CN100383144C - Intermediate of olanzapine, preparation and application thereof - Google Patents
Intermediate of olanzapine, preparation and application thereof Download PDFInfo
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- CN100383144C CN100383144C CNB2006100535098A CN200610053509A CN100383144C CN 100383144 C CN100383144 C CN 100383144C CN B2006100535098 A CNB2006100535098 A CN B2006100535098A CN 200610053509 A CN200610053509 A CN 200610053509A CN 100383144 C CN100383144 C CN 100383144C
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- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title claims description 52
- 229960005017 olanzapine Drugs 0.000 title claims description 51
- 238000002360 preparation method Methods 0.000 title claims description 22
- 238000000034 method Methods 0.000 claims abstract description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- FHPIXVHJEIZKJW-UHFFFAOYSA-N 4'-N-desmethylolanzapine Chemical compound S1C(C)=CC2=C1NC1=CC=CC=C1N=C2N1CCNCC1 FHPIXVHJEIZKJW-UHFFFAOYSA-N 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical group CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- -1 diester dicarbonate Chemical class 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 6
- 125000005418 aryl aryl group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- FHRRJZZGSJXPRQ-UHFFFAOYSA-N benzyl phenylmethoxycarbonyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OC(=O)OCC1=CC=CC=C1 FHRRJZZGSJXPRQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910000085 borane Inorganic materials 0.000 claims description 3
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 229940113088 dimethylacetamide Drugs 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 150000005690 diesters Chemical class 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 229940049706 benzodiazepine Drugs 0.000 abstract 1
- 150000001557 benzodiazepines Chemical class 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000003513 alkali Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000003912 environmental pollution Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012022 methylating agents Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- SFWJCBPXQCTXTO-UHFFFAOYSA-N 4-(2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-yl)piperazine-1-carbaldehyde Chemical compound S1C(C)=CC2=C1NC1=CC=CC=C1N=C2N1CCN(C=O)CC1 SFWJCBPXQCTXTO-UHFFFAOYSA-N 0.000 description 1
- XBHJKVPDWMINIW-UHFFFAOYSA-N C=1C=CSC=1.N1N=CC=CC2=CC=CC=C12 Chemical compound C=1C=CSC=1.N1N=CC=CC2=CC=CC=C12 XBHJKVPDWMINIW-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses an intermediate of aonitrogen level with structural formula in the formula (II) and preparing method and application of 2-methyl-4-[4-formic ether-piperazine]-10H-thiophene [2,3-b][1,5] benzodiazepines, wherein R is C1-6 alkyl or C6-18 aryl or heteroaromatic group or benzyl.
Description
(I) technical field
The present invention relates to a novel intermediate for the preparation of olanzapine: 2-methyl-4- [ 4-formate-piperazinyl]-10H-thieno [2, 3-b][1，5]Benzodiazepine
As well as a preparation method and application thereof in preparing olanzapine.
(II) background of the invention
Olanzapine (OLP) belongs to a novel atypical antipsychotic acting on the central nervous system and being thiophene benzodiazepine
A serotonin/dopamine antagonist. First introduced into the united states in 1996 by american gifts and in the uk in 4 months in 1997.
Olanzapine has the chemical name: 2-methyl-4- [ 4-methyl-1-piperazinyl]-10H-thieno [2, 3-b][1，5]Benzodiazepine
The structural formula is as follows:
european patent EP0454436 discloses two processes for the preparation of olanzapine:
the method comprises the following steps:
the organic solvent used in the process may be anisole, toluene, dimethylformamide or methyl sulfoxide, and the reaction is preferably carried out at a temperature of from 100 to 150 ℃.
The second method comprises the following steps:
the starting material for this process is obtained from ethyl cyanoacetate through a series of laborious steps requiring special complex reaction conditions, reactants and reducing agents, and solvents with high boiling points that are difficult to remove, such as toluene, DMF, DMSO, etc.
Both of these methods have poor yields and generate a large amount of impurities, which require repeated crystallization to remove, which adversely affects the process efficiency.
PCT patent WO200400847 discloses a process for the preparation of olanzapine starting from N-demethylolanzapine, the reaction formula is as follows:
the reaction of N-demethylolanzapine with ethyl formate to prepare N-demethyl-N-formyl olanzapine, followed by reduction with sodium borohydride, has the disadvantages of low yield and poor product quality.
PCT patent WO2005090359 also discloses a process for the preparation of olanzapine starting from N-demethylolanzapine, of the formula:
the method is characterized in that virulent methyl iodide is used as a methylating agent, more impurities are generated, and a purification means is used for obtaining pure olanzapine, for example, olanzapine alkali is formed into a salt, and the salt is converted into the pure olanzapine, so that the cost is increased and the yield is reduced.
US20060035887 also discloses a process for the preparation of olanzapine starting from N-demethylolanzapine, of the formula:
the methylating agent used in the reaction is virulent methyl iodide or dimethyl sulfate, which is not beneficial to industrial production.
Disclosure of the invention
In order to solve the defects of low preparation yield, dangerous operation, serious environmental pollution and the like of olanzapine in the prior art, the invention provides a new intermediate for preparing olanzapine and a preparation method thereof, and the preparation method of olanzapine has high yield, safe operation and small environmental pollution.
The technical scheme adopted by the invention for achieving the aim of the invention is as follows:
an intermediate of olanzapine: 2-methyl-4- [ 4-formate-piperazinyl]-10H-thieno [2, 3-b][1，5]Benzodiazepine
The structural formula is shown as formula (II):
wherein R in the formula (II) is C1～C6Alkyl of (2), or C6～C18Aryl, or heteroaryl, or benzyl.
A process for preparing an intermediate of said olanzapine, said process comprising: reacting a compound of formula (III): dissolving N-demethylolanzapine in an organic solvent A,
adding a compound with a structural formula (IV) in an environment of-10 ℃: diester dicarbonate, reacting at normal temperature to obtain the intermediate of olanzapine, wherein the organic solvent A is C1～C8Alcohol of (2), or C2～C6Or toluene, or benzene, or dichloromethane, or chloroform, R in formula (IV) being as defined for R in formula (II).
The preparation method specifically comprises the steps of dissolving N-demethylolanzapine in an organic solvent A, adding the diester dicarbonate in an environment of-10 ℃, adjusting the pH value to 7-14 by using alkali, and reacting for 0.5-3 hours at 10-60 ℃ to obtain the intermediate of olanzapine. The pH value is preferably 8-9, the alkali is inorganic alkali formed by organic alkali, and the organic alkali is triethylamine or diethylamine; the inorganic base is an alkali metal carbonate, an alkali metal bicarbonate or an alkali metal hydroxide. The alkali is preferably sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
The amount ratio of the N-demethylolanzapine to the diester dicarbonate reactant is 1: 1 to 1: 3. The dicarbonate is di-tert-butyl dicarbonate or dibenzyl dicarbonate.
The organic solvent A is methanol, ethanol, isopropanol, butanol, tetrahydrofuran, methyl tert-butyl ether, toluene, benzene, dichloromethane or chloroform.
The invention also provides another method for preparing an intermediate of olanzapine, which comprises the following steps: 4-amino-2-methyl-10H-thieno [2, 3-b ] represented by the formula (V)][1，5]Benzodiazepine
With N-formic acid ester piperazine shown as a formula (VI) in an organic solvent B at 8Reacting at 0-150 ℃ to obtain an intermediate of olanzapine,
r in formula (VI) is as defined for R in formula (II).
In the method, the ratio of the amount of the substances of the formula (VI) and the formula (V) is 3: 1-6: 1, and the ratio of the amount of the substances of the formula (V) and the formula (VI) is 8: 1-12: 1.
The organic solvent B is one of the following or a mixture of two or more of the following: dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, toluene and benzene.
The intermediates of olanzapine represented by the formula (II) are useful for preparing olanzapine. The preparation method of olanzapine comprises the following steps: reacting a compound represented by the formula (II): 2-methyl-4- [ 4-formate-piperazinyl]-10H-thieno [2, 3-b][1，5]Benzodiazepine
Reducing with a reducing agent to obtain olanzapine shown as a formula (I);
r in the formula (II) is C1～C6Alkyl of (C)6～C18Aryl, heteroaryl, benzyl of (a).
