CN103570502A - Preparation method for varenicline intermediate - Google Patents
Preparation method for varenicline intermediate Download PDFInfo
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- CN103570502A CN103570502A CN201210249849.3A CN201210249849A CN103570502A CN 103570502 A CN103570502 A CN 103570502A CN 201210249849 A CN201210249849 A CN 201210249849A CN 103570502 A CN103570502 A CN 103570502A
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- JQSHBVHOMNKWFT-UHFFFAOYSA-N C1C2c3cc4nccnc4cc3C1CNC2 Chemical compound C1C2c3cc4nccnc4cc3C1CNC2 JQSHBVHOMNKWFT-UHFFFAOYSA-N 0.000 description 1
- IEGYXSAHRKJELM-UHFFFAOYSA-N C1C2c3ccccc3C1C=C2 Chemical compound C1C2c3ccccc3C1C=C2 IEGYXSAHRKJELM-UHFFFAOYSA-N 0.000 description 1
- HLICORNWZFXTSX-UHFFFAOYSA-N COC(C1c2ccccc2C2C1)C2OC Chemical compound COC(C1c2ccccc2C2C1)C2OC HLICORNWZFXTSX-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/48—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by oxidation reactions with formation of hydroxy groups
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Abstract
The invention relates to a preparation method for a varenicline intermediate. The method includes: subjecting 1, 4-dihydro-1, 4-methanonaphthalene to an oxidation reaction under the action of an oxidizing agent so as to generate the varenicline intermediate. The oxidizing agent is an osmic acid salt or its hydrate, the oxidation reaction undergoes in a solvent in the presence of N-methyl-N-morpholine oxide, and the solvent is a mixed solvent of water and any one or more of the following organic solvents: C1-C6 alcohol solvents, ketone solvents, ether solvents and nitrile solvents. For the mixed solvent, water and the organic solvent are in a volume ratio of 1:0.1-9. The method provided by the invention has the advantages of low production cost, simple operation, mild reaction conditions and environmental friendliness, and can prepare the product that is easy to purify and has purity up to over 99%. With high yield, the method is suitable for both small-scale preparation in laboratories and large-scale industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate, be specifically related to 1,2,3,4-tetrahydrochysene-Isosorbide-5-Nitrae-endo-methylene group-naphthalene-cis-2, the preparation method of 3-glycol.
Background technology
The medicine that is used for the treatment of nicotine addiction that 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h Shi You Pfizer Inc. develops.Its commodity are called Chantix, successively in May, 2006 and August, go on the market respectively at U.S. FDA and European EMEA approval.7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is that first produces the medicine of smoking cessation effect by affecting nicotine dependence neuromechanism, is also first smoking cessation prescription drugs that U.S. FDA is ratified nearly ten years, and its smoking cessation curative effect is better than benzene azatropylidene-L-TARTARIC ACID salt, and (molecular formula is C
17h
19n
3o
6, CAS registration number: 375815-87-5).
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h (Varenicline), its chemistry 2,3,4,5-by name tetrahydrochysene-1,5-first bridge-1H-3-benzazepine, structural formula as follows:
7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h can be combined with neuronal nicotinic sample acetylcholine receptor a4 hypotype high selectivity.Its smoking cessation effect is thought to be combined with nAChR hypotype, and exciting n receptor produces the effect of mild or moderate Nicotine sample, stimulates a small amount of Dopamine HCL to discharge, and alleviates the habituation of ES to Nicotine; It can also block the combination of Nicotine and a4 acceptor simultaneously, the stimulatory effect of nicotine elimination to mesolimbic system's dopaminergic neuron, and the joyful sense that blocking-up smoking produces, thus eliminate smoker's habituation and dependent basic substance, reduce smoking desire.7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is mainly used in the assisting therapy of smoking cessation, and clinical test results shows that the result for the treatment of of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h is obviously better than other stop smoking medicines.In clinical application, the modal untoward reaction of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h has Digestive tract reaction (as dry, feel sick, vomiting, flatulence, maldigestion, stomachache, constipation, dysgeusia), neural system reaction (as esophageal reflux and headache, dreaminess, insomnia, sleep disordered etc.), Respiratory symptoms (as rhinorrhea, expiratory dyspnea), and transformation reactions (as skin pruritus, drug rash etc.).
