CN101084222A - Synthesis of 2-methyl-4-(4-methyl-1-piperazinyl)-10h-thieno[2, 3-b][1,5]benzodiazepine and salts thereof - Google Patents
Synthesis of 2-methyl-4-(4-methyl-1-piperazinyl)-10h-thieno[2, 3-b][1,5]benzodiazepine and salts thereof Download PDFInfo
- Publication number
- CN101084222A CN101084222A CN 200580015935 CN200580015935A CN101084222A CN 101084222 A CN101084222 A CN 101084222A CN 200580015935 CN200580015935 CN 200580015935 CN 200580015935 A CN200580015935 A CN 200580015935A CN 101084222 A CN101084222 A CN 101084222A
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- Prior art keywords
- olanzapine
- acid
- methyl
- organic
- acid salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000003839 salts Chemical class 0.000 title claims abstract description 92
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- 238000003786 synthesis reaction Methods 0.000 title description 3
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- 239000000243 solution Substances 0.000 claims description 66
- FHPIXVHJEIZKJW-UHFFFAOYSA-N 4'-N-desmethylolanzapine Chemical compound S1C(C)=CC2=C1NC1=CC=CC=C1N=C2N1CCNCC1 FHPIXVHJEIZKJW-UHFFFAOYSA-N 0.000 claims description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
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- ZTTWQKYKGNLCCA-UHFFFAOYSA-N 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine Chemical compound N1C2=CC=CC=C2N=C(N)C2=C1SC(C)=C2 ZTTWQKYKGNLCCA-UHFFFAOYSA-N 0.000 claims description 3
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- CQCVGXWYFQCZKX-UHFFFAOYSA-N benzoic acid 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine Chemical compound OC(=O)c1ccccc1.CN1CCN(CC1)C1=Nc2ccccc2Nc2sc(C)cc12 CQCVGXWYFQCZKX-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N nmp n-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- ZDYUUBIMAGBMPY-UHFFFAOYSA-N oxalic acid;hydrate Chemical class O.OC(=O)C(O)=O ZDYUUBIMAGBMPY-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
Abstract
The invention pertains to organic chemistry field, and relates to a novel method for purifying olanzapine, including preparing acid addition salt of olanzapine, and transforming the same into pharmaceutical acceptable final product which is purified and decolored. The invention further relates to a novel process for preparing olanzapine.
Description
Technical field
The invention belongs to organic chemistry filed, and relate to 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine (olanzapine, olanzapine) novel method of purification, comprise the acid salt for preparing olanzapine and convert it into pharmaceutically acceptable pure and the decolouring the finished product.The invention still further relates to the method for the pure olanzapine of preparation.
Background technology
Olanzapine is the pharmaceutically active substances in the antipsychotic drug class, can be used for treating different mental disorderes and symptom, for example, and central nervous system disorder, schizophrenia, illusion, acute mania, dysthymia disorders etc.
It is chemically belonging to benzodiazepine derivatives and is being 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine (formula 1).
In the general formula 1 of patent GB 1,533,235, comprise olanzapine and analogue thereof first.Although this reference discloses the general alkylation that is used for synthetic 4-substitutive derivative, clearly do not mention such methylating.Alkylated reaction carries out in ethanol, and the use triethylamine is as alkali and use R '-Cl (the wherein different group of R ' representative) as alkylating agent.
At GB 1,533, in 235, with general formula two kinds of route of synthesis are disclosed, it is described in detail among the basic patent EP454436B1.EP454436B1 discloses two kinds of different single stage method that are used for the olanzapine preparation.Described first method is 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride and N methyl piperazine in organic solvent (for example methyl-phenoxide, toluene, dimethyl formamide or methyl-sulphoxide), preferably 100 to 150 ℃ of reactions to produce olanzapine (graphic 1).
Graphic 1
Disclosed second method is N methyl piperazine and 2-(2-amino-benzene the amido)-reaction (graphic 2) of 5-thiotolene-3-methyl-formiate in the presence of titanium tetrachloride among the EP 454436B1.
Graphic 2
This patent is also mentioned the formation of acid salt of olanzapine and they potential use as intermediate in the olanzapine method of purification and when pharmaceutical purpose.Yet, do not prepare or characterize any such acid salt, and do not have the method or the experiment of any described acid salt of public use.
Be to use the painted of the finished product that the thiophene-based chemical technology causes with these two kinds synthetic relevant subject matters.
As disclosed among EP454436B1 and the U.S. patent families US5229382, obtain olanzapine according to first kind synthetic (graphic 1), purify by recrystallization from acetonitrile then, and further purify and recrystallization from acetonitrile by the column chromatography on florisil (Florisil) according to the olanzapine that second kind of approach (graphic 2) made.
The coloring problem of olanzapine is known and has been described in the EP733635B1 of reference United States Patent (USP) 5,229,382.These two reference all show, even olanzapine still contains the unacceptable color of trace after purifying with gac.In EP733635B1, the contriver has attempted to solve coloring problem by the new crystalline form of preparation olanzapine.
Describe other in the prior art and be used to prepare the synthetic method of olanzapine.For example, patent application WO 04/000847 discloses at reductibility N-under (using formaldehyde and the metal borohydride) effect that methylates by 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] the benzodiazepine hydrochloride is via 2-methyl-4-(1-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine (N-demethyl olanzapine just) carry out two the step synthesis methods.WO 04/000847 has described the process that methylates in methyl alcohol.The shortcoming of disclosed method is that yield is low among the WO 04/000847, and the finished product is of poor quality.
At Bioorganic ﹠amp; Medicinal Chemistry Letters, the 7th volume, No. 1, the 25-30 page or leaf discloses 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride and piperazine reaction in 1997 with manufacturing N-demethyl olanzapine (graphic 3).The mixture that uses methyl-sulphoxide/toluene=1/4 is as solvent mixture.
Graphic 3
WO04/089313 discloses hydrochlorate, solvate and the eutectic of olanzapine and they are as the purposes of active pharmaceutical ingredient in preparation.Fumaric acid, toxilic acid and the propanedioic acid additive salt of olanzapine are disclosed in WO 04/089313.Disclosed olanzapine acid salt has the specific water-soluble degree of 50 mcg/ml to 100 mg/ml in this application.
The technician is well known that most chemical reactions do not carry out fully, may be reversible or with some other parallel reactor carry out simultaneously.Usually find starting material or side reaction product as impurity in isolating primary product, therefore, product should further be purified.The simplest method of purification comprises various recrystallizations and precipitation program, if impurity has the physical and chemical performance closely similar with primary product, these programs are more ineffective usually.
When disclosed single stage method prepares olanzapine in according to EP 454436 B1, in the final product olanzapine, find starting material 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine as impurity.
Above-mentioned comment Bioorganic ﹠amp; Medicinal Chemistry Letters, the 7th volume, No. 1, the 25-30 page or leaf, the shortcoming of disclosed reaction is that product darkens in 1997.
By when disclosed two-step approach prepares olanzapine among the patent application WO 04/000847; 4-amino-2-methyl-10H-thieno-[2; 3-b] [1; 5] existence of benzodiazepine hydrochloride is not crucial; but can be used as impurity and find various other similar compounds; 4-(formyl piperazine base)-2-methyl isophthalic acid 0H-thieno-[2,3-b] [1.5] benzodiazepine and N-demethyl olanzapine for example.Contain the impurity of thieno-benzodiazepine loop systems for all these as the part of molecular skeleton; and because it constitutes the major part of molecule, described loop systems is compared physicochemical property for described impurity with olanzapine similarity is conclusive.
Have been found that now rough olanzapine is repeated crystallization can not be separated olanzapine effectively with the impurity of its height correlation.
Therefore need develop the method that other prepares pharmaceutically acceptable pure and decolouring olanzapine.
Brief summary of the invention
We have found that the novel and simple and easy method of purification of olanzapine, comprised olanzapine is changed into its acid salt, separating step, reverts to olanzapine from described additive salt then.
In the first embodiment, the present invention relates to the method for purification of olanzapine, it is characterized in that described method comprises the following steps:
A) olanzapine and organic acid are mixed in organic solvent or ORGANIC SOLVENT MIXTURES with formation olanzapine acid salt,
B) make olanzapine acid salt precipitation and separate and
C) the olanzapine acid salt is changed into olanzapine.
In another embodiment, the present invention relates to prepare the method for N-demethyl olanzapine, comprise and make 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride and piperazine at solvent or comprise in the solvent mixture of at least a fatty alcohol with higher and react.
In another embodiment, the present invention relates to synthetic light 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2 that does not have burgundy or green hue, 3-b] [1,5] method of benzodiazepine (olanzapine), comprise with methylating agent N-demethyl olanzapine N-is methylated, choose wantonly and in organic solvent or ORGANIC SOLVENT MIXTURES, carrying out in the presence of the highly basic.
