CN106632018A - Preparation method of liranaftate - Google Patents
Preparation method of liranaftate Download PDFInfo
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- CN106632018A CN106632018A CN201611250807.6A CN201611250807A CN106632018A CN 106632018 A CN106632018 A CN 106632018A CN 201611250807 A CN201611250807 A CN 201611250807A CN 106632018 A CN106632018 A CN 106632018A
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- liranaftate
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- crude product
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- temperature control
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of liranaftate, and belongs to the technical field of medicine preparation technologies. The method comprises the steps that 2-methoxy-6-methylamino pyridine and 15-20-fold absolute ethyl alcohol are stirred and mixed, then, 0.3-0.6-fold anhydrous sodium carbonate and 2-2.5-fold purified water are added, then, 1-2-fold 2-(5,6,7,8-tetrahydronaphthoxyl) phenyl chlorothionocarbonate is slowly added, the temperature is controlled to be 10-30 DEG C for performing a reaction for 2-3 h, 10-fold purified water is added and stirred for 30 min, centrifuging is performed, drying is performed under the temperature of 45-55 DEG C to obtain a crude liranaftate, and the refined liranaftate is obtained through refining. The preparation method of liranaftate is easy to implement, stable in technology and low in cost, raw and auxiliary materials are easy to purchase, no methyl alcohol or other industrial waste gas is generated in the production process, by-products in the intermediate process is sodium chloride, the environmental influence is small, and the obtained liranaftate is environmentally friendly and high in product yield.
Description
Technical field
The invention belongs to the fabricating technology field of medicine, and in particular to a kind of preparation method of Liranaftate.
Background technology
Liranaftate (liranaftate) is cyclooxygenase inhibitors of squalene and Cell wall synthesis inhibitor, can be pressed down
The squalene cyclization of fungal cell processed, suppresses the biosynthesis of the constituent ergosterol of cell membrane, anti-so as to play
Fungi acts on, it is adaptable to the local treatment of dermatophytid infection.
In the market the kind main production is chemical synthesis, more with the chloro- 6- picolilamines of 2- as raw material, first
Generate 2- methoxyl group -6- picolilamines with methyl alcohol reaction, then successively with carbon disulfide, 2,4, dinitrofluorobenzene, 5,6,7,8-
Tetralol reaction generates Liranaftate.This kind of complex operation, yield is low, and the first of volatilization can be produced in production process
The solid waste such as alcohol gas, carbon disulfide, in the case where national environmental protection supervision is increasingly severe large-scale production is unfavorable for.
The content of the invention
It is an object of the invention to provide a kind of technological operation is simple, process stabilizing, supplementary material is easily purchased, and cost is relatively low,
Less generation industrial waste gas in production process, pilot process accessory substance has fewer environmental impacts, environmentally friendly, and product yield is high
Liranaftate preparation method.
A kind of preparation method of Liranaftate of the present invention, comprises the following steps：
(1) preparation of Liranaftate crude product：By 2- methoxyl group -6- picolilamines and 15-20 times of absolute ethyl alcohol and stirring
After mixing, 0.3-0.6 times of natrium carbonicum calcinatum, 2-2.5 times of purified water are added, be then slowly added into 1-2 times of 2- (5,6,7,8- tetra-
Hydrogen naphthoxy) chlorinated thio formic acid esters, 10～30 DEG C of temperature control reacts 2-3 hours, plus 10 times of purified water is stirred 30 minutes, from
The heart, the drying at 45-55 DEG C, obtain Liranaftate crude product；
(2) preparation of Liranaftate fine work：Absolute ethyl alcohol is with Liranaftate crude product according to 1:(5-6) after feeding intake, profit is added
Draw the medical charcoal of naphthalene ester crude product quality 0.05-0.07 times, the decolourings of 55～65 DEG C of temperature control, removal of impurities 30 minutes, aseptic filtration is to stainless
In steel reactor, 55-65 DEG C of crystallization of temperature control, centrifugation, dry, crushing, packaging obtain Liranaftate fine work.
Step 2) during aseptic filtration using 0.22 μm of filter core and 10 μm of titanium rods.
The preparation method of described Liranaftate, comprises the following steps：
(1) preparation of Liranaftate crude product：By 2- methoxyl group -6- picolilamines and the mixing of 20 times of absolute ethyl alcohol and stirring
Afterwards, 0.5 times of natrium carbonicum calcinatum, 2.5 times of purified waters are added, is then slowly added into 1.5 times of 2- (5,6,7,8- tetrahydrochysene naphthoxy)
Chlorinated thio formic acid esters, 15-25 DEG C of temperature control reacts 2.5 hours, plus 10 times of purified water is stirred 30 minutes, centrifugation, at 45-55 DEG C
Lower drying, obtains Liranaftate crude product；
(2) preparation of Liranaftate fine work：Absolute ethyl alcohol is with Liranaftate crude product according to 1:After 5 feed intake, profit is added to draw naphthalene
The medical charcoal that 0.06 times of ester crude product quality, 60 DEG C of decolourings of temperature control, removal of impurities 30 minutes, in aseptic filtration to stainless steel cauldron, control
Warm 60 DEG C of crystallizations, