cepacia lipase (Pseudomonas cepacia lipase) (Fluka products catalogue numbering 62309); NovozymCALB L (Candida antarctica lipase B (mycocandida South Pole lipase B)) (Novozymes A/S); Novozym 435 (Candida antarctica lipase B (mycocandida South Pole lipase B)) (Novozymes A/S); Or Lipozyme TL IM (the continuous shape lipase (Thermomyces lanuginosus lipase) of tea toadstool) (Novozymes A/S), be preferably fixing form.
Pass through at inert solvent aptly, ether for example, be suitably in the tetrahydrofuran (THF) and for example thionyl chloride, methylsulfonyl chloride or toluene sulfonyl chloride reaction of reagent, the alcohol radical of the cis-alcohol of wushu (Va) is converted into suitable leavings group, for example halogen (such as Cl or Br, preferred Cl) or sulphonate (such as methanesulfonates or tosylate).Resulting compound has formula (VI), and wherein LG is leavings group:
Figure GSA00000090167000121
In a preferred embodiment, LG is Cl, that is, and and the cis muriate of formula (VIa):
Compound vi, for example LG be chlorine then at suitable solvent, for example ketone such as methyl iso-butyl ketone (MIBK) or methyl ethyl ketone, in the preferable methyl isobutyl ketone, at alkali, for example under the existence of salt of wormwood, reacts with 2,2-lupetazin.With resulting compound (VII):
Figure GSA00000090167000123
Methylate in secondary amine functional groups, suitable to using suitable reagent (for example formaldehyde, paraformaldehyde, trioxane or methylene diethyl ether (DEM)) reduction amination, obtain the free alkali of formula (I) compound.
Figure GSA00000090167000131
Perhaps, when with compound vi, for example wherein LG is the compound vi of Cl, during reaction, can replace 2,2-lupetazin directly introduce methyl by using 1,2,2-tri methyl piperazine (following formula VIII), thereby synthesis step is shortened a step.
Figure GSA00000090167000132
In addition; can [wherein PG be protecting group by making compound vi and following formula (IX) compound; such as but not limited to phenyl methoxycarbonyl (being commonly called Cbz or Z, tertiary butyl oxygen base carbonyl (being commonly called BOC), ethoxy carbonyl or phenmethyl)] react the piperazine part of introducing this molecule, thus obtain the compound of following formula (X).
This product deprotection is become (VII) afterwards, and what discussed the enforcement front methylates, and namely obtains the final product Compound I.Perhaps, can use suitable reductive agent, lithium aluminum hydride for example, with protecting group for example ethoxy carbonyl be converted into methyl.
Between synthesis phase, in final product, form some cis diastereomers as the formula I compound of impurity (being 4-((1S, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2, the 2-tri methyl piperazine).This impurity mainly is owing to formed the trans forms (wherein LG is Cl for for example (1S, 3R)-3,5-two chloro-1-phenyl indans) of some (VI) in the step that forms compound vi.Therefore, can be by from the mixture of cis and trans (VI), the cis form of needed compound vi being crystallized out, thus impurity is minimized; When the LG of compound vi is Cl, can be by this mixture and suitable solvent (for example alkane, such as heptane) be stirred together, thus precipitating the cis-isomeride of needed VI, the trans-isomer(ide) of unwanted compound vi then enters solution.By filtering, use described solvent wash and dry, the cis form (for example working as LG is Cl) of needed compound vi is separated.
If there is the cis form of compound vi in compound vi I synthetic in the batch of material of employed (VI), this will cause in (VII) as the trans forms of the compound vi I of impurity (namely, 4-(1S, 3S)-and 6-chloro-3-phenyl indan-1-yl)-3, the 3-lupetazin) increase; This second that has provided the cis form of avoiding Compound I in final product is selected: have been found that the suitable salt that can pass through precipitation (VII) compound, for example the organic acid of formula (VII) compound, such as the salt of organic diprotic acid, be suitably difumarate or dimaleate, randomly carry out again subsequently a recrystallization to remove the cis form of compound vi I.
In addition, have been found that the suitable salt that can pass through precipitation (I) compound, for example organic acid salt such as the salt of organic diacid, is suitably the salt of fumaric acid, the difumarate of formula (I) compound for example, randomly carry out subsequently the one or many recrystallize, the impurity of effectively removing the cis diastereomeric form in (I) (is 4-((1S, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine).
Another aspect of the present invention relates to the intermediate for the synthesis of formula (I) compound described herein, that is, and and the salt of intermediate (Va), VI, for example VIa and VII or compound vi I particularly.In the context of this article, be to be understood that then this steric isomer is the main component of this compound when limiting stereoisomeric forms in any ratio.Especially, when limiting this enantiomeric forms, then this compound has the described enantiomer of enantiomeric excess.
Therefore, one embodiment of the invention relate to formula (Va) compound, preferably have at least 60% enantiomeric excess (60% enantiomeric excess refers to that in described mixture Va is 80: 20 with respect to the ratio of its enantiomer), at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably at least 98%.In addition, the diastereomer of this compound is excessive to be preferably at least 70% (70% diastereomer is excessive to be referred in described mixture, compound Va is 85: 15 with respect to the ratio of compound (1R, 3S)-6-chloro-3-phenyl indan-1-alcohol), at least 80%, at least 85%, at least 90% or at least 95%.An embodiment relates to basically pure compound Va.
Another embodiment of the invention relates to formula (VI) compound, preferably has at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferred at least 98% enantiomeric excess.