In another embodiment, the present invention relates to prepare the method for the olanzapine of acid salt form, comprise
A) olanzapine is mixed in solvent or solvent mixture with organic acid and
B) make olanzapine acid salt precipitation and separate by crystal separation.
In another embodiment, the present invention relates to prepare the method for the olanzapine of acid salt form, comprise the following steps: to make 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride and N methyl piperazine react with the generation olanzapine, and the gained olanzapine is changed into its acid salt.
In another embodiment, the present invention relates to the olanzapine of acid salt form, wherein said acid is selected from phenylformic acid and sulfonic acid.
In another embodiment, the present invention relates to prepare the method for olanzapine, prepare by reverting to olanzapine by described acid salt by the olanzapine acid salt.
In another embodiment, the present invention relates to prepare the method for olanzapine crystalline form I, crystal is separated with organic solvent by the acid salt of olanzapine.
In another embodiment, the present invention relates to prepare the method for olanzapine Form II, crystal is separated with organic solvent by the acid salt of olanzapine.
In another embodiment, the present invention relates to the purposes of organic acid in the olanzapine preparation method, wherein by forming the olanzapine acid salt olanzapine of purifying.
In another embodiment; the present invention relates to the preparation method of the N-demethyl olanzapine derivative of formula 2; wherein R is meant organic group; for example ethanoyl, propionyl, chloracetyl etc., comprise the organic acid derivatives that makes N-demethyl olanzapine and organic acid or organic acid that replaces or formula RX or with the organic acid anhydride reaction.Described RX is equivalent to organic acid derivatives, is preferably the organic acid carboxylic acid halides especially, for example acetyl halide, propionyl halogen, chloro-acetyl halide etc., and wherein X is selected from Cl, Br or I, is preferably Cl especially.Used organic acid acid anhydrides can be diacetyl oxide, propionic anhydride, Tetra hydro Phthalic anhydride etc.
In another embodiment, the present invention relates to the olanzapine made by methylation method by N-demethyl olanzapine, this method makes that the content of N-demethyl olanzapine is lower than 0.1% in the final olanzapine product.
In another embodiment, the present invention relates to the preparation method of the olanzapine of acid salt form, comprise the following steps:
A) make the reaction of N-demethyl olanzapine and methylating agent with the generation olanzapine,
B) gained reaction mixture dilute with water is also used acidifying,
C) in reaction mixture, add organic solvent and making and be separated,
D) in and the gained water, and with olanzapine with organic solvent extraction with obtain the organic solvent phase and
E) (wherein R represents organic group to add organic acid or the organic acid that replaces or the organic acid derivatives of above-mentioned formula RX in organic phase; for example ethanoyl, propionyl, chloracetyl; and X is selected from Cl, Br or I, is preferably Cl especially) or above-mentioned organic acid acid anhydrides replace N-demethyl olanzapine derivative with the N-that forms formula 2:
F) choose evaporation gained organic solvent wantonly mutually also with the second organic solvent diluting resistates,
G) in the gained diluting soln or directly in from the olanzapine extraction liquid that extracts described in the step d), add organic acid and
H) separate sedimentary olanzapine acid salt separation by crystalline.
In another embodiment, the present invention relates to the olanzapine made by the N-methylation method by N-demethyl olanzapine, it comprises and is less than 0.05% piperazine 1,4-two 4-bases-(2-methyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine.
In another embodiment, the present invention relates to prepare the method for olanzapine, comprise the following steps:
A) 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride is changed into 2-methyl-4-(1-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine,
B) 2-methyl-4-(1-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine is changed into rough olanzapine,
C) rough olanzapine is changed into its acid salt and
D) acid salt with olanzapine changes into olanzapine.
In another embodiment, (pharmaceutical composition of 4-methyl isophthalic acid-piperazinyl-10H-thieno-[2,3-b] [1,5] benzodiazepine (olanzapine), this olanzapine is made by its acid salt to the present invention relates to comprise 2-methyl-4-.
In another embodiment, the present invention relates to be used to prepare the purposes of the medicament of various mental disorderes of treatment and symptom according to the olanzapine that one of method disclosed by the invention is made.
In another embodiment, the present invention relates to comprise at least a pharmaceutically acceptable composition and the pharmaceutical preparation of the olanzapine made according to one of method disclosed by the invention.
In another embodiment, the present invention relates to the purposes of the olanzapine made according to one of method disclosed by the invention, be used for at least a pharmaceutically acceptable composition useful in preparing drug formulations.
Detailed Description Of The Invention
The invention provides the novel method of purification of olanzapine, comprise olanzapine is changed into its acid salt, separating step, reverts to olanzapine from described additive salt.
Be known that in the prior art situation, form a kind of acid salt of material and make its crystallization from solution, can be successfully with described material from the impurity that can not form acid salt and from forming such salt but purify the very big impurity of its character and described material difference.It is found that, by the olanzapine of the doping impurity of height correlation can by convert it into have excellent purification ability can be from solvent sedimentary acid salt and effectively purifying.Other olanzapine salt, particularly inorganic salt of this and olanzapine itself and some are opposite.We find that the appropriate organic that can be used for preparing the olanzapine acid salt with separating power is the carboxylic acid that contains at least one carboxyl, for example oxalic acid, fumaric acid and phenylformic acid, preferably oxalic acid.Also can use sulfonic acid.
Olanzapine method of purification of the present invention comprises the following steps:
A) olanzapine and organic acid are mixed in organic solvent or ORGANIC SOLVENT MIXTURES with formation olanzapine acid salt,
B) make olanzapine acid salt precipitation and separate and
C) the olanzapine acid salt is changed into olanzapine.
Preferred organic acid is selected from sulfonic acid or carboxylic acid in the step a).Preferred carboxylic acid is selected from oxalic acid, fumaric acid and phenylformic acid.
Preferred organic is selected from tetrahydrofuran (THF), acetone, dimethyl formamide and acetonitrile in the step a).
The preferred organic mixture is the mixture of tetrahydrofuran (THF) and at least a polar solvent in the step a).Preferred polar solvent is selected from dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone (pyrimidinone), 1,3-dimethyl-2-imidazolidone, tetramethyl-urea, methyl-sulphoxide, tetramethylene sulfone, acetone and acetonitrile.
Preferred purification method of the present invention comprises following substep in step (c):
It is i) acid salt of olanzapine is water-soluble,
Ii) the pH value with gained solution is adjusted to about 8-10,
Iii) with olanzapine from water be extracted into organic solvent mutually and
Iv) by solution concentration is separated with crystalline, the acid salt and the organic solvent of olanzapine is separated.
Another embodiment of the present invention is the method for the olanzapine of preparation acid salt form, it is characterized in that described method comprises the following steps:
A) olanzapine is mixed in solvent or solvent mixture with organic solvent (being preferably selected from phenylformic acid and sulfonic acid) and
B) separate by crystalline and make olanzapine acid salt precipitation and separate.
Preferably, the mixture of described organic solvent, organic solvent and polar solvent respectively as hereinbefore.
Another embodiment of the present invention is the method for the olanzapine of preparation olanzapine, preferred crystallized form, it is characterized in that its by the olanzapine acid salt by recovering to make from described salt.
Preferably, described recovering step comprises the substep of aforesaid step (c).
The suitable acidic organic compound that is used for this purification step is commercially available.On the other hand, can be according to prior art (for example at EP454436B1; US5,229,382; Among EP733635B1 or the WO04/089313) the synthetic olanzapine of disclosed synthesis method as the raw material product.
We have found that other method of preparation olanzapine, it can be chosen wantonly according to the disclosed the present invention in front and purify.
Therefore, the present invention further provides by the novel method of 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride via synthetic pure decolouring olanzapine in as the N-demethyl olanzapine of intermediate.The optional then purification process that enters of the rough olanzapine of gained wherein forms the olanzapine acid salt, then with its separation in first step.Thus, still stay in the solution from the impurity of rough olanzapine preparation process.In the further step of purifying, being easy to the olanzapine acid salt changed into does not have dark-toned pure and pharmaceutically acceptable olanzapine.
Also can be used for the olanzapine that forms by single stage method by the described method of purification that olanzapine is changed into its acid salt, in described single stage method, 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine and N-methyl-piperazine reaction, and produce the rough olanzapine that directly enters purification process.Can finally make by the olanzapine that program of the present invention is purified with various crystalline forms, for example I shape or II shape.
In addition, have been found that, when preparing the olanzapine acid salt by the rough olanzapine of making via N-demethyl olanzapine intermediate by two step synthesis methods, N-demethyl olanzapine can precipitate with the acid salt form from solvent, and stays in the finished product as pollutent.Yet, be surprised to find that very much, the derivative of N-demethyl olanzapine, ethanoyl for example can not precipitate from organic solvent and stays in the mixture after forming rough olanzapine acid salt as acid salt.Thus, N-demethyl olanzapine can separate with olanzapine.Described method of purification can guarantee very effectively that any single content of planting impurity of pharmaceutical grade olanzapine is lower than 0.1%, and this method particularly important for removing described N-demethyl olanzapine (its otherwise very difficult separate with olanzapine).Even the content of impurity is very high in the rough olanzapine, also can reduce impurity level significantly.