Specifically, the application is as follows: in the presence of a reducing agent, dropwise adding the compound shown in the formula (II) into an organic solvent C at the temperature of-10 ℃: 2-methyl-4- [ 4-formate-piperazinyl]-10H-thieno [2, 3-b][1，5]BenzodiazepineAnd reacting the mixture with an inert solvent for 1 to 26 hours to obtain the olanzapine. The reaction can be carried out at-10 to 100 ℃.
The reducing agent is lithium aluminum hydride, lithium borohydride or borane, and the organic solvent C is C1～C8Alcohol of (2), or C2～C6Or toluene, or benzene, or dichloromethane, or chloroform.
According to the process of the present invention, crude olanzapine is produced as pure as obtained by the prior art process under mild conditions, with relatively short reaction times and low reaction temperatures. The generation of a large amount of impurities is avoided.
The invention has the following beneficial effects: provides a new intermediate for preparing olanzapine, has high olanzapine preparation yield, safe operation and little environmental pollution and is beneficial to industrialized production.
(IV) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
example 1: 2-methyl-4- [ 4-carboxylic acid tert-butyl ester-piperazinyl]-10H-thieno [2, 3-b][1，5]Benzodiazepine
Synthesis of (2)
10g (0.0336mol) of N-demethylolanzapine and 40mL of THF were cooled to about 0 ℃ with stirring, and 8.1g (0.0369mol) of di-tert-butyl dicarbonate and 2.7g (0.067mol) of sodium hydroxide in 5.5mL of an aqueous solution were successively added, followed by reaction at room temperature for one hour. Adding 150mL of dichloromethane and 150mL of water, extracting, separating, collecting organic layer, extracting water layer with dichloromethane, mixing organic layers, and adding anhydrous Na2SO4Drying, distilling under reduced pressure to obtain brown solid, recrystallizing with ethanol to obtain yellow powder (yield 70%, HPLC > 99.5%)
MS-ESI(％)399.5[M+1]
1H NMR(400MHz，CDCl3)：1.47(s，9H)，2.30(s，3H)，3.45-3.50(m，8H)，5.03(s，1H)，6.28(s，1H)，6.60(d，1H)，6.90(t，1H)，6.94-7.02(m，2H)
Example 2: 2-methyl-4- [ 4-carboxylic acid benzyl ester-piperazinyl]-10H-thieno [2, 3-b][1，5]Benzodiazepines
Synthesis of (2)
In the same manner as in example 1, di-tert-butyl dicarbonate was replaced with dibenzyl dicarbonate (yield: 68%).
MS-ESI(％)433.5 [M+1]
Example 3: synthesis of N-tert-butyl formate piperazine
10g (0.122mol) of piperazine was dissolved in 167mL of dichloromethane, cooled to about 0 ℃ with stirring, and 5.3g (0.0244mol) of di-tert-butyl dicarbonate was dissolved in 84mL of dichloromethane, added dropwise to the above solution, and then reacted at room temperature overnight. Filtering, distilling the filtrate under reduced pressure to obtain yellow viscous liquid, dissolving in ice brine, extracting with diethyl ether, and extracting the organic layer with anhydrous Na2SO4Drying, and distilling under reduced pressure to obtain yellow viscous liquid.
Example 4: synthesis of N-benzyl formate piperazine
The procedure is as in example 3 except that di-tert-butyl dicarbonate is replaced by dibenzyl dicarbonate.
Example 5: 2-methyl-4- [ 4-carboxylic acid tert-butyl ester-piperazinyl]-10H-thieno [2, 3-b][1，5]Benzodiazepine
Synthesis of (2)
11.6g of tert-butyl N-carboxylate piperazine (0.076mol) obtained in example 3, 2.75g (0.012mol) of 4-amino-2-methyl-10H-thieno [2, 3-b ]][1，5]Benzodiazepine
Adding hydrochloride, 15mL of DMSO and 15mL of toluene in sequence under stirring, heating to reflux for 16 hours, cooling the reacted solution, pouring into ice water, adding dichloromethane, extracting and layering to obtain an organic layer, and using anhydrous Na for the organic layer2SO4Drying, distilling under reduced pressure to obtain a tan solid, and recrystallizing with ethanol to obtain a yellow solid 3.30g with a yield of 69%.