Figure GSA00000090167000151
Wherein LG is potential leavings group, is preferably selected from halogen, for example muriate or sulphonate.An embodiment relates to the purity of compound vi diastereomer; Namely, the diastereomer of compound is excessive preferably to be at least 10% (10% diastereomer is excessive refer in described mixture compound vi with respect to the cis diastereomer (for example when the LG=Cl, be (1S, 3R)-3,5-two chloro-1-phenyl indans) ratio is 55: 45), at least 25% or at least 50%.An embodiment relates to basically pure compound vi.
Therefore, the invention still further relates to the have following formula compound of (VIa),
Figure GSA00000090167000152
Its enantiomeric excess is at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably be at least 98%.An embodiment relates to the purity of this compound diastereomer; Namely, the diastereomer of compound is excessive to be preferably at least 10%, and (10% diastereomer is excessive to refer to that in described mixture this Compound Phase is for cis diastereomer ((1S for example, 3R)-3,5-two chloro-1-phenyl indans) ratio is 55: 45), at least 25% or at least 50%.An embodiment relates to basically pure compound vi, and wherein LG is Cl.
The invention still further relates to the compound (VII) with following structure:
Its enantiomeric excess is preferably at least 60% (in the mixture of discussing, 60% enantiomeric excess refers to that VII is 80: 20 with respect to the ratio of its enantiomer), at least 70%, at least 80%, at least 85%, at least 90%, at least 96%, preferably be at least 98% or its salt, fumarate for example, for example difumarate or maleate dimaleate for example.An embodiment relates to the purity of compound vi I diastereomer; Namely, the diastereomer of compound is excessive to be preferably at least 10% (10% diastereomer is excessive to refer to that in described mixture this compound vi I is 55: 45 with respect to the ratio of cis-(1S, 3S)-diastereomer), at least 25%, at least 50%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, at least 98%.An embodiment relates to basically pure compound vi I or its salt.
Another aspect relates to Compound I and salt thereof, and is particularly obtainable, particularly can be by fumarate, malonate or the succinate of the inventive method acquisition as herein described.
Another aspect relates to compound vi I or its salt, and is for example obtainable, particularly can be by the fumarate of the inventive method acquisition as herein described.
Medicinal use
The physicals of the salt of the compounds of this invention I shows that they are useful especially as medicine.
Therefore, the invention still further relates to the succinate of formula (I) compound, particularly succsinic acid hydrogen salt as herein described (for example described α or β type), or the pharmaceutical composition of malonate, particularly bimalonate.The invention still further relates to the medical usage that this class salt and composition for example are used for the treatment of following disease: central nervous system disease, comprise psychosis, particularly schizophrenia or other relate to the disease of psychotic symptoms, schizophrenia for example, Schizophreniform illness (Schizophreniform Disorder), dissociation of sensibility venereal disease disease (SchizoaffectiveDisorder), vain hope property mental disorder (Delusional Disorder), short-time characteristic mental disorder (Brief Psychotic Disorder), the property shared mental disorder (Shared PsychoticDisorder), and other exist mental illness or the disease of psychotic symptoms, for example the mania in the bipolar disorder (mania in bipolar disorder).
In addition, the 5-HT of compound of the present invention 2Antagonistic activity shows that this compound may have the risk of the outer side effect of relatively low pyramidal tract.
The invention still further relates to succinate of the present invention or malonate, succsinic acid hydrogen salt (for example alpha-crystal form) or the bimalonate of preferred formula (I) compound, the purposes that is used for the treatment of following disease: anxiety disorder, affective disorder comprise the refreshing syndromes of Parkinson, cocaine abuse, Nicotine abuse, excessive drinking and other abuse illnesss that dysthymia disorders, somnopathy, migraine, antipsychotics cause.
One wider aspect, the present invention relates to treat the method for the mania in Schizophreniform illness, dissociation of sensibility venereal disease disease, vain hope property mental disorder, short-time characteristic mental disorder, the property shared mental disorder or the bipolar disorder, comprise the administering therapeutic significant quantity trans-4-(6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine compound or its salt.
Here employed term " trans-4-(6-chloro-3-phenyl indan-1-yl)-1; 2; the 2-tri methyl piperazine ", namely, without any the concrete indication of enantiomeric form (for example, with (+) and (-) or according to R/S-rule), refer to any in two kinds of enantiomers of this compound, i.e. 4-((IR, 3S)-and 6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) or 4-((1S, 3R)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine, or the two mixture, for example racemic mixture.Yet in this article, the content that preferably is equivalent to the enantiomer of formula I compound is at least 50%, that is, at least as racemic mixture, preferred formula I compound is enantiomeric excess.
In this article, medicinal use is understood to when limiting compound trans-4-(6-chloro-3-phenyl indan-1-yl)-1,2, during the enantiomeric forms of 2-tri methyl piperazine (for example suc as formula (I)), then this compound is relatively three-dimensional chemical pure as mentioned above, preferred enantiomeric excess at least 80% (80% enantiomeric excess refers to that in described mixture I is 90: 10 with respect to the ratio of its enantiomer), at least 90%, at least 96% or preferably be at least 98%.In preferred embodiments, the diastereomer of formula I compound is excessive, and (90% diastereisomericallypure pure degree refers to that Compound I is with respect to cis-4-((1S at least 90%, 3S))-and 6-chloro-3-phenyl indan-1-yl)-1, the ratio of 2,2-tri methyl piperazine is 95: 5), at least 95%, at least 97% or at least 98%.
In preferred embodiments, the present invention relates to treat the method for the mania in Schizophreniform illness, dissociation of sensibility venereal disease disease, vain hope property mental disorder, short-time characteristic mental disorder, the property shared mental disorder or the bipolar disorder, comprise formula (I) compound of administering therapeutic significant quantity [namely, 4-((1R, 3S)-and 6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine] or its salt.