In addition, we have found that, (4-amino-2-methyl-10H-thieno-[2 just in the first step of olanzapine two step synthesis method, 3-b] [1,5] reaction of benzodiazepine and piperazine), form the by product of the dipolymer that is confirmed as starting compound, wherein two molecule 4-amino-2-methyl-10H-thieno-s [2,3-b] [1,5] benzodiazepine hydrochloride is connected on the nitrogen-atoms of piperazine.The chemistry of this by product is called piperazine 1,4-two 4-bases-(2-methyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine (graphic 4).
Graphic 4
HPLC analysis revealed, the appearance amount of described dimer impurity are about 1-4% of gained N-demethyl olanzapine.We also find, the raw material piperazine produces less described dipolymer during with respect to the amino-2-methyl of the 4-in the reaction mixture-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride molar excess.
In two step of olanzapine synthesis method of the present invention, make the reaction of 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride and piperazine to form N-demethyl olanzapine.Obtain olanzapine (graphic 5) by methylating of described N-demethyl olanzapine then:
Graphic 5
Be surprised to find that, if prepare olanzapine via the separation of N-demethyl olanzapine by two step synthesis methods of the present invention, can be (just: 4-amino-2-methyl-10H-thieno-[2 by dark-brown or green material product, 3-b] [1,5] benzodiazepine hydrochloride) obtain to have required glassy yellow olanzapine.
EP454436B1 discloses the synthetic of olanzapine, comprise and make 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride and excessive N methyl piperazine react in 1: 4 mixture of DMSO and toluene, and this is the reaction (just using the N methyl piperazine substituted-amino) (graphic 4) with the disclosed same type of this paper first step (just using the piperazine substituted-amino).
We are surprised to find that, for the speed of reaction and the reaction yield of described reaction type, use at least a have the branching of higher or not branched aliphatic alcohols be better.According to the present invention, higher is meant and preferably is higher than 100 ℃, more preferably is higher than 115 ℃ boiling point.Preferred aliphatic series alcohol with higher is propyl carbinol.Perhaps, can use and contain at least a the have branching of higher or not branched aliphatic alcohols and at least a solvent mixture, preferably use propyl carbinol with Non-alchoholic solvents of higher.The Non-alchoholic solvents that preferably has higher is an aromatic solvent, especially dimethylbenzene, toluene, ethylbenzene, methyl-phenoxide etc.Suitable mixture is the mixture of propyl carbinol and dimethylbenzene or propyl carbinol and toluene for example, and the ratio of propyl carbinol/aromatic hydrocarbons=30/70 is to 100/0, preferred 40/60 to 70/30.
Can in reaction mixture, add additional inorganic or organic bases to replace excessive piperazine.Preferred alkali is tertiary amine, for example triethylamine, ethyl diisopropylamine or diazabicyclo octane.
When reacting in the solvent system that is comprising propyl carbinol, in reaction mixture, add after the warm water N-demethyl olanzapine precipitated.Gained N-demethyl olanzapine has lost dark-brown or green substantially.By using organic solvent, ester for example, for example washing N-demethyl olanzapines such as ethyl acetate, isopropyl acetate, butylacetate can further be removed residual color.Warm water has about 25 to about 70 ℃, preferably approximately 30 to about 50 ℃ temperature.By using warm water, the block throw out melt into of viscosity is than small-particle.Thus, can realize better filterableness and better quality product (relevant) with color.
Synthetic second goes on foot methylate (referring to graphic 6) of the piperazinyl that is equivalent to N-demethyl olanzapine to form rough olanzapine.For methylating, can use different methylating agents, for example methyl-sulfate or methylmesylate; For example toluenesulphonic acids methyl esters, methanesulfonic methyl esters, trifluoromethayl sulfonic acid methyl esters; Or methyl halogenide, preferable methyl iodine.Reaction can be carried out in different organic solvents, for example ether or cyclic ethers, for example tetrahydrofuran (THF); Ketone, for example acetone; Acid amides, for example dimethyl formamide; Nitrile, for example acetonitrile; The perhaps alcohol or the mixture of described solvent and other solvent, the preferably mixture of tetrahydrofuran (THF) and polar solvent.These polar solvents are acid amides, for example dimethyl formamide, N,N-DIMETHYLACETAMIDE and N-Methyl pyrrolidone; Urea, for example 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone, 1,3-dimethyl-2-imidazolidone and tetramethyl-urea; With other solvent, for example methyl-sulphoxide, tetramethylene sulfone, acetone, acetonitrile etc.This mixture of tetrahydrofuran (THF) and polar solvent is guaranteed in the product higher rate of olanzapine with respect to non-methylating (N-demethyl olanzapine just) and dimethyl product (for example N, N-dimethyl olanzapine) (graphic 6) excellently.
Graphic 6
For described methylation reaction, preferred alkaline condition.Can use different amine, the highly basic of triethylamine, Diisopropylamine, dicyclohexyl amine, ethyl diisopropylamine and diazabicyclo octane or basic metal or alkaline-earth metal for example, for example oxyhydroxide, hydride or alcoholate, for example sodium hydride, hydrolith, potassium tert.-butoxide, sodium hydroxide or potassium, and other mineral alkali, for example salt of wormwood or sodium.After N-demethyl olanzapine methylates under the described conditions, obtain glassy yellow olanzapine without any brown or green hue, it does not require the subsequent removal color.
As above disclosed, must from olanzapine, remove reaction and finish N-demethyl olanzapine residual in the afterreaction mixture.Therefore, the reaction mixture that obtains afterwards that methylates of N-demethyl olanzapine can at first be used organic solvent extraction, for example ether, for example diethyl ether; Ester, for example ethyl acetate; Or preferred chlorating organic solvent, for example methylene dichloride and chloroform.After being separated, can wash organic phase with water.In organic phase, add organic acid or organic acid that replaces or organic acid derivatives or the aforesaid organic acid acid anhydrides of aforesaid formula RX then, replace N-demethyl olanzapine derivative with the N-that forms formula 2.
The suitable reagent that can be used for this reaction is the organic acid and the organic acid derivatives of organic acid, replacement, and for example Mono Chloro Acetic Acid, chlorethamin, benzyl are smelt, Tetra hydro Phthalic anhydride, diacetyl oxide etc.Replace the reaction of N-demethyl olanzapine for the described N-that forms formula 2, can use different amine, for example dicyclohexyl amine, Diisopropylamine, triethylamine, diisopropylethylamine, diazabicyclo octane, quadrol, Isopropylamine, butylamine, diethylamine, dipropyl amine, propylamine, dibutylamine etc., with different mineral alkalis, for example K
2CO
3, Na
2CO
3, NaOH, KOH, LiOH, Ca (OH)
2, NaH etc.
As final step, can choose wantonly by olanzapine being changed into its acid salt it is purified according to the invention described above.In this case, in reaction mixture, add organic acid, for example sulfonic acid or carboxylic acid, preferred oxalic acid, fumaric acid or phenylformic acid etc., more preferably oxalic acid, to form the olanzapine acid salt, it can be precipitated out from mixture after cooling also can filtering.The water-soluble degree of the olanzapine oxalic acid additive salt of making approximately is up to about 800 mg/ml.
Then that the olanzapine acid salt is water-soluble, and add hydrochloric acid so that the pH value is adjusted to about 1.0-5.0, preferred 2.0, thus the olanzapine acid salt is changed into the pure olanzapine of crystalline form I or II.In gained solution, add charcoal.After mixture being stirred about 5 minutes, the filtering charcoal also washes filter cake with water.Filtrate and washing water are merged, add low boiling point organic solvent then, for example diethyl ether, methylene dichloride, chloroform, ethyl acetate etc., preferably methylene dichloride.Use the charcoal treatment reaction mixture under about 2 pH, this is equivalent to the final purification of olanzapine, and can remove above-mentioned dipolymer (piperazine 1,4-two 4-bases-(2-methyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine are referring to graphic 4).Next step is to add alkali, preferred mineral alkali, for example ammonia, K
2CO
3, KOH, NaH, Na
2CO
3, LiOH, Ca (OH)
2Deng, more preferably NaOH is to obtain the pH value of about 7-11, the pH value of preferably approximately 9-10.After obtaining required pH value, can extract mixture with low boiling point organic solvent, wherein can use different solvents, for example ether, for example diethyl ether; Chlorating hydrocarbon, for example methylene dichloride, chloroform; Ester, for example ethyl acetate; Or the like, preferred methylene dichloride.After extraction, can partly remove organic solvent by rotary evaporation, and remaining mixture can be cooled to approximately-20 ℃ to about 0 ℃, preferably approximately-15 ℃ is to about-5 ℃, and is settled out the olanzapine crystalline form I.The gained olanzapine comprises the described dipolymer (piperazine 1,4-two-4-base-(2-methyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine) of very low amount, for example is lower than about 0.05%.