Example 6: 2-methyl-4- [ 4-carboxylic acid benzyl ester-piperazinyl]-10H-thieno [2, 3-b][1，5]Benzodiazepine
Synthesis of (2)
The specific operation method is the same as example 5, and the N-tert-butyl formate piperazine is replaced by the N-benzyl formate piperazine obtained in example 4 to obtain 2-methyl-4- [ 4-benzyl formate-piperazinyl]-10H-thieno [2, 3-b][1，5]Benzodiazepine
Solid, yield 63%.
Example 7: synthesis of olanzapine
4.8g (0.126mol) of LiAlH430mL of THF was cooled to about 0 ℃ with stirring, and then a mixed solution of 14.0g of the starting material (II) obtained in example 1 and 50mL of THF was added dropwise under nitrogen atmosphere, followed by reaction at room temperature overnight. Slowly adding proper amount of Na under stirring2SO4·10H2O, standing for half an hour, filtering, distilling the filtrate under reduced pressure to obtain yellow viscous liquid, and crystallizing with ethanol to obtain yellow solid (yield 71%, HPLC > 99.6%)。
1H NMR(CDCl3)：2.30(s，3H)，2.28(s，3H)，2.45(m，4H)，3.49(m，4H)，5.00(broad s，1H)，6.23(broad s，1H)，6.35-7.10(m，4H)
Example 8: synthesis of olanzapine
The starting material (II) from example 1 was dissolved in THF, borane gas was then bubbled through, after the reaction was complete, the solution was quenched with methanol, spun-dried to give a yellow viscous liquid, which was then crystallized from ethanol to give a yellow solid (68% yield, > 99.5% HPLC).
1H NMR(CDCl3)：2.30(s，3H)，2.28(s，3H)，2.45(m，4H)，3.49(m，4H)，5.00(broad s，1H)，6.23(broad s，1H)，6.35-7.10(m，4H)
Example 9 (comparative): preparation of olanzapine: methylation of N-demethylolanzapine using methyl iodide
N-demethylolanzapine (2.8g, 9.4mmol), methyl iodide (1.33g, 9.4mmol) and potassium carbonate (3.89g, 28.2mmol) were stirred in 20ml methanol at room temperature for 8 hours. Subsequently, 20ml of distilled water was added to the mixture, and the whole was cooled in an ice bath until a pale yellow precipitate was formed. The precipitate is filtered off and washed with water to yield 1.5g olanzapine having a purity of 90% according to HPLC (yield 51%)
Claims (11)
1. An intermediate of olanzapine: 2-methyl-4- [ 4-formate-piperazinyl]-10H-thieno [2, 3-b][1，5]Benzodiazepine
The structural formula is shown as formula (II):
wherein,r in the formula (II) is C1～C6Alkyl of (2), or C6～C18Aryl, or heteroaryl, or benzyl.
2. A process for the preparation of an intermediate of olanzapine according to claim 1, characterized in that said process comprises: reacting a compound of formula (III): dissolving N-demethylolanzapine in an organic solvent A,
adding a compound with a structural formula (IV) in an environment of-10 ℃: diester dicarbonate, reacting at normal temperature to obtain the intermediate of olanzapine, wherein the organic solvent A is C1～C8Alcohol of (2), or C2～C6Or toluene, or benzene, or dichloromethane, or chloroform, R in formula (IV) is the same as R in formula (II), R in formula (II) is C1～C6Alkyl of (2), or C6～C18Aryl, or heteroaryl, or benzyl.
3. The preparation method of the intermediate of olanzapine as claimed in claim 2, characterized in that the preparation method comprises the steps of dissolving N-demethylolanzapine in an organic solvent A, adding a diester dicarbonate in an environment of-10 ℃ to 10 ℃, adjusting the pH value to 7 to 14 with a base, and reacting at 10 ℃ to 60 ℃ for 0.5 to 3 hours to obtain the intermediate of olanzapine.