One embodiment of the invention relate to the method for the treatment of schizoid positive symptom, negative symptoms and schizoid depressive symptom, it comprise the administering therapeutic significant quantity trans-4-(6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine compound or its salt, preferred formula (I) compound or its salt, perhaps, in preferred embodiments, be succinate or the malonate of formula (I) compound, succsinic acid hydrogen salt or the bimalonate of preferred formula (I) compound.
Another embodiment of the invention relates to the method for the treatment of the schizophrenia positive symptom, comprise the administering therapeutic significant quantity trans-4-(6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine compound or its salt, preferred formula (I) compound or its salt, perhaps, in preferred embodiments, succinate or the malonate of formula (I) compound, succsinic acid hydrogen salt or the bimalonate of preferred formula (I) compound.
Another embodiment of the invention relates to the method for the treatment of schizoid negative symptoms, it comprise the administering therapeutic significant quantity trans-4-(6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine compound or its salt, preferred formula (I) compound or its salt, perhaps, in preferred embodiments, succinate or the malonate of formula (I) compound, succsinic acid hydrogen salt or the bimalonate of preferred formula (I) compound.
Another embodiment of the invention relates to the method for the treatment of schizophrenia depressibility symptom, comprise the administering therapeutic significant quantity trans-4-(6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine compound or its salt, preferred formula (I) compound or its salt, perhaps, in preferred embodiments, be succsinic acid hydrogen salt or the bimalonate of formula (I) compound.
Another aspect of the present invention relates to the method for the treatment of the mania in the bipolar disorder and/or keeping bipolar disorder, it comprise the administering therapeutic significant quantity trans-4-(6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine compound or its salt, preferred formula (I) compound or its salt, or be succinate or the malonate of formula (I) compound in preferred embodiments, succsinic acid hydrogen salt or the bimalonate of preferred formula (I) compound.
Another aspect of the present invention relates to the method for the treatment of the parkinsonism that antipsychotics causes, it comprise the administering therapeutic significant quantity trans-4-(6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine compound or its salt, preferred formula (I) compound or its salt, or be succinate or the malonate of formula (I) compound in preferred embodiments, succsinic acid hydrogen salt or the bimalonate of preferred formula (I) compound.
The invention still further relates to the therapeutant abuse, the method of Nicotine abuse, excessive drinking or cocaine abuse for example, comprise the administering therapeutic significant quantity trans-4-(6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine compound or its salt, preferred formula (I) compound or its salt, perhaps, in preferred embodiments, be succinate or the malonate of formula (I) compound, succsinic acid hydrogen salt or the bimalonate of preferred formula (I) compound.
Can be by any suitable method, for example the mode of oral, cheek, hypogloeeis or parenterai administration is used salt of the present invention or composition, and this salt can exist to be used for such method of application with any suitable form, for example, the form of tablet, capsule, powder, syrup or injection solution or dispersion liquid.In one embodiment, salt of the present invention is to use with the form of solid pharmaceutical unit, is suitably the form of tablet or capsule.
The method for preparing solid pharmaceutical preparation is technology known in the art.Therefore, can by with activeconstituents and common auxiliary, weighting agent and mixing diluents, then in suitable tabletting machine, compress this mixture and prepare tablet.The example of auxiliary, weighting agent and thinner comprises W-Gum, lactose, talcum, Magnesium Stearate, gelatin, lactose, natural gum etc.Also can use any other auxiliary or additive such as pigment, perfume compound, sanitas etc., if they can with the activeconstituents compatibility.
Can prepare by the following method injection solution: salt of the present invention and possible additive are dissolved in a part of solvent for injection, preferred sterilized water, with the volume-adjustment of solution to needed volume, with solution sterilization and fill it in the suitable ampoule or bottle.Can add the conventional employed any suitable additive in this area, such as tonicity agents (tonicity agent), sanitas, antioxidant, solubilizing agent etc.
The per daily dose of above-mentioned formula (I) compound calculates with free alkali and is suitably 1.0～160mg/ days, is preferably 1～100mg, and is for example preferred 2～55, or 3～55mg.
Here the term " treatment " that employed and disease or illness or obstacle are relevant also comprises possible prevention.
Will be in the present invention of following nonrestrictive embodiment illustrated of the present invention.
Embodiment
The preparation of compound
Analyze
The enantiomeric excess of the compound among the embodiment 1a (Va)(to use by chirality HPLC
Figure GSA00000090167000201
The OD post, 0.46cm ID * 25cm L, 10 μ m are under 40 ℃) measure.Use normal hexane/alcohol 95: 5 (v/v) as moving phase, flow velocity is 1.0ml/ minute, and detection uses the UV detector to implement under 220nm.
HPLC to the transformation efficiency that is used for embodiment 1b analyzes:
Post: Lichrospher RP-8 post, 250 * 4mm (5 μ m particle diameter)
Eluent: the MeOH/ water of the buffering that is prepared as follows, with 1.1ml Et 3N joins in the 150ml water, adds 10%H 3PO 4(aqueous solution) is until pH=7 and add entry until volume reaches 200ml.This mixture is joined among the 1.8L MeOH.
The enantiomeric excess of compound among the example I b (Va)(to use by chirality HPLC
Figure GSA00000090167000202
The AD post, 0.46cm ID * 25cm L, 10 μ m are under 21 ℃) measure.Heptane/ethanol/diethylamine 89.9: 10: 0.1 (v/v/v) is as moving phase in use, and flow velocity is 1.0ml/ minute, and detection uses the UV detector to implement under 220nm.