In another embodiment, the invention provides the method for preparing Form II, wherein remove organic solvent in the final step (rather than the part described in the leading portion is removed) fully, add organic solvent then by rotary evaporation.Can use different solvents, for example ether, for example diethyl ether; Nitrile, for example acetonitrile, ester, for example ethyl acetate; Deng, preferred diethyl ether to form olanzapine solution, can go out the olanzapine Form II from this solution precipitation after cooling.
Another embodiment of the present invention is to make the method for olanzapine crystalline form I via the olanzapine acid salt.In order to obtain rough olanzapine, use preassigned reaction among the EP454436B1.Reaction comprises makes N methyl piperazine and the reaction of 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride.There are height boil organic solvent (for example methyl-sulphoxide, N,N-DIMETHYLACETAMIDE, butanols, dimethyl formamide, toluene, dimethylbenzene, ethylbenzene, methyl-phenoxide etc., preferred methyl-sulphoxide) under the situation, ℃ reacts at approximately 80-150 ℃, preferably approximately 115-130.
By the present invention, from gained solution, extract with the gained solution that comprises rough olanzapine after the water treatment with organic solvent, wherein can use different solvents, for example ketone, for example mibk; Chlorating hydrocarbon, for example methylene dichloride and chloroform, preferably methylene dichloride.After this can add organic acid, carboxylic acid for example, for example oxalic acid, fumaric acid, phenylformic acid or sulfonic acid etc. are to form the acid salt of olanzapine.Can filtering olanzapine acid salt, and optional water-soluble, and with organic solvent (for example ketone, for example mibk; Chlorating hydrocarbon, for example methylene dichloride and chloroform) from solution, come together.After this evaporation by solvent separates acid salt.By at first water-soluble and add hydrochloric acid, gained olanzapine acid salt is changed into olanzapine the pH value is adjusted to about 1.0-5.0, preferred 2.0.In gained solution, add charcoal.After mixture being stirred about 5 minutes, the filtering charcoal, and wash filter cake with water.Filtrate and washing water are merged, add low boiling point organic solvent then, for example diethyl ether, methylene dichloride, chloroform, ethyl acetate etc., preferably methylene dichloride.Next step is to add alkali, preferred mineral alkali, for example ammonia, K
2CO
3, KOH, NaH, Na
2CO
3, LiOH, Ca (OH)
2Deng, more preferably NaOH is to obtain the pH value of about 7-11, the pH value of preferably approximately 9-10.After obtaining required pH value, can extract mixture with low boiling point organic solvent, wherein can use different solvents, for example ether, for example diethyl ether; Chlorating hydrocarbon, for example methylene dichloride, chloroform; Ester, for example ethyl acetate; Or the like, preferred methylene dichloride.After extraction, can partly remove organic solvent by rotary evaporation, and remaining mixture can be cooled to approximately-20 ℃ to about 0 ℃, preferably approximately-15 ℃ is to approximately-5 ℃, and the olanzapine crystalline form I is precipitated and filtering.
Another optional method is included in the surplus solution of handling in the last synthesis step from any olanzapine crystallisation step.Can directly use organic acid, carboxylic acid for example, for example oxalic acid, fumaric acid, phenylformic acid or sulfonic acid etc. are handled rest solution after the filtering olanzapine.The olanzapine acid salt of Xing Chenging precipitates immediately thus, or can at first described surplus solution be concentrated by evaporating solvent, and can be more suitable for sedimentary solvent of acid salt or solvent mixture by other, preferably, solution is further diluted by adding methylene dichloride and methanol mixture.Gained olanzapine acid salt can further change into pure olanzapine by said procedure.
Olanzapine and the vehicle made by method of the present invention can be mixed with pharmaceutical preparation according to methods known in the art.The olanzapine of making by the inventive method is adapted at the medicinal application in any pharmaceutical preparation.
Can be used for preventing and/or treating different mental disorderes and symptom, for example central nervous system disorder, schizophrenia, illusion, acute mania, dysthymia disorders etc. subsequently by method of the present invention olanzapine that make and corresponding preparation.
According to the present invention, the method of treatment mental disorder and symptom is provided, for example central nervous system disorder, schizophrenia, illusion, acute mania, dysthymia disorders etc., it comprises the olanzapine that combines the administering therapeutic significant quantity with pharmaceutically acceptable diluent or carrier.
Embodiment
Illustrate by the following example but do not limit the present invention in any way:
Abbreviation:
The DMAC N,N-DIMETHYLACETAMIDE
The DMF dimethyl formamide
DMI 1,3-dimethyl-2-imidazolidone
DMPU 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone
The DMSO methyl-sulphoxide
The NMP N-Methyl pyrrolidone
The preparation of N-demethyl olanzapine
Embodiment 1
10.7 gram merchantable qualityes and dark-brown 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochlorides (0.040 mole) are suspended in 70 milliliters of propyl carbinols and the 30 milliliters of dimethylbenzene, add piperazine (31.5 grams; 0.37 mole), be heated to and reflux and, determine the termination of reaction by HPLC this temperature restir 4 hours.After finishing reaction, evaporating solvent also adds 200 milliliters of warm water.The precipitation that filtering forms, and restrain product (yields: 92%) to produce 11.0 with 20 milliliters of ethyl acetate washings.
Embodiment 2
10.7 gram merchantable qualityes and dark-brown 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride (0.040 mole) are suspended in 100 milliliters of propyl carbinols, add piperazine (31.5 grams; 0.37 mole), be heated to and reflux and, determine the termination of reaction by HPLC this temperature restir 8 hours.After finishing reaction, evaporating solvent also adds 200 milliliters of warm water, and the precipitation that filtering forms restrains product (yields: 97%) with 20 milliliters of ethyl acetate washings to produce 11.7.
Embodiment 3
10.7 gram merchantable qualityes and dark-brown 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochlorides (0.040 mole) are suspended in 50 milliliters of propyl carbinols and the 50 milliliters of toluene, add piperazine (31.5 grams; 0.37 mole), be heated to and reflux and, determine the termination of reaction by HPLC this temperature restir 7 hours.After finishing reaction, evaporating solvent also adds 200 milliliters of warm water.The precipitation that filtering forms, and restrain product (yields: 81%) to produce 9.7 with 20 milliliters of ethyl acetate washings.
Prepare rough olanzapine by N-demethyl olanzapine
Embodiment 4
10 gram N-demethyl olanzapines (0.034 mmole) are dissolved in 240 milliliters of tetrahydrofuran (THF)s, and when stirring, are cooled to-10 ℃.Add 9.4 milliliters of triethylamines and 5 milliliters of (0.080 mole) methyl-iodides.Reaction mixture was stirred 4 hours at-10 ℃, determine the termination of reaction by HPLC.After finishing reaction, add 500 milliliters of softening waters, and the evaporation tetrahydrofuran (THF), the title compound crystallization is a yellow crystals.Filtering precipitate, and wash with water, the rough olanzapine of 8.6 grams (yield: 82%) produced.
Embodiment 5
10 gram N-demethyl olanzapines (0.034 mmole) are dissolved in 240 milliliters of tetrahydrofuran (THF)s, and when stirring, are cooled to-15 ℃.Add 3 gram sodium hydroxide and 5 milliliters of (0.080 mole) methyl-iodides.Reaction mixture was stirred 4 hours at-15 ℃, determine the termination of reaction by HPLC.After finishing reaction, add 500 milliliters of softening waters, and the evaporation tetrahydrofuran (THF), the title compound crystallization is a yellow crystals.The filtering precipitation, and wash with water, the rough olanzapine of 10.3 grams (yield: 98%) produced.
Embodiment 6
10 gram N-demethyl olanzapines (0.034 mmole) are dissolved in 120 milliliters of tetrahydrofuran (THF)s, and when stirring, are cooled to-10 ℃.Add 1.6 gram sodium hydride and 5 milliliters of (0.080 mole) methyl-iodides.Reaction mixture was stirred 3 hours at-10 ℃, determine the termination of reaction by HPLC.After finishing reaction, add 60 milliliters of softening waters, and the evaporation tetrahydrofuran (THF), adding 200 ml methanol then, the title compound crystallization is a yellow crystals.The filtering precipitation, and wash with water, the rough olanzapine of 10.3 grams (yield: 98%) produced.
Embodiment 7
10 gram N-demethyl olanzapines (0.034 mmole) are dissolved in 240 milliliters of tetrahydrofuran (THF)s, and when stirring, are cooled to 0 ℃.Add 4.48 gram potassium tert.-butoxide and 5 milliliters of (0.080 mole) methyl-iodides.Reaction mixture was stirred 2 hours at 0 ℃, determine the termination of reaction by HPLC.After finishing reaction, add 200 milliliters of softening waters, and the evaporation tetrahydrofuran (THF), the title compound crystallization is a yellow crystals.The filtering precipitation, and wash with water, the rough olanzapine of 10.4 grams (yield: 99%) produced.