Known, 1,2,3,4-tetrahydrochysene-Isosorbide-5-Nitrae-endo-methylene group-naphthalene-cis-2,3-glycol (CAS registration number: be 4453-90-1) important intermediate (calling Compound I I in the following text) of synthetic 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h, structural formula is as follows:
The synthetic route of existing 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate mainly contains following three:
1) synthetic route that US6410550B1 provides is to take adjacent bromofluorobenzene as raw material is successively through D-A reaction, and oxidation obtains 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate.Its synthetic route is as follows:
The method adopts perosmic anhydride as oxidising agent at second step, and perosmic anhydride is highly toxic product, and environmental pollution is large, expensive.Owing to being subject to reagent restriction and considering the aspects such as environment, operability, this route industrialization is restricted.
2) document Chem.Commun., 1999,819 – 820 disclose following method, by potassium permanganate oxidation Compound I, obtain Compound I I, but yield low (only reaching 49%) is not suitable for industry and amplifies.Its synthetic route is as follows:
3) document SYNTHESIS 2004, No.11, and pp 1755 – 1758 openly use K
2osO
4.2H
2o/NaClO
2oxidation system oxygenated compound I obtains Compound I I.But the method long reaction time, needs 3 days, yield low (only reaching 30%), repeatability is bad, and obtains the very difficult purifying of product, is not suitable for equally amplifying and produces.Its synthetic route is as follows:
In sum, the synthetic method of the disclosed 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate of existing patent documentation (Compound I I), ubiquity cost is higher, production efficiency is lower, product is difficult to purifying, unfriendly to environment, be not suitable for the defects such as large suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, a kind of preparation method of improved 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate is provided, its low production cost, reaction conditions is gentle, simple to operate, product is easy to purifying, environmentally friendly, yield is high, is suitable for large suitability for industrialized production.
For solving above technical problem, the present invention takes following technical scheme:
The preparation method of a kind of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (II), the chemical name of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate is 1,2,3,4-tetrahydrochysene-1,4-endo-methylene group-naphthalene-cis-2,3-glycol, the method comprises makes Isosorbide-5-Nitrae-dihydro-1, under oxygenant effect, there is the step that oxidizing reaction generates 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (II) in 4-methanonaphthalene (I)
Particularly, described oxygenant is osmate or its hydrate, and oxidizing reaction exists lower and carries out in solvent at N-methyl-N-morpholine oxide (NMO), and wherein solvent is water and is selected from C
1~ C
6the mixed solvent of any one or several organic solvents in alcoholic solvent, ketones solvent, ether solvent and nitrile solvents, in mixed solvent, the volume ratio of water and organic solvent is 1:0.1 ~ 9.
According to further embodiment of the present invention: the molar ratio of Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, oxygenant and N-methyl-N-morpholine oxide is 1:0.4 ~ 0.6:2.5 ~ 3.5, and a preferred molar ratio is about 1:0.5:3.
According to the present invention, described osmate is preferably one or more the combination being selected from osmic acid an alkali metal salt and osmic acid alkaline earth salt.More preferably, described osmate is for being selected from potassium osmate, sodium osmic acid, the combination of one or more in potassium osmate dihydrate and sodium osmic acid hexahydrate.
According to the present invention, described mixed solvent is preferably water and one or more the mixture being selected from methyl alcohol, ethanol, Virahol, Virahol, the trimethyl carbinol, acetone, acetonitrile and tetrahydrofuran (THF), concrete mixed solvent can be for example methanol/water, ethanol/water, isopropanol/water, butanol/water, acetone/water, acetonitrile/water, tetrahydrofuran (THF)/water etc.
According to the present invention, the temperature of described oxidizing reaction is generally 0 ℃ ~ 100 ℃.In this temperature range, with other functional groups in not destroying reactant and be conducive to react into principle of conduct, select different temperature of reaction to carry out.The temperature of oxidizing reaction is preferably 10 ℃ ~ 60 ℃, more preferably 20 ℃ ~ 30 ℃.