The enantiomeric excess of Compound IMeasure by fused quartz capillary electrophoresis (CE), wherein use following condition: kapillary 50 μ m ID * 64.5cm L, buffer reagent flows: the 1.25mM beta-cyclodextrin that is dissolved in the 25mM SODIUM PHOSPHATE, MONOBASIC, pH 1.5, voltage 16kV, temperature: 22 ℃, injection: 50mbar continues 5 seconds, detect: post photodiode array detection 192nm, sample concentration: 500 μ g/ml.In this system, the retention time of Compound I is about 33 minutes, and the retention time of another enantiomer is about 35 minutes.
1 H NMR spectrumUnder 500.13MHz, use Bruker Avance DRX 500 instruments or under 250.13MHz, record at Bruker AC 250 instruments.Use chloroform (99.8%D) or methyl-sulphoxide (99.8%D) as solvent, and use tetramethylsilane (TMS) as interior mark.
The cis/trans ratio of Compound I and VIIBy using 1H NMR measures, such as B φ ges φ etc., and J.Med.Chem.1995,38,4380～4392 (p4388, right hurdles) are described.The cis/trans of compound vi is by using in chloroform than also 1H NMR measures, and for the signal integration at cis-isomeride use 5.3ppm place, uses the signal integration at 5.5ppm place for trans-isomer(ide).Usually, can detect by NMR the content of about 1% unwanted isomer.
X-ray powder diffraction figureBe on PANalytical X ' Pert PRO X-RayDiffractometer, use CuK α 1The ray record.Under the reflective-mode at 5～40 2 θ angles of spending, to measure.
Fusing pointTo use dsc (DSC) to measure.This equipment be one with 5 ° of/minute calibrations to obtain fusing point as the TA-Instruments DSC-2920 of initial value.Under nitrogen gas stream one gently the sealing crucible in 5 ° of/minute samples that heat about 2mg.
Synthesizing of crucial starting material compound
From IV, adopt such as B φ ges φ J.Med.Chem., 1983,26,935 described methods are by using sodium borohydride (NaBH 4) reduction, use ethanol as solvent, and under about 0 ℃, react with synthetic compound V.Two kinds of compounds are all such as J.Med.Chem.1995 such as B φ ges φ, and 38,4380～4392 is described.Compound IV is from II from such as Sommer etc., J.Org.Chem.1990, and 55,4822 described general methods are synthetic, and the document has also been described Compound I I and synthetic method thereof.
Embodiment 1a is by utilizing chiral chromatography to synthesize (1S, 3S)-6-chloro-3-phenyl indan-1-alcohol (Va)
Racemic cis 6-chloro-3-phenyl indan-1-alcohol (V) (492g) by preparative chromatography, is used
Figure GSA00000090167000211
AD post, 10cm ID * 50cm L, 10 μ m are 40 ℃ of lower fractionations.Use methyl alcohol as moving phase, and flow velocity is 190ml/ minute, detection is by using the UV detector to carry out under 287nm.Form with the methanol solution of 50000ppm is injected racemic alcohol (V); All fractions that will comprise the title compound that surpasses 98% enantiomeric excess with 28 minutes intervals injection 90ml. are mixed and used the rotatory evaporator evaporate to dryness, and are lower dry at 40 ℃ in " vacuum " subsequently.Obtain 220 gram solids.Confirm its structure by ultimate analysis and NMR, according to chirality HPLC method, its enantiomeric excess is higher than 98%, [α] D 20+ 44.5 ° (c=1.0, methyl alcohol).
Embodiment 1b is by synthetic (1S, the 3S)-6-chloro-3-phenyl indan of enzyme Split Method-1-alcohol
Compound V (5g, 20.4mmol) is dissolved in 150ml unit water-toluene.Add 0.5gNovozym 435 (Candida Antarctica lipase B (mycocandida South Pole lipase B)) (Novozymes A/S, Fluka products catalogue numbering 73940), add subsequently vinyl butyrate (13ml, 102.2mmol).Use mechanical stirrer at 21 ℃ of lower these mixtures that stir.After one day, add again 0.5g Novozym 435.After 4 days, transformation efficiency is 54%, filter this mixture, and vacuum concentration obtains the (1R of 99.2% enantiomeric excess, 3R)-mixture (99.6% compound Va and 0.4% (1R, 3R)-cis-6-chloro-3-phenyl indan-1-alcohol) of cis-6-chloro-3-phenyl indan-1-alcohol-butyric ester and needed compound Va.
(I) synthetic and remove the impurity of cis diastereomeric form by the difumarate that precipitates (I)
Embodiment 2 (1S, 3S)-3,5-two chloro-1-phenyl indans (VI, LG=Cl) synthetic
To be dissolved in THF (1500ml) and be cooled to-5 ℃ by the described cis that obtains-(1S, the 3S) of example I a-6-chloro-3-phenyl indan-1-alcohol (Va) (204 gram).The thionyl chloride (119 gram) that dropwise adds the solution form that is dissolved in THF (500ml) with 1 hours.At room temperature this mixture is stirred and spend the night.In reaction mixture, add ice (100g).When the ice fusing, water (A) is separated with organic phase (B), use saturated sodium bicarbonate (200ml) with organic phase B washed twice.Sodium bicarbonate phase and water A are merged, use sodium hydroxide (28%) that the pH value is adjusted to 9, and use it for and again wash organic phase B.Resulting water (C) separates with organic phase B, uses ethyl acetate extraction water C.Ethyl acetate phase and organic phase B are merged, use dried over mgso, and use the rotatory evaporator evaporate to dryness, obtain the title compound of oily.Output 240g is directly used in embodiment 5 with it.According to NMR, the cis/trans ratio is 77: 23.