Embodiment 8
10 gram N-demethyl olanzapines (0.034 mmole) are dissolved in 200 ml methanol.Add 20 gram salt of wormwood and 4.4 milliliters of (0.046 mole) methyl-sulfates.Reaction mixture was stirred 2 hours at 25 ℃, determine the termination of reaction by HPLC.After finishing reaction, add 350 milliliters of softening waters, and evaporation methyl alcohol, the title compound crystallization is a yellow crystals.The filtering precipitation, and wash with water, the rough olanzapine of 6.3 grams (yield: 60%) produced.
Embodiment 9
10 gram N-demethyl olanzapines (0.034 mmole) are dissolved in 200 milliliters of acetone, and when stirring, are cooled to-10 ℃.Add 20 gram salt of wormwood and 4.4 milliliters of (0.046 mole) methyl-sulfates.Reaction mixture was stirred 4 hours at-10 ℃, determine the termination of reaction by HPLC.After finishing reaction, add 350 milliliters of softening waters, and evaporation acetone, the title compound crystallization is a yellow crystals.The filtering precipitation, and wash with water, the rough olanzapine of 4.8 grams (yield: 46%) produced.
Prepare the olanzapine acid salt by isolating rough olanzapine
The preparation of olanzapine oxalate
Embodiment 10
In the solution of 0.45 gram olanzapine in 18 milliliters of DMI, add the solution of 0.26 gram oxalic acid in 0.5 milliliter of DMI.After 10 minutes, begin crystallization 25 ℃ of stirrings.Suspension was stirred 1 hour at 25 ℃, in ice bath, continue then to stir 1 hour.Filtering separation product then.With product with 25 milliliters of washed with dichloromethane, and 50 ℃ dry 2 hours in a vacuum.
Output: 0.27 gram yellow crystal powder
mp：235℃
1H NMR：(300.1MHz，DMSO-d6)
δ=2.275 (s, 3H, CH
3), 2.625 (s, 4H, NCH
3CO), 2.754 (s, 3H, CH
3), 3.141 (4H, piperazinyl-H), 3.193 (s, 4H, CH
2NCH
3CO), 3.582 (4H, piperazinyl-H), 6.436 (s, 1H, thiophenyl-H), 6.579 (s, 4H, HC=CH), 6.651 (s, 6.74 (m, 1H, Ar), 6.909 (m, 3H, Ar), 7.954 (s, 1H, NH), 9.301 (wide, 3H, NH, OH).
Embodiment 11
In the solution of 0.45 gram olanzapine in 18 milliliters of DMI, add the solution of 0.26 gram oxalic acid in 0.5 milliliter of DMAC.After 10 minutes, begin crystallization 25 ℃ of stirrings.Suspension was stirred 1 hour at 25 ℃, in ice bath, continue then to stir 1 hour.Filtering separation product then.With product with 25 milliliters of washed with dichloromethane, and 50 ℃ dry 2 hours in a vacuum.
Output: 0.75 gram yellow crystal powder
mp：221℃
1H NMR：(300.1MHz，DMSO-d6)
δ=1.955 (s, 3H, CH
3CON), (s, 3H, 2.275 (s, 3H, CH
3), 2.625 (s, 4H, NCH
3CO), 2.707 and 2.754 (2s, 6H, CH
3, CONCH
3), 2.940 (s, 3H, CONCH
3), 3.180 (4H, piperazinyl-H), 3.583 (4H, piperazinyl-H), 6.416 (s, 1H, thiophenyl-H), 6.416 (m, 1H, Ar), 6.579 (m, 3H, Ar), 7.846 (s, 1H, NH), 8.787 (wide, 3H, NH, OH).
Embodiment 12
In the suspension of 0.45 gram olanzapine in 18 milliliters of acetonitriles, add the solution of 0.26 gram oxalic acid in 2 milliliters of acetonitriles.Suspension was stirred 1 hour at 25 ℃, in ice bath, continue then to stir 1 hour.Filtering separation product then, with 25 milliliters of acetonitriles washings, and 60 ℃ dry 15 hours in a vacuum.
Output: 0.58 gram yellow crystal powder
mp：235℃
Analyze: 73.5%
Oxalic acid: 24.3%
Acetonitrile: 3 moles of %
Embodiment 13
In the suspension of 0.45 gram olanzapine in 18 milliliters of acetonitriles, add the solution of 0.26 gram oxalic acid in 0.5 milliliter of ethanol.After adding oxalic acid solution, product begins crystallization from solution.Suspension was stirred 1 hour at 25 ℃, in ice bath, continue then to stir 1 hour.Filtering separation product then.With 25 milliliters of washing with alcohol products, and 60 ℃ dry in a vacuum 2 hours.
Output: 0.56 gram yellow crystal powder
mp：224℃
Analyze: 75.8%
Oxalic acid: 24.0%
Embodiment 14
In the solution of 0.45 gram olanzapine in 18 milliliters of Virahols, add the solution of 0.26 gram oxalic acid in 2 milliliters of Virahols.After adding oxalic acid solution, the beginning crystallization.Suspension was stirred 1 hour at 25 ℃, in ice bath, continue then to stir 1 hour.Filtering separation product then, with 25 milliliters of washed with isopropyl alcohol, and 60 ℃ dry 15 hours in a vacuum.
Output: 0.60 gram yellow crystal powder
mp：230℃
Analyze: 65.18%
Oxalic acid: 21.5%
Virahol: 94 moles of %
The preparation of olanzapine fumarate
Embodiment 15
In the solution of 0.45 gram olanzapine in 18 milliliters of Virahols, add 0.26 gram fumaric acid.The suspension that forms was stirred 1 hour at 25 ℃, in ice bath, continue then to stir 1 hour.Filtering separation product then.With 25 milliliters of washed with isopropyl alcohol products, and 60 ℃ dry in a vacuum 15 hours.
Output: 0.55 gram yellow crystal powder
mp：231℃
Analyze: 75.5%
Fumaric acid: 17.3%
Virahol: 50 moles of %
1H NMR：(300.1MHz，DMSO-d6)
δ=2.334 (s, 3H, CH
3), 2.443 (s, 3H, CH
3), 2.729 (4H, piperazinyl-H), 3.434 (4H, piperazinyl-H), 5.753 (s, 1.36H, CH
2Cl
2), 6.346 (s, 1H, thiophenyl-H), 6.579 (s, 4H, COHC=CHCO), 6.651 (s, 6,643 (m, 1H, ArH), 6.834 (m, 3H, Ar), 7.634 (s, 1H, NH).
The preparation of olanzapine benzoate
Embodiment 16
In the solution of 0.45 gram olanzapine in 18 milliliters of acetone, add 0.26 gram phenylformic acid.The suspension that forms was stirred 1 hour at 25 ℃, in ice bath, continue then to stir 1 hour.Filtering separation product then.With 25 milliliters of washed with isopropyl alcohol products, and 60 ℃ dry in a vacuum 15 hours.
Output: 0.60 gram yellow crystal powder
mp：205℃
Analyze: 70.0%
Phenylformic acid: 26.1%
Acetone: 5.2 moles of %
1H NMR：(300.1MHz，DMSO-d6)
δ=2.334 (s, 3H, CH
3), 2.443 (s, 3H, CH
3), 2.729 (4H, piperazinyl-H), 3.434 (4H, piperazinyl-H), 6.365 (s, 1H, thiophenyl-H), 6.579 (s, 4H, COHC=CHCO), 6.651 (s, 6,643 (m, 1H, ArH), 6.834 (m, 3H, ArH), 7.686 (s, 1H, NH).
With the beginning that methylates of N-demethyl olanzapine, directly the synthesis method by olanzapine prepares the olanzapine acid salt
The preparation of olanzapine oxalate
Embodiment 17
180 milliliters of THF and 120 milliliter 1, the solution in the mixture of 3-methylimidazole alkane ketone (DMI) is cooled to approximately-20 ℃ with 12.0 gram N-demethyl olanzapines (0.040 mole).At-19 ℃, in solution, add 8.19 gram Diisopropylamines, add 13.7 gram methyl-iodides (0.097 mole) then.Reaction mixture after 45 minutes, is added 6.4 milliliters of concentrated hydrochloric acids and the solution of 6.36 gram thiocarbamides in 50 ml waters-19 ℃ of stirrings, and reaction mixture was stirred 15 minutes at 20 ℃.Add after 50 ml waters, mixture is evaporated to about 160 milliliters under the gentle 50-60 millibar of 35 ℃ bath.Add 400 ml waters and 120 milliliters of methylene dichloride then, and the pH value is adjusted to 2.0 with 6N HCl.After being separated, with water with twice of 120 milliliters of washed with dichloromethane.At aqueous phase, add 180 milliliters of methylene dichloride, and adding 1N NaOH is adjusted to 9.0 with the pH value.After stirring 5 minutes, separate each phase, and with alkaline water with twice of 90 milliliters of dichloromethane extraction.Merge organic phase, and mixture is diluted with 37.5 methyl alcohol, and under agitation in 15 minutes, add the solution of 7.46 gram oxalic acid in 10.5 ml methanol.Gained suspension was stirred about 1 hour at about 20 ℃, stirred 1 hour at about 0 ℃ then.