According to the present invention, in described mixed solvent, the volume ratio of water and organic solvent is preferably 1:0.2 ~ 5.
According to a concrete aspect of the present invention, described preparation method is implemented as follows: in reaction vessel, add Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, N-methyl-N-morpholine oxide, oxygenant, organic solvent and water, system clarification after stirring, under design temperature, stir, it is complete that high performance liquid chromatography (HPLC) detects raw material reaction, and concentrating under reduced pressure boils off organic solvent, add water, after stirring, filter, described 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate is dried and obtained to filter cake, through washing.
According to the present invention, Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene can be SILVER REAGENT or technical grade purity product; Also can adopt existing or known method and technology to synthesize.N-methyl-N-morpholine oxide that the present invention uses especially, another name N-methylmorpholine oxide compound, is for No. CAS 7529-22-8, commercially available acquisition or adopt existing or known method and technology to synthesize.Other mentioned reagent of the present invention are the conventional reagent in this area, can be by commercially available.
Owing to taking above technical scheme, the present invention compared with prior art tool has the following advantages:
The inventive method raw material sources are extensive, low production cost, and synthesis step is simple to operate, and reaction conditions is gentle, environmentally friendly, product is easy to purifying, and product purity can reach more than 99.0%, yield is high, has both been applicable to laboratory and has prepared on a small scale, is also applicable to large-scale industrial production.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the invention is not restricted to following examples.
Embodiment 1
In 1000mL there-necked flask, add 50g(352mmol, 1.0eq) Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, 123.6g(1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg(0.18mmol, 0.05%eq) two hydration potassium osmates, 250mL methyl alcohol, 250mL water, after stirring, system clarification, stirs 8 hours at 20 ~ 30 ℃.HPLC detection raw material reaction is complete, and reaction system concentrating under reduced pressure boils off methyl alcohol, adds water to 250mL, after stirring, filters, and filter cake washs with sherwood oil 50mL.Filter cake obtains 53g powdery solid after drying and is 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (Compound I I), 176 ~ 178 ℃ of fusing points, content 98%, purity 99.7%, yield 83.8%.
Embodiment 2
In 1000mL there-necked flask, add 50g(352mmol, 1.0eq) Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, 123.6g (1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg (0.18mmol, 0.05%eq) two hydration potassium osmates, 350mL methyl alcohol, 150mL water, after stirring, system clarification, stirs 15 hours at 10 ~ 20 ℃.HPLC detection raw material reaction is complete, and reaction system concentrating under reduced pressure boils off methyl alcohol, adds water to 250mL, after stirring, filters, and filter cake washs with sherwood oil 50mL.Filter cake obtains 52g powdery solid after drying and is 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (Compound I I), 176 ~ 178 ℃ of fusing points, content 99%, purity 99.5%, yield 83.1%.
Embodiment 3
In 1000mL there-necked flask, add 50g(352mmol, 1.0eq) Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, 123.6g (1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg (0.18mmol, 0.05%eq) two hydration potassium osmates, 50mL methyl alcohol, 450mL water, after stirring, system clarification, stirs 30 hours at 40 ~ 50 ℃.HPLC detection raw material reaction is complete, and reaction system concentrating under reduced pressure boils off methyl alcohol, adds water to 250mL, after stirring, filters, and filter cake washs with sherwood oil 50mL.Filter cake obtains 46g powdery solid after drying and is 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (Compound I I), 176 ~ 178 ℃ of fusing points, content 98%, purity 99.0%, yield 72.7%.
Embodiment 4
In 1000mL there-necked flask, add 50g(352mmol, 1.0eq) Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, 123.6g (1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg (0.18mmol, 0.05%eq) two hydration potassium osmates, 250mL acetone, 250mL water, after stirring, system clarification, stirs 8 hours at 20 ~ 30 ℃.HPLC detection raw material reaction is complete, and reaction system concentrating under reduced pressure boils off methyl alcohol, adds water to 250mL, after stirring, filters, and filter cake washs with sherwood oil 50mL.Filter cake obtains 54g powdery solid after drying and is 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (Compound I I), 176 ~ 178 ℃ of fusing points, content 98%, purity 99.3%, yield 85.5%.