Embodiment 33,3-lupetazin-2-ketone synthetic
Use toluene (1.50L) to stir salt of wormwood (390 gram) and quadrol (1001 gram).Toluene (750ml) solution that adds 2-isobutyl ethyl bromide (500 gram).This suspension is heated to backflow spends the night, and filter.Use toluene (500ml) washing leaching cake.Heat the filtrate (4.0L) of converging and under 0.3atm, use the Ke Laisen device to distill in water-bath; At first at 35 ℃ of lower 1200ml overhead products (temperature of mixture is 75 ℃) of collecting.Add again toluene (600ml), and (temperature in the mixture is 80 ℃) collects the 1200ml overhead product again under 76 ℃.Again add toluene (750ml), and (temperature of mixture is 71 ℃) collects the overhead product of 1100ml under 66 ℃.Stir this mixture and insulation at ice bath, thereby be settled out product.By this product of filtering separation, use toluene wash, and in vacuum drying oven 50 ℃ of lower dried overnight.Obtain 3 of 171g (52%), 3-lupetazin-2-ketone.NMR is consistent with structure.
Embodiment 42,2-lupetazin synthetic
With (60kg) mixture heating up to 50 of 3,3-lupetazin-2-ketone (8.28kg, 64.6mol) and tetrahydrofuran (THF) (THF)～60 ℃.Obtain slightly muddy solution.Under nitrogen, stir THF (50kg), and add LiAlH 4(250g is in soluble plastics bag, from Chemetall) causes slow Exhaust Gas.After venting stops, adding again LiAlH 4(altogether using 3.0kg, 79.1mol), and because heat release, temperature rises to 50 ℃ from 22 ℃.With the solution of 2 hours at 41～59 ℃ of lower slowly adding 3,3-lupetazin-2-ketone.Under 59 ℃ with this suspension restir 1 hour (jacket temperature is 60 ℃).Cool off this mixture, and add entry (3L) with 2 hours, keep simultaneously temperature to be lower than 25 ℃ (must use 0 ℃ jacket temperature to cool off).Then with 20 minutes 23 ℃ lower add sodium hydroxide (15%, 3.50kg), cooling when needing.Add more water (9L) (cooling when needing) with half-hour period, and under nitrogen, this mixture stirring is spent the night.Add filtering medium Celit (4kg), and filter this mixture.Use THF (40kg) washing leaching cake.The concentrated filtrate of converging in reactor is until the temperature in the reactor is 70 ℃ (66 ℃ of distillation temperatures) under 800mbar.In Rotary Evaporators, residuum (12.8kg) further is concentrated into about 10L.At last, this mixture of under atmospheric pressure fractionation, and at 163～164 ℃ of lower products of collecting.5.3 kilograms of output (72%).NMR conforms to structure.
Embodiment 5 anti-form-1s-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-3,3-lupetazin (VII) synthetic
With cis-(1S, 3S)-3,5-two chloro-1-phenyl indans (VI, LG=Cl) (240g) are dissolved in fourth-2-ketone (1800ml).Add salt of wormwood (272g) and 2,2-lupetazin (in embodiment 4, preparing) and (113g) and under reflux temperature heated this mixture 40 hours.In this reaction mixture, add ether (2L) and hydrochloric acid (1M, 6L).Be separated, and use concentrated hydrochloric acid that the pH value of aqueous phase is reduced to 1. these waters from 8 to be used to again wash this organic phase, in guaranteeing that all products all are soluble in the aqueous phase.Add sodium hydroxide (28%) until the pH value is 10 to water, then use ether (2L) aqueous phase extracted 2 times.Converge this ether extraction liquid, use dried over sodium sulfate, and use the rotatory evaporator evaporate to dryness.Output: 251g oily title compound, this compound is used directly to next embodiment.According to NMR, the cis/trans ratio is 82: 18.
Embodiment 6 trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) difumarate synthetic
With rough anti-form-1-((1R, 3S)-and 6-chloro-3-phenyl indan-1-yl)-3, (37% the aqueous solution 300ml) and formic acid (366 gram) mixing, and slowly is heated to backflow with this mixture for 3-lupetazin (VII) (250 gram) and formaldehyde.Under refluxing, stir this mixture 3.5 hours, be cooled to room temperature, then add entry (1200ml).Use ether (1200ml) to extract this mixture twice, then by adding sodium hydroxide (28%, about 500ml) water is alkalized.Use ether (900ml) aqueous phase extracted three times.Converge organic phase and use salt solution (650ml) washed twice, make water (500ml) washed twice.By this organic phase of dried over sodium sulfate, filter, and on rotatory evaporator evaporate to dryness.Obtain 212 the gram oilies trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine free alkali (I) according to NMR, contains 19% cis diastereomer.This compound is dissolved in 1-propyl alcohol (3.18L) and with this mixture heating up to 50 ℃, obtains clear solution.Add fumaric acid (69.3g), obtain clear solution.Cool off this mixture, thus the precipitation title compound.By this product of filtering separation, use the washing of 1-propyl alcohol, and " in a vacuum " is lower dry at 60 ℃.Output: 182 grams comprise＜1% cis diastereomer according to NMR.Ultimate analysis and NMR conform to structure.According to chirality capillary electrophoresis (CE), enantiomeric excess is higher than 99%.[α] D 20=-22.8 (c=1.0, methyl alcohol).
The unhindered amina and the redeposition that discharge (I) from difumarate become succsinic acid hydrogen salt and bimalonate
Embodiment 7 4-(1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine free alkali (I) synthetic
With trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) difumarate (25.0 gram) is suspended in the toluene (125ml).Add ammoniacal liquor 25% (75ml).Stir this three-phase until all solids disappears.Separate organic phase, and use toluene (25ml) washing water.The toluene phase that water (25ml) washing is converged.Abandon water, and use dry this organic phase of first aqueous sodium persulfate (35 gram), filter this slurry, then use rotatory evaporator with the filtrate evaporate to dryness, obtain the title compound of oily.Need not to be further purified and to use this rough free alkali (15 gram).