The filtering separation product, with 100 milliliters of washed with dichloromethane and 50 ℃ dry in a vacuum 2 hours.
Output: 15.15 grams (69.2%)
mp： 228℃
Analyze: 54.1%
HPLC-purity: 98.2 area %
N-demethyl olanzapine: 0.95 area %
Oxalic acid: 31.6%
DMI:6 mole %
Methylene dichloride: 0.5 mole of %
Embodiment 18
The 12.0 gram solution of N-demethyl olanzapines (0.040 mole) in 240 milliliters of N,N-DIMETHYLACETAMIDEs (DMAC) are cooled to approximately-20 ℃.At-20 ℃, in solution, add 8.19 gram Diisopropylamines, add 7.19 gram methyl-iodides (0.050 mole) then.Reaction mixture after 95 minutes, is added 6.4 milliliters of concentrated hydrochloric acids and the solution of 6.36 gram thiocarbamides in 50 ml waters-20 ℃ of stirrings, and reaction mixture was stirred 15 minutes at 20 ℃.Add 400 ml waters and 120 milliliters of methylene dichloride then, and the pH value is adjusted to 2.0 with 6N HCl.After being separated, with water with twice of 140 milliliters of washed with dichloromethane.At aqueous phase, add 180 milliliters of methylene dichloride, and adding 1NNaOH is adjusted to 9.0 with the pH value.After stirring 5 minutes, separate each phase, and with alkaline water with twice of 90 milliliters of dichloromethane extraction.Merge organic phase, and add 380 milligrams of diacetyl oxides, and mixture was stirred 5 minutes.Then mixture is diluted with 37.5 methyl alcohol, and under agitation in 15 minutes, add the solution of 7.46 gram oxalic acid in 10.5 ml methanol.Gained suspension was stirred about 1 hour at about 20 ℃, stirred 1 hour at about 0 ℃ then.The filtering separation product, with 100 milliliters of washed with dichloromethane and 25 ℃ dry in a vacuum 15 hours.
Output: 13.76 grams (72.0%)
mp： 233℃
Analyze: 59.4%
HPLC-purity: 98.3 area %
N-demethyl olanzapine: 0.15 area %
Oxalic acid: 29.1%
Methylene dichloride: 69.9 moles of %
DMAC:2.3 mole %
Embodiment 19
At 240 milliliter 1,3-dimethyl-3,4,5,6-tetrahydrochysene-1, the solution in the 3-pyrimidone are cooled to approximately-20 ℃ with 12.0 gram N-demethyl olanzapines (0.040 mole).At-20 ℃, in solution, add 8.19 gram Diisopropylamines, add 7.57 gram methyl-iodides (0.053 mole) then.Reaction mixture after 60 minutes, is added 7.2 milliliters of concentrated hydrochloric acids and the solution of 6.36 gram thiocarbamides in 50 ml waters-20 ℃ of stirrings, and reaction mixture is heated to 20 ℃, and stirred 5 minutes at uniform temp.Add 400 ml waters and 120 milliliters of methylene dichloride then, and the pH value is adjusted to 2.0 with 6N HCl.After separating layer, with water with twice of 120 milliliters of washed with dichloromethane.At aqueous phase, add 180 milliliters of methylene dichloride, and adding 1N NaOH is adjusted to 9.0 with the pH value.After stirring 5 minutes, separate each layer, and with alkaline water layer with twice of 90 milliliters of dichloromethane extraction.Merge organic layer, and add 380 milligrams of diacetyl oxides, and mixture was stirred 5 minutes.Evaporating solvent in a vacuum then, and the oiliness resistates is dissolved in the mixture of 360 milliliters of methylene dichloride, 37.5 ml methanol and 0.72 ml water.The crystal seed that in this solution, adds the olanzapine oxalate, and when stirring, in 20 minutes, add the solution of 7.71 gram oxalic acid in 10.5 ml methanol.Gained suspension was stirred about 1 hour at about 25 ℃, stirred 1 hour at about 0 ℃ then.The filtering separation product, with 100 milliliters of washed with dichloromethane and 60 ℃ dry in a vacuum 15 hours.
Output: 14.8 gram (82.4%) yellow crystal powder
mp： 229℃
Analyze: 64.1%
HPLC-purity: 99.5 area %
N-demethyl olanzapine:＜0.1 area %
Oxalic acid: 32.4%
Methylene dichloride: 10.4 moles of % (50 ℃ of dryings 24 hours)
DMPU:0.5 mole %
Embodiment 20
With 30.0 gram 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5]-benzodiazepine hydrochlorides (0.113 mole) and the mixture heating up to 117 of 81 milliliters of N methyl piperazines (0.729 mole) in 186 milliliters of DMSO ℃.Under this temperature, stir and make nitrogen bubble pass through after the mixture 17 hours gained solution to be cooled to room temperature (R.T.), add 570 milliliters of methylene dichloride and 570 ml waters then.After mixture is stirred 5 minutes, separate each layer.With alkaline water layer with 300 milliliters of dichloromethane extractions.In the organic layer that merges, add 250 ml waters, and adding 6M HCl is adjusted to 2.0 with the pH value.At layer after separating, with organic layer with 90 ml water extracting twice.Acid water layer with 4.5 gram charcoal treatment merging.Stir after 5 minutes, the filtering charcoal, and filter cake washed with 100 ml waters.Merging filtrate and washing water, and after adding 950 milliliters of methylene dichloride, add 5MNaOH the pH value is adjusted to 9.0.Layer after separating, with alkaline water layer with 125 milliliters of dichloromethane extractions.Merge organic layer, and evaporation in a vacuum.The oiliness resistates is dissolved in the mixture of 1075 milliliters of methylene dichloride, 140 ml methanol and 3.6 ml waters, and is heated to about 29-30 ℃.In solution, add after the olanzapine oxalate crystal seed, in 30 minutes, add the solution of 18.7 gram oxalic acid in 27 ml methanol.Gained suspension was stirred about 1 hour at about 25 ℃, stirred 2 hours at about 0 ℃ then.The filtering separation product, with 150 milliliters of washed with dichloromethane and 60 ℃ dry in a vacuum 6 hours.
Output: 43.3 gram (82.2%) yellow crystal powder
mp： 224℃
Analyze: 62.7%
HPLC-purity: 99.6 area %
Oxalic acid: 26.1%
Methylene dichloride: 22 moles of %
The preparation of olanzapine fumarate
Embodiment 21
In the solution of olanzapine (, making) in the mixture of 360 milliliters of methylene dichloride, 37.5 methyl alcohol and 0.72 milligram of water, add olanzapine fumarate crystal seed and 0.96 gram fumaric acid by 12.0 gram raw material N-demethyl olanzapines according to embodiment 16.Gained suspension was stirred about 1 hour at 25 ℃, stirred 2 hours at about 0 ℃ then.The filtering separation product, with 150 milliliters of washed with dichloromethane, and 60 ℃ dry in a vacuum 6 hours.
Output: 11.4 gram (65.7%) light yellow crystalline powders
mp： 217℃
Analyze: 65.7%
HPLC-purity: 97.8 area %
N-demethyl olanzapine: 0.15 area %
Fumaric acid: 23.2%
Methylene dichloride: 48 moles of %
Embodiment 22
Will be according to embodiment 5 by 30.0 gram 4-amino-2-methyl-10H-thieno-s [2,3-b] the olanzapine solution made in 186 milliliters of DMSO of [1,5]-benzodiazepine hydrochloride (0.113 mole) and 81 milliliters of N methyl piperazines (0.729 mole) is heated to 29-30 ℃.Under this temperature, add olanzapine fumarate crystal seed and 14.4 gram fumaric acid.Gained suspension was stirred about 1 hour at 29-30 ℃, stirred 2 hours at about 0 ℃ then.The filtering separation product, with 150 milliliters of washed with dichloromethane and 60 ℃ dry in a vacuum 6 hours.
Output: 41.9 gram (85.2%) light yellow crystalline powders
mp： 217℃
Analyze: 68.5%
HPLC-purity: 99.7 area %
Fumaric acid: 23.0%
Methylene dichloride: 48 moles of %
Prepare pure olanzapine crystalline form I by the olanzapine oxalate
Embodiment 23
7.40 gram olanzapine oxalate are dissolved in 75 ml waters and add 6N HCl the pH value of solution value is adjusted to 2.0.In the clear solution of gained olanzapine oxalate, add 0.75 gram charcoal.Stir after 5 minutes, the filtering charcoal also washs filter cake with 50 ml waters.Merging filtrate and washing water, and after adding 125 milliliters of methylene dichloride, interpolation 1N NaOH is adjusted to 9.0 with the pH value of combined mixture.Stir after 5 minutes, separate each layer, and with 25 milliliters of dichloromethane extraction waters.Organic layer is merged, and after with the yellow soda ash drying, solution is concentrated into 27 ml volumes in a vacuum.Then concentrated solution is heated to reflux temperature under normal pressure, and after the crystal seed that adds the olanzapine crystalline form I, solution is cooled off on ice bath immediately.Continue to add described crystal seed, begin crystallization until olanzapine.Gained suspension was stirred on ice bath 15 minutes, approximately-20 ℃ stirring 15 minutes then.Filtering separation olanzapine then.Washed with dichloromethane filter cake with 3 milliliters-20 ℃.With product 25 ℃ dry in a vacuum two days.