Embodiment 5
In 1000mL there-necked flask, add 50g(352mmol, 1.0eq) Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, 123.6g (1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg (0.18mmol, 0.05%eq) two hydration potassium osmates, 450mL acetone, 50mL water, after stirring, system is muddy, at 10 ~ 20 ℃, stirs 10 hours.HPLC detection raw material reaction is complete, and reaction system concentrating under reduced pressure boils off acetone, adds water to 250mL, after stirring, filters, and filter cake washs with sherwood oil 50mL.Filter cake obtains 51g powdery solid after drying and is 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (Compound I I), 176 ~ 178 ℃ of fusing points, content 99%, purity 99.1%, yield 81.5%.
Embodiment 6
In 1000mL there-necked flask, add 50g(352mmol, 1.0eq) Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, 123.6g (1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg (0.18mmol, 0.05%eq) two hydration potassium osmates, 450mL acetone, 50mL water, after stirring, system is muddy, at 40 ~ 50 ℃, stirs 4 hours.HPLC detection raw material reaction is complete, and reaction system concentrating under reduced pressure boils off acetone, adds water to 250mL, after stirring, filters, and filter cake washs with sherwood oil 50mL.Filter cake obtains 48g powdery solid after drying and is 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (Compound I I), 176 ~ 178 ℃ of fusing points, content 98%, purity 99.2%, yield 75.9%.
Embodiment 7
In 1000mL there-necked flask, add 50g(352mmol, 1.0eq) Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, 123.6g (1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg (0.18mmol, 0.05%eq) two hydration potassium osmates, 200mL acetonitrile, 300mL water, after stirring, system clarification, stirs 12 hours at 20 ~ 30 ℃.HPLC detection raw material reaction is complete, and reaction system concentrating under reduced pressure boils off acetonitrile, adds water to 250mL, after stirring, filters, and filter cake washs with sherwood oil 50mL.Filter cake obtains 49g powdery solid after drying and is 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (Compound I I), 176 ~ 178 ℃ of fusing points, content 98%, purity 99.0%, yield 77.5%.
Embodiment 8
In 1000mL there-necked flask, add 50g(352mmol, 1.0eq) Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, 123.6g(1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg (0.18mmol, 0.05%eq) two hydration potassium osmates, 350mL acetonitrile, 150mL water, after stirring, system is muddy, at 20 ~ 30 ℃, stirs 16 hours.HPLC detection raw material reaction is complete, and reaction system concentrating under reduced pressure boils off acetonitrile, adds water to 250mL, after stirring, filters, and filter cake washs with sherwood oil 50mL.Filter cake obtains 47g powdery solid after drying and is 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (Compound I I), 176 ~ 178 ℃ of fusing points, content 98%, purity 99.2%, yield 74.3%.
Comparative example 1
In 1000mL there-necked flask, add 50g(352mmol, 1.0eq) Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, 62mg (0.18mmol, 0.05%eq) two hydration potassium osmates, 350mL acetonitrile, 150mL water, after stirring, system clarification, stirs 16 hours at 20 ~ 30 ℃.HPLC does not detect product, and reaction system concentrating under reduced pressure boils off acetonitrile, obtains brown oil.Through HPLC, detect as raw material.
Comparative example 2
In 1000mL there-necked flask, add 50g(352mmol, 1.0eq) 1,4-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, 123.6g (1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg (0.18mmol, 0.05%eq) two hydration potassium osmates, 450mL acetone, after stirring, system is muddy, at 40 ~ 50 ℃, stirs 96 hours.HPLC detects product 15%, and reaction system concentrating under reduced pressure boils off acetone, adds water to 250mL, filters sherwood oil 50mL washing for filter cake after stirring.Filter cake obtains 3g powdery solid after drying and is 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (Compound I I), 174 ~ 176 ℃ of content 97% of fusing point, purity 99.2%, yield 3.9%.
Comparative example 3
In 1000mL there-necked flask, add 50g(352mmol, 1.0eq) Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, 123.6g (1.05mol, 3.0eq) N-methyl-N-morpholine oxide, 62mg (0.18mmol, 0.05%eq) two hydration potassium osmates, 500mL water, system layering after stirring, stirs 96 hours at 40 ~ 50 ℃.HPLC detects water and does not detect product, and it is raw material that HPLC detects upper strata.