Embodiment 8 trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) succsinic acid hydrogen salt synthetic
With embodiment 7 obtain rough trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) (8,50 gram oily matter) is dissolved in acetone (30ml).Preparation succsinic acid (3,25 the gram) in acetone (32ml) suspension and add trans-4-((1R, 3S)-and 6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) solution, the succsinic acid dissolving, trans-4-((1R soon subsequently, 3S)-and 6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) succsinic acid hydrogen salt is precipitated out.By centrifugation should the precipitation before, with suspension be cooled to 0 ℃ 90 minutes.Abandon supernatant liquid and use acetone (20ml) to wash this precipitation.This slurry is carried out centrifugation and abandons this supernatant liquid, and precipitate 50 ℃ of lower dry being somebody's turn to do in " in the vacuum ".
Output 8.56 grams.
When implementing this step for the first time, the product that separates is the β type, causes forming the α type of more stable formula I compound succsinic acid hydrogen salt after repeating this step.
Can use the acetone in the above-mentioned test of aqueous acetone solution (95%) replacement, obtain equally the α type of formula I compound succsinic acid hydrogen salt.
Dsc (DSC) shows that a starting temperature is 140 ℃ endothermic process, and one corresponding to the α type at 141 ℃ peak.The XRPD diffractogram conforms in the α type.
Embodiment 9 trans-4-(1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) bimalonate
With among the embodiment 7 resulting rough trans-4-(1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) (1.0 the gram, 2.81mmol) be dissolved in 2-propyl alcohol (5ml).Preparation propanedioic acid (0.291 gram, 2.46mmol) 2-propyl alcohol (5ml) solution, and add trans-4-((1R, 3S)-and 6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine solution, thereby precipitate trans-4-((1R, 3S)-and 6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine bimalonate.Before by this precipitation of centrifugation, this suspension is cooled to room temperature.Abandon supernatant liquor and use 2-propyl alcohol (5ml) to wash this precipitation.This slurry is carried out centrifugation and abandons this supernatant liquor, and precipitate 50 ℃ of lower dry being somebody's turn to do in " in the vacuum ".Output: 0.98 gram (84%).Ultimate analysis conforms to structure.X-ray diffractogram conforms to the diffractogram of as shown in Figure 3 bimalonate.
(I) synthetic, salt formation (VII) to be removing the cis diastereomer of (VII), and form the succsinic acid hydrogen salt from rough (I)
Embodiment 10 anti-form-1s-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-3,3-lupetazin (VII) dimaleate synthetic
Repeat embodiment 2 and 5, obtain the rough anti-form-1 of oily-((1R, 3S)-and 6-chloro-3-phenyl indan-1-yl)-3,3-lupetazin (VII) (about 20 grams), then by the (eluent: ethyl acetate/ethanol/triethylamine 90: 5: 5) be further purified, subsequently evaporate to dryness on Rotary Evaporators of flash chromatography on silica gel.Obtain 12 gram oily title compounds (according to NMR, the cis/trans ratio is 90: 10).This oily matter is dissolved in ethanol (100ml), and adds the ethanolic soln of toxilic acid to this solution, until the pH value is 3.At room temperature stir resulting mixture 16 hours, and collect formed precipitation by filtering.The volume of reduction ethanol, and collect another batch precipitation.Obtain 3.5 gram solid title compounds (according to NMR, not detecting cis-isomeride).
Fusing point: 175～178 ℃.
Embodiment 11 anti-form-1s-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-3,3-lupetazin (VII)
At room temperature with anti-form-1-((1R, 3S)-and 6-chloro-3-phenyl indan-1-yl)-3, the mixture of 3-lupetazin dimaleate (VII) (9.9 gram), strong aqua (100ml), salt solution (150ml) and ethyl acetate (250ml) stirred 30 minutes.Be separated, and use ethyl acetate again to extract water one time.The organic phase of using the salt water washing to converge is used dried over mgso, filters and evaporate to dryness under vacuum.Obtain 7.5 gram oily matter.
Embodiment 12 trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2, the preparation of 2-tri methyl piperazine free alkali (I)
With anti-form-1-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-3,3-lupetazin (8.9 restrain) (VII) is dissolved in formic acid (10.5ml) and adds formaldehyde (10.5ml) in this solution.Be heated to 60 ℃ and kept this temperature 2.5 hours.After the reaction mixture, add entry (50ml) and hexane (50ml).Use NaOH (27%, 33ml) the pH value is adjusted to pH value＞12.Use the NaCl aqueous solution (20ml) to wash hexane mutually with water (20ml).Use acetone (90ml) azeotropic exchange hexane and concentrated this mixture.The rough free alkali that is dissolved in acetone (10ml) need not purifying and can use.
Embodiment 13 trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) succsinic acid hydrogen salt
Rough trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2, acetone (10ml) solution of 2-tri methyl piperazine (I).Acetone (20ml) suspension of preparation succsinic acid (3.4 gram), and add trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2, then 2-tri methyl piperazine (I) solution extremely reflux this mixture heating up (55 ℃).Succsinic acid dissolves and at the trans-4-of cooling ((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2, begins precipitation during 2-tri methyl piperazine (I) the succsinic acid hydrogen salt.Suspension is left standstill a whole night to precipitate.By filtering separation trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine succsinic acid hydrogen salt also uses acetone (20ml) washing.In a vacuum at 60 ℃ of lower dry these products.
Output: 7.9 grams.
Dsc shows one since 140 ℃ and the endotherm that peak value is equivalent to alpha-crystal form occurs at 141 ℃.The XRPD diffractogram conforms to the α type.[a] D 20=-22.04 ° (c=1.0, methyl alcohol).