Output: 3.63 grams (72.6%)
HPLC-purity: 99.9%
IR-is identical with olanzapine crystalline form I object of reference
XRD-is identical with olanzapine crystalline form I object of reference
Prepare pure olanzapine Form II by the olanzapine oxalate
Embodiment 24
7.40 gram olanzapine oxalate are dissolved in 75 ml waters, and adding 6N HCl is adjusted to 2.0 with the pH value of solution value.In the clear solution of gained olanzapine oxalate, add 0.75 gram charcoal.Stir after 5 minutes, the filtering charcoal also washs filter cake with 50 ml waters.
Merging filtrate and washing water, and after adding 125 milliliters of methylene dichloride, interpolation 1N NaOH is adjusted to 8-10 with the pH value of the mixture of merging.Stir after 5 minutes, separate each layer, and with 25 milliliters of dichloromethane extraction waters.Organic layer is merged, and the evaporation methylene dichloride.Add ethyl acetate then, and olanzapine begins crystallization.Gained suspension was stirred on ice bath 15 minutes.Filtering separation olanzapine then.With product 60 ℃ dry in a vacuum 2 hours.
Output: 3.4 grams
HPLC-purity: 99.9%
IR-is identical with olanzapine Form II object of reference
XRD-is identical with olanzapine Form II object of reference
Prepare pure olanzapine by N-demethyl olanzapine via the olanzapine acid salt
Embodiment 25
The 20.0 gram solution of N-demethyl olanzapines (0.067 mole) in the mixture of 150 milliliters of THF and 60 milliliters of DMAC are cooled to approximately-15 ℃.In reaction mixture, add 20 milliliters of Diisopropylamines at-15 ℃, in 30-40 minute, be added on the 6 milliliters of methyl-iodides (0.96 mole) among 30 milliliters of THF then.With reaction mixture at-5 to-10 ℃ of restir after 60 minutes, add 16 milliliters of concentrated hydrochloric acids in 100 ml waters with the solution of 3.3 gram thiocarbamides in 100 ml waters, and reaction mixture stirred 15 minutes at 20 ℃.
THF is evaporated to about 200 milliliters volume under the pressure of 35 ℃ the gentle 50-60 millibar of bath.Add 300 milliliters of methylene dichloride then, and the pH value is adjusted to 8.9-9 with 40%NaOH.After being separated, with water with twice of 100 milliliters of washed with dichloromethane.Merge organic phase also with 100 ml waters washing five times.Merge organic phase, add 0.5 ml acetic anhydride, and mixture was stirred 5 minutes.In 15 minutes, add the solution of 10.34 gram two oxalic acid hydrates in 40 ml methanol.Gained suspension was stirred about 1 hour at about 20 ℃, stirred 1 hour at about 0 ℃ then.The filtering separation product, with 100 milliliters of washed with dichloromethane and 50 ℃ dry in a vacuum 2 hours.
Output: 25.1 grams
25 gram olanzapine oxalate are dissolved in 250 ml waters, and interpolation 6N HCl is adjusted to 2.0 with the pH value of solution value.In the clear solution of gained olanzapine oxalate, add 2.5 gram charcoals.Stir after 5 minutes, the filtering charcoal also washs filter cake with 50 ml waters.Merging filtrate and washing water, and after adding 300 milliliters of methylene dichloride, interpolation 10N NaOH will merge the pH value and be adjusted to 9-10.Stir after 5 minutes, separate each layer, and with 50 milliliters of dichloromethane extraction waters.Organic layer is merged, and solution is concentrated into 50 ml volumes in a vacuum.Then concentrated solution is heated to reflux temperature under normal pressure, and after the crystal seed that adds the olanzapine crystalline form I, solution is cooled off on ice bath immediately.Continue to add described crystal seed, begin crystallization until olanzapine.Gained suspension was stirred on ice bath 15 minutes, approximately-20 ℃ stirring 15 minutes then.Filtering separation olanzapine then.Washed with dichloromethane filter cake with 10 milliliters-20 ℃.With product 80 ℃ dry in a vacuum 4 hours.
Output: 11.5 grams
Table 1 has shown intermediate olanzapine oxalate and the analytical results of the final product olanzapine made according to the method described in the embodiment 16.
Table 1:
| The olanzapine oxalate | Olanzapine | |
| HPLC-purity | 98.3％ | 99.8％ |
| m.p. | 228℃ | 191℃ |
| N-demethyl olanzapine | ≤0.10％ | ≤0.05％ |
| N, N-dimethyl olanzapine | ≤1.0％ | ≤0.05％ |
| The ethanoyl olanzapine | ≤0.20％ | ≤0.05％ |
| Piperazine 1,4-two-4-base-(2-methyl)-10H-thieno-[2,3-b] [1,5]-benzodiazepines (dipolymer) | ≤0.6％ | ≤0.05％ |
The description that HPLC analyzes:
In Waters Alliance 2695 separation modules, detector PDA 2996, software Empower5.0, carry out HPLC.Buffer reagent is 15mM NaH
2PO
4, pH=6.2:2.34 restrains NaH
2PO
4* H
2The O/1000 ml water is regulated pH value to 6.2 with 5M NaOH
Chromatographiccondition:
1. moving phase:
A: buffer reagent 15mM NaH
2PO
4, pH=6.2/ACN/MeOH 70/20/10 (v/v/v)
B: buffer reagent 15mM NaH
2PO
4, pH=6.2/MeOH 25/75 (v/v)
2. post: BetaBasic C-83 μ m, 100 * 4.6 millimeters
3. temperature: 30 ℃
4. flow velocity: 0.55 ml/min
5. wavelength: 254 nanometers
6. injection volume: 5 liters
7. gradient table:
t ％A ％B
0 83 17
12 83 17
25 0 100
45 0 100
46 83 17
1The description that H NMR analyzes:
On Bruker Avance 300 equipment, use standard instrument program record
1The H spectrum.Sample is dissolved in DMSO-d6 with the concentration of about 15 mg/ml and measures at ambient temperature.Use solvents signals as interior mark: for
1H NMR2.50ppm.For
1H, operating frequency is 300MHz.
Claims (43)
1. the method for purification of olanzapine is characterized in that described method comprises the following steps:
A) olanzapine and organic acid are mixed in organic solvent or ORGANIC SOLVENT MIXTURES with formation olanzapine acid salt,
B) make described olanzapine acid salt precipitation and separate and
C) described olanzapine acid salt is changed into olanzapine.
2. according to the process of claim 1 wherein that the organic acid in the step (a) is selected from the group of being made up of sulfonic acid or carboxylic acid.
3. according to the method for claim 2, wherein carboxylic acid is selected from the group of being made up of fumaric acid and phenylformic acid.
4. according to the process of claim 1 wherein that the organic solvent in the step (a) is selected from the group of being made up of tetrahydrofuran (THF), acetone, dimethyl formamide and acetonitrile.
5. according to the process of claim 1 wherein that the ORGANIC SOLVENT MIXTURES in the step (a) is the mixture of tetrahydrofuran (THF) and at least a polar solvent.
6. according to the method for claim 5, wherein said polar solvent is selected from by dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone, 1, the group that 3-dimethyl-2-imidazolidone, tetramethyl-urea, methyl-sulphoxide, tetramethylene sulfone, acetone and acetonitrile are formed.
7. according to the method for claim 1, it is characterized in that step (c) comprises following substep:
It is i) acid salt of olanzapine is water-soluble,
Ii) the pH value with gained solution is adjusted to about 8-10,
Iii) with olanzapine from water be extracted into organic solvent mutually and
Iv) by solution concentration is separated with crystalline, the described acid salt and the organic solvent of olanzapine is separated.
8. by 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] method of the synthetic N-demethyl olanzapine of benzodiazepine and piperazine is characterized in that describedly syntheticly being at solvent or comprising in the solvent mixture of at least a fatty alcohol with higher and carry out.
9. according to the N-demethyl olanzapine synthesis method of claim 8, wherein said solvent comprises propyl carbinol.
10. according to the N-demethyl olanzapine synthesis method of claim 8, wherein said solvent mixture comprises propyl carbinol and at least a aromatic hydrocarbons with higher.
11. according to the N-demethyl olanzapine synthesis method of claim 8, wherein said aromatic hydrocarbons with higher is dimethylbenzene and/or toluene.