Above the present invention is described in detail; its object is to allow the personage who is familiar with this art can understand content of the present invention and be implemented; can not limit the scope of the invention with this; the equivalence that all spirit according to the present invention are done changes or modifies, and all should be encompassed in protection scope of the present invention.
Claims (10)
1. the preparation method of a 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (II), the chemical name of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate is 1,2,3,4-tetrahydrochysene-1,4-endo-methylene group-naphthalene-cis-2,3-glycol, described method comprises makes Isosorbide-5-Nitrae-dihydro-1, under oxygenant effect, there is the step that oxidizing reaction generates 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate (II) in 4-methanonaphthalene (I)
It is characterized in that: described oxygenant is osmate or its hydrate, described oxidizing reaction is under N-methyl-N-morpholine oxide exists and carry out in solvent, and wherein said solvent is water and be selected from C
1~ C
6the mixed solvent of any one or several organic solvents in alcoholic solvent, ketones solvent, ether solvent and nitrile solvents, in mixed solvent, the volume ratio of water and organic solvent is 1:0.1 ~ 9.
2. the preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate according to claim 1, is characterized in that: the molar ratio of Isosorbide-5-Nitrae-dihydro-Isosorbide-5-Nitrae-methanonaphthalene, oxygenant and N-methyl-N-morpholine oxide is 1:0.4 ~ 0.6:2.5 ~ 3.5.
3. the preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate according to claim 1, is characterized in that: described osmate is one or more the combination being selected from osmic acid an alkali metal salt and osmic acid alkaline earth salt.
4. the preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate according to claim 3, is characterized in that: described osmate is for being selected from potassium osmate, sodium osmic acid, the combination of one or more in potassium osmate dihydrate and sodium osmic acid hexahydrate.
5. the preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate according to claim 1, is characterized in that: described mixed solvent is water and one or more the mixture being selected from methyl alcohol, ethanol, Virahol, Virahol, the trimethyl carbinol, acetone, acetonitrile and tetrahydrofuran (THF).
6. according to the preparation method of the 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate described in any one claim in claim 1 ~ 5, it is characterized in that: the temperature of described oxidizing reaction is 0 ℃ ~ 100 ℃.
7. the preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate according to claim 6, is characterized in that: the temperature of described oxidizing reaction is 10 ℃ ~ 60 ℃.
8. the preparation method of 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate according to claim 7, is characterized in that: the temperature of described oxidizing reaction is 20 ℃ ~ 30 ℃.
9. according to the preparation method of the 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate described in any one claim in claim 1 ~ 5, it is characterized in that: in described mixed solvent, the volume ratio of water and organic solvent is 1:0.2 ~ 5.
10. according to the preparation method of the 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate described in any one claim in claim 1 ~ 5, it is characterized in that: described preparation method is implemented as follows: in reaction vessel, add 1,4-dihydro-1,4-methanonaphthalene, N-methyl-N-morpholine oxide, oxygenant, organic solvent and water, system clarification after stirring, under design temperature, stir, it is complete that high performance liquid chromatography detects raw material reaction, concentrating under reduced pressure boils off organic solvent, add water, after stirring, filter, described 7,8,9,10-tetrahydro-6H-6,10-methanopyrazino[2,3-h intermediate is dried and obtained to filter cake, through washing.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6043250A (en) * | 1994-02-18 | 2000-03-28 | Cell Therapeutics, Inc. | Methods for using therapeutic compounds containing xanthinyl |
| CN1715280A (en) * | 1997-12-31 | 2006-01-04 | 辉瑞产品公司 | Aryl fused azapolycyclic compounds |
-
2012
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6043250A (en) * | 1994-02-18 | 2000-03-28 | Cell Therapeutics, Inc. | Methods for using therapeutic compounds containing xanthinyl |
| CN1715280A (en) * | 1997-12-31 | 2006-01-04 | 辉瑞产品公司 | Aryl fused azapolycyclic compounds |
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