Use the synthetic I of 1,2,2-tri methyl piperazine
Embodiment 14 3,3,4-tri methyl piperazine-2-ketone synthetic
With 3,3-lupetazin-2-ketone (50 gram) be suspended in 1，2-ethandiol dme (DME) (150ml) in and add salt of wormwood (70 gram).Add methyl iodide (66.4 gram) with half-hour period, cool off a little this mixture simultaneously, reach 50 ℃ with allowable temperature.Under 40～45 ℃ this mixture was stirred 9 hours in oil bath, and take out sample and carry out the NMR analysis, NMR shows, still has 8% raw material residual (at the signal of 2.8ppm).Add again methyl iodide (4.6 gram), and 40 ℃ under with this mixture restir 2.5 hours, and new NMR sample shows fully conversion.Filter this mixture, and use DME to wash this filter cake.With the filtrate evaporate to dryness, obtain 41 gram title compounds.NMR conforms to structure.
Embodiment 15 1,2,2-tri methyl piperazine synthetic
In oil bath, the solution (1.0M, Aldrich cat. no 21,277-6,90ml) of lithium aluminum hydride in tetrahydrofuran (THF) (THF) is heated to 50 ℃.With rough 3,3,4-tri methyl piperazine-2-ketone (10g) is suspended among the THF, and slowly adds, and at this moment emits gas.Under 45～56 ℃, resulting mixture was stirred 4 hours, according to NMR, be converted into title compound (at 1.2ppm place less than the signal from raw material) fully.Cool off this mixture, and add entry (3.3ml), emit gas.Then add sodium hydroxide the aqueous solution (15%, 3.3ml), emit more gases, add at last entry (10ml).Filtering mixt, and use THF (100ml) to wash this filter cake.Use rotatory evaporator (0.3atm. and 60 ℃, in water-bath) concentrated filtrate.Resistates is dissolved in THF (200ml) and uses dried over sodium sulfate, then filter this mixture, and use rotatory evaporator (0.2atm and 60 ℃, in water-bath) concentrated filtrate to obtain 6.4 gram title compounds.NMR conforms to structure, and this material comprises some THF.
Embodiment 16 is from compound vi synthesis of trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) difumarate
Use embodiment 5 described methods, with cis-(1S, 3S)-3,5-two chloro-1-phenyl indans (VI of LG=Cl) (17.8 gram) are with distilled 1,2,2-tri methyl piperazine (VIII) (8.7 gram) coupling.Use embodiment 6 described methods, the raw product that will comprise the unhindered amina (15.7 gram) of 6% cis-isomeride is used to form difumarate.Obtain 15.7 gram title compounds; NMR conforms to structure, does not observe cis-isomeride.
Synthesizing of the beta crystal of formula I compound succsinic acid hydrogen salt
Embodiment 17 trans-4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2,2-tri methyl piperazine (I) succsinic acid hydrogen salt, beta crystal synthetic
Formula I compound succsinic acid hydrogen salt (50 milligrams) is suspended in water (1ml) and make its balance 3 days.By removing by filter any undissolved material.During the spontaneous evaporation solvent, form the beta crystal of formula I compound succsinic acid hydrogen salt.Behind complete evaporating solvent, by XRPD and this beta crystal of dsc analysis.Analytical results: dsc (DSC) shows and to start from 135.6 ℃ and at 137.5 ℃ of endotherms corresponding to this beta crystal that peak value occurs.XRPD conforms to this beta crystal.
The sign of salt
The solubleness of the salt of embodiment 18 formulas (I) compound
Measure the solubleness of salt in water by the salt that in the water of 2ml, adds excessive (50mg).This suspension is placed in the impeller at least 24 hours, subsequently pH value determination and measure concentration by HPLC.Separate this solid precipitation and in the laboratory, make its drying.The result is as described in Table 1.
Table 1: salt at room temperature solubleness in water
Figure GSA00000090167000291
The stability of the salt of embodiment 19 formulas (I) compound
Study under the following conditions the stability of salt: the heating, 60 ℃/80% relative humidity: under 80% relative humidity at 60 ℃ with 1 week of sample retention.Then analyze with its dissolving and by HPLC.
The heating, 90 ℃: comprising under 90 ℃ of temperature preserve in 1 encloses container that drips sample (～10mg).Then analyze with its dissolving and by HPLC.
Light: sample is placed 250w/m 2Light box in 24 hours.Then analyze with its dissolving and by HPLC.
Except the peak that is equivalent to this material or acid, summarize the peak area in the chromatogram.Succinate of the present invention does not demonstrate any degraded.
Table 2
Figure GSA00000090167000292
The water absorbability of the salt of embodiment 20 formulas (I) compound
Fumarate, succinate (alpha-crystal form) and malonate water absorbability are adsorbed (DVS) by dynamic steam and are measured.Find that fumarate and succinate are non-hygroscopic.When relative humidity was elevated to 95%, malonate progressively absorbed the water up to 1%, but did not have hysteresis phenomenon.

Claims (35)

1. for the manufacture of 4-((1R, 3S)-6-chloro-3-phenyl indan-1-yl)-1,2, the method for 2-tri methyl piperazine (formula I) or its salt, the method comprise that the formula Va compound with cis-configuration is converted into formula I compound, and its Chinese style I and Va are as follows:
Figure FSB00000968135000011
The compound of its Chinese style Va is that chiral chromatography or the enzyme Split Method of through type V compound obtains:
Figure FSB00000968135000012
2. the method for claim 1, it comprises that the hydroxyl with the cis-alcohol of formula Va is converted into leavings group LG, obtains formula VI compound:
Figure FSB00000968135000013
Wherein LG is halogen or sulfonate radical.