12. according to the N-demethyl olanzapine synthesis method of claim 8, wherein with respect to 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine, excessive interpolation piperazine.
13., wherein in reaction mixture, add extra inorganic or organic bases according to the N-demethyl olanzapine synthesis method of claim 8.
14. the N-demethyl olanzapine synthesis method according to claim 8 to 13 is characterized in that after described method, makes N-demethyl olanzapine precipitated and washs with ester with warm water.
15. according to the N-demethyl olanzapine synthesis method of claim 14, wherein said ester is selected from the group of being made up of ethyl acetate, propyl acetate and butylacetate.
16. there is not light 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2 of burgundy or green hue, 3-b] [1,5] preparation method of benzodiazepine (being olanzapine), it is characterized in that described method comprises with methylating agent and in organic solvent or ORGANIC SOLVENT MIXTURES N-demethyl olanzapine N-being methylated.
17. according to the olanzapine preparation method of claim 16, wherein N-demethyl olanzapine is according to the disclosed method preparation of claim 8 to 15.
18. according to the olanzapine preparation method of claim 16, wherein said method further comprises as the disclosed olanzapine purification step of claim 1 to 7.
19. the method for the olanzapine of preparation acid salt form is characterized in that described method comprises the following steps:
A) olanzapine is mixed in solvent or solvent mixture with organic acid and
B) separate by crystalline and make described olanzapine acid salt precipitation and separate.
20. according to the method for claim 19, wherein said organic acid is selected from the group of being made up of phenylformic acid and sulfonic acid.
21. according to the method for claim 19, wherein said organic solvent, ORGANIC SOLVENT MIXTURES and polar solvent are respectively described in claim 4,5 and 6.
22. the method for the olanzapine of preparation acid salt form is characterized in that described method comprises the following steps:
A) make the reaction of 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride and N methyl piperazine with produce olanzapine and
B) the gained olanzapine is changed into its acid salt.
23., it is characterized in that step b) comprises following substep according to the method for claim 22:
I) with gained reaction mixture dilute with water,
Ii) with the dilution the reaction mixture organic solvent extraction,
Iii) evaporate organic phase, and with the second solvent cut resistates obtaining solution,
Iv) in solution, add organic acid so that olanzapine acid salt precipitation and
V) separate sedimentary olanzapine acid salt is separated by crystalline.
24. the method for the olanzapine of preparation acid salt form is characterized in that described method comprises the following steps:
A) make the reaction of N-demethyl olanzapine and methylating agent with the generation olanzapine,
B) gained reaction mixture dilute with water is also used acidifying,
C) in reaction mixture, add organic solvent and making and be separated,
D) in and the gained water, and with olanzapine with organic solvent extraction with obtain the organic solvent phase and
E) in organic phase, add organic acid or the organic acid of replacement or organic acid derivatives or the organic acid acid anhydrides of formula RX; R represents organic group among the formula RX, for example ethanoyl, propionyl, chloracetyl, and X is selected from Cl, Br or I; thereby the N-demethyl olanzapine derivative that the N-that forms formula 2 replaces
F) optional evaporation gained organic solvent phase, and with the second organic solvent diluting resistates,
G) in the gained diluting soln or directly deriving from add in the olanzapine extraction liquid that extracts described in the step d) organic acid and
H) separate sedimentary olanzapine acid salt separation by crystalline.
25. according to the method for claim 24, wherein step (c) and (d) in organic solvent be the chlorating solvent.
26. according to the method for claim 25, wherein said chlorating solvent is a methylene dichloride.
27. according to the method for claim 24, wherein step (c) and (d) in organic solvent be methylene dichloride, and described second solvent in the step (f) is a methyl alcohol.
28., it is characterized in that comprising that the residual solution that obtains separating final olanzapine with organic acid thereafter handles according to the method for preparing the olanzapine acid salt of claim 19 to 27.
29. the method for the olanzapine of preparation olanzapine, preferred crystallized form is characterized in that it is prepared by reverting to olanzapine from described salt by the olanzapine acid salt.
30. according to claim 29 prepare the method for olanzapine by the olanzapine acid salt, it is characterized in that it comprises substep as claimed in claim 1.
31. according to claim 29-30 prepare the method for olanzapine crystalline form I by the olanzapine acid salt, crystal is separated with organic solvent.
32. according to claim 29-30 prepare the method for olanzapine Form II by the olanzapine acid salt, crystal is separated with one or more organic solvents.
33. prepare the method for olanzapine, comprise the following steps:
A) 4-amino-2-methyl-10H-thieno-[2,3-b] [1,5] benzodiazepine hydrochloride is changed into 2-methyl-4-(1-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine,
B) 2-methyl-4-(1-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine is changed into rough olanzapine,
C) rough olanzapine is changed into its acid salt and
D) acid salt with olanzapine changes into olanzapine.
34. the method for the N-demethyl olanzapine derivative of preparation formula 2 as claimed in claim 24 is included in the organic acid derivatives or the organic acid acid anhydrides that add in the N-demethyl olanzapine as being defined as RX in the claim 24.
35. according to the olanzapine that disclosed any preceding method among claim 1-7 and the 29-33 is made, the content that it is characterized in that N-demethyl olanzapine in the final olanzapine product is less than 0-1%.
36. according to the olanzapine that disclosed any preceding method among claim 1-7,16-18 and the 29-33 is made, it contains and is less than 0.05% piperazine 1,4-two-4-base-(2-methyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine.
37. olanzapine, it is and the organic acid acid salt form that is selected from phenylformic acid and sulfonic acid.
38.2-the phenylformic acid additive salt of methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno-[2,3-b] [1,5] benzodiazepine.
39. pharmaceutical preparation comprises olanzapine and at least a pharmaceutically acceptable composition, it is characterized in that olanzapine is by making according to the method for claim 1-7,16-18 or 29-33.
40. the purposes of organic acid in the olanzapine preparation method is wherein by forming acid salt purification olanzapine.
41., be used to prepare the medicament of treatment mental disorder and symptom by the purposes of the olanzapine made according to the method for claim 1-7,16-18 or 29-33.
42. the purposes by the olanzapine made according to the method for claim 1-7,16-18 or 29-33 is used for at least a pharmaceutically acceptable composition useful in preparing drug formulations.
43. the method for treatment mental disorder and symptom, for example central nervous system disorder, schizophrenia, illusion, acute mania, dysthymia disorders etc., it comprises the olanzapine made according to the method for claim 1-7,16-18 or 29-33 of passing through that combines the administering therapeutic significant quantity with pharmaceutically acceptable diluent or carrier.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200400079A SI21747A (en) | 2004-03-18 | 2004-03-18 | SYNTHESIS OF 2-METHYL-4-(4-METHYL-1-PIPERAZINYL)-10H-THIENO(2,3 b)(1,5)BENZODIAZEPE |
| SIP200400079 | 2004-03-18 | ||
| SIP200400311 | 2004-11-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101084222A true CN101084222A (en) | 2007-12-05 |
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ID=35265796
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200580015935 Pending CN101084222A (en) | 2004-03-18 | 2005-03-17 | Synthesis of 2-methyl-4-(4-methyl-1-piperazinyl)-10h-thieno[2, 3-b][1,5]benzodiazepine and salts thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101084222A (en) |
| SI (1) | SI21747A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102199162A (en) * | 2011-03-30 | 2011-09-28 | 安徽美诺华药物化学有限公司 | Preparation method for olanzapine intermediate compound |
| CN102924470A (en) * | 2011-08-31 | 2013-02-13 | 江苏豪森药业股份有限公司 | Olanzapine preparation method |
| WO2021224830A1 (en) * | 2020-05-05 | 2021-11-11 | Syneurx International (Taiwan) Corp. | Salts of neuroceuticals and uses thereof |
-
2004
- 2004-03-18 SI SI200400079A patent/SI21747A/en not_active IP Right Cessation
-
2005
- 2005-03-17 CN CN 200580015935 patent/CN101084222A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102199162A (en) * | 2011-03-30 | 2011-09-28 | 安徽美诺华药物化学有限公司 | Preparation method for olanzapine intermediate compound |
| CN102199162B (en) * | 2011-03-30 | 2013-06-05 | 安徽美诺华药物化学有限公司 | Preparation method for olanzapine intermediate compound |
| CN102924470A (en) * | 2011-08-31 | 2013-02-13 | 江苏豪森药业股份有限公司 | Olanzapine preparation method |
| CN102924470B (en) * | 2011-08-31 | 2014-12-03 | 江苏豪森药业股份有限公司 | Novel olanzapine preparation method |
| WO2021224830A1 (en) * | 2020-05-05 | 2021-11-11 | Syneurx International (Taiwan) Corp. | Salts of neuroceuticals and uses thereof |
| TWI803867B (en) * | 2020-05-05 | 2023-06-01 | 心悅生醫股份有限公司 | Salts of neuroceuticals and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| SI21747A (en) | 2005-10-31 |
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