4. The process for preparing an intermediate of olanzapine according to claim 2 wherein the amount ratio of N-demethylolanzapine to the diester reaction mass of dicarbonate is 1: 1 to 1: 3.
5. A process for the preparation of an intermediate of olanzapine as claimed in claim 2 wherein said dicarbonate is di-tert-butyl dicarbonate or dibenzyl dicarbonate.
6. The process for preparing an intermediate of olanzapine according to claim 2, characterized in that the organic solvent a is methanol, or ethanol, or isopropanol, or butanol, or tetrahydrofuran, or methyl tert-butyl ether, or toluene, or benzene, or methylene chloride, or chloroform.
7. A process for the preparation of an intermediate of olanzapine according to claim 1, said process comprising: 4-amino-2-methyl-10H-thieno [2, 3-b ] represented by the formula (V)][1，5]BenzodiazepineReacting with N-formic ether piperazine shown in a formula (VI) in an organic solvent B at the temperature of 80-150 ℃ to obtain an intermediate of olanzapine,
r in formula (VI) is as defined for R in formula (II) wherein R is C1～C6Alkyl of (2), or C6～C18Aryl, or heteroaryl, or benzyl.
8. The process for preparing an intermediate of olanzapine according to claim 7 wherein the organic solvent B is one of the following or a mixture of two or more thereof: dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, toluene and benzene.
9. Use of an intermediate of olanzapine of formula (II) for the preparation of olanzapine, said use being: the preparation method of olanzapine comprises the following steps: reacting a compound represented by the formula (II): 2-methyl-4- [ 4-formate-piperazinyl]-10H-thieno [2, 3-b][1，5]Benzodiazepine
Reducing with a reducing agent to obtain olanzapine shown as a formula (I);
r in the formula (II) is C1～C6Alkyl of (2), or C6～C18Aryl, or heteroaryl, or benzyl.
10. The use according to claim 9, characterized in that said use is: in the presence of a reducing agent, dropwise adding the compound 2-methyl-4- [ 4-formate-piperazinyl shown in the formula (II) into an organic solvent C at the temperature of-10 DEG C]-10H-thieno [2, 3-b][1，5]Benzodiazepine
And reacting the mixture with an inert solvent for 1 to 26 hours to obtain the olanzapine.
11. The method of claim 10, wherein the reducing agent is lithium aluminum hydride, lithium borohydride, or borane, and the organic solvent C is C1～C8Alcohol of (2), or C2～C6Or toluene, or benzene, or dichloromethane, or chloroform.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0454436A1 (en) * | 1990-04-25 | 1991-10-30 | Lilly Industries Limited | Pharmaceutical compounds |
| WO2004000847A1 (en) * | 2002-06-20 | 2003-12-31 | Adamed Sp. Z O.O. | A process for the preparation of olanzapine and an intermediate therefor |
| WO2005090359A2 (en) * | 2004-03-18 | 2005-09-29 | Lek Pharmaceuticals D.D. | Synthesis of 2-methyl-4-(4-methyl-1-piperazinyl)-10h-thieno[2, 3-b][1,5]benzodiazepine and salts thereof |
| US20060035887A1 (en) * | 2004-07-02 | 2006-02-16 | Dr. Reddy's Laboratories Limited | Process for preparing olanzapine |
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2006
- 2006-09-11 CN CNB2006100535098A patent/CN100383144C/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0454436A1 (en) * | 1990-04-25 | 1991-10-30 | Lilly Industries Limited | Pharmaceutical compounds |
| WO2004000847A1 (en) * | 2002-06-20 | 2003-12-31 | Adamed Sp. Z O.O. | A process for the preparation of olanzapine and an intermediate therefor |
| WO2005090359A2 (en) * | 2004-03-18 | 2005-09-29 | Lek Pharmaceuticals D.D. | Synthesis of 2-methyl-4-(4-methyl-1-piperazinyl)-10h-thieno[2, 3-b][1,5]benzodiazepine and salts thereof |
| US20060035887A1 (en) * | 2004-07-02 | 2006-02-16 | Dr. Reddy's Laboratories Limited | Process for preparing olanzapine |
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