3. the method for claim 2, wherein LG is Cl or Br.
4. the method for claim 2, wherein LG is Cl.
5. the method for claim 2, wherein the reaction of compound vi and 2,2-lupetazin obtains formula VII compound:
Figure FSB00000968135000021
6. the method for claim 5, it is included in to methylate on the secondary amine and obtains the free alkali of formula I compound.
7. the method for claim 5, the precipitated salify of its Chinese style VII compound, wherein said salt is organic acid salt.
8. the method for claim 7, wherein said salt is the salt of organic dibasic acid.
9. the method for claim 6, the precipitated salify of its Chinese style VII compound, wherein said salt is organic acid salt.
10. the method for claim 9, wherein said salt is the salt of organic dibasic acid.
11. the method for claim 2, wherein the reaction of compound vi and 1,2,2-tri methyl piperazine (formula VIII) obtains the free alkali of formula (I) compound:
Figure FSB00000968135000022
12. the method for claim 2, it comprises:
-with 2 of compound vi and 1-protection, 2-lupetazin (IX) reaction, wherein PG is blocking group, thereby obtains formula X compound; And
-the compounds X deprotection is obtained compound vi I, perhaps compounds X is converted into Compound I,
Wherein compound vi I, IX and X are as follows:
Figure FSB00000968135000031
13. the method for claim 12, wherein blocking group PG is selected from phenyl methoxycarbonyl, tertbutyloxycarbonyl, ethoxy carbonyl and phenmethyl.
14. the method for preparation I compound or its salt, it comprises the compound with formula VIa, be that LG is the compound vi of Cl, with 2, the reaction of 2-lupetazin, thus formula VII compound obtained, methylate at secondary amine subsequently, its Chinese style I such as claim 1 definition, formula VI such as claim 2 definition and formula VII such as claim 5 definition.
15. the method for preparation I compound or its salt, it comprises makes formula VIa compound, and namely wherein LG is the compound vi of Cl),
React in the presence of alkali with 2,2-lupetazin, use subsequently suitable reagent to carry out reduction amination, subsequently the formula I compound of separated free alkali form or its salt form.
16. the method for claim 15, wherein said reagent are formaldehyde, paraformaldehyde, three
Figure FSB00000968135000033
Alkane or methylene diethyl ether.
17. make 4-(it comprises formula VII compound is converted into formula I compound for (1R, 3S)-(6-chloro-3-phenyl indan-1-yl)-1,2, the method for 2-tri methyl piperazine (formula I) or its salt, its Chinese style VII such as claim 5 definition.
18. each method of claim 1～17, the precipitated salify of its Chinese style (I) compound is to remove unwanted cis diastereomer, and wherein said salt is organic acid salt.
19. the method for claim 18, wherein said salt are the salt of organic dibasic acid.
20. the method for claim 18, wherein formed salt is the difumarate of formula I compound.
21. each method of claim 1～17, it comprises the succsinic acid hydrogen salt of preparation formula (I) compound, and this salt is formula (I) compound succsinic acid hydrogen salt crystal, and this crystal is characterised in that and uses CuK α 1Ray,
Figure FSB00000968135000041
The X-ray powder diffraction figure that obtains demonstrates the peak at following 2 θ angles: 9.36; 10.23; 11.81; 13.45; 16.21; 16.57; 17.49; 18.89; 19.20; 19.63; 20.01; 20.30; 21.15; 21.53; 21.93; 22.34; 24.37; 25.34; 27.27; 29.65.
22. the method for claim 21, wherein this crystal is characterised in that the X-ray powder diffraction figure corresponding to accompanying drawing 1.
23. the method for claim 21, wherein this crystal is characterised in that and has the dsc trace that demonstrates at the endotherm of 139～141 ℃ of beginnings.
24. each method of claim 21～23, wherein the succsinic acid hydrogen salt of this Compound I prepares in ketone solvent.
25. the method for claim 24, wherein said solvent is acetone.
26. the method for claim 24, wherein said solvent is aqueous acetone.
27. such as each method of claim 1～17, it comprises the bimalonate of preparation formula (I) compound, this salt is formula (I) compound bimalonate crystal, and this crystal is characterised in that and uses CuK α 1Ray,
Figure FSB00000968135000042
The X-ray powder diffraction figure that obtains demonstrates the peak at following 2 θ angles: 8.3; 10.6; 11.5; 12.8; 14.2; 14.5; 14.7; 15.8; 16.5; 17.4; 17.6; 18.0; 18.6; 19.2; 21.2; 22.0; 22.9; 23.7; 24.7; 28.8.
28. the method for claim 27, this crystal are characterised in that X-ray powder diffraction figure as shown in Figure 3.
29. each method of claim 27～28, wherein the bimalonate of this Compound I prepares in alcoholic solvent.
30. the method for claim 29, wherein said solvent are the 2-propyl alcohol.
31. each method of claim 1～17, it comprises that the free alkali with formula (I) compound is converted into such as claim 21～23 and 27～28 each defined salt.
32. the method for claim 31, the alkali of the formula that wherein obtains (I) is at first separated with its difumarate, it is randomly by the recrystallization one or many, then use this difumarate of alkaline purification with release type (I) compound free alkali, then be translated into its succsinic acid hydrogen salt or bimalonate.
33. each method of claim 1～17 is separated the formula I compound with free alkali or its salt form subsequently.
34. the method for claim 33, wherein said salt are such as each defined succsinic acid hydrogen salt of claim 21～23 or such as each defined bimalonate of claim 27～28.
35. each method of claim 1～16, wherein compound Va splits compound V by enzyme and obtains
Figure FSB00000968135000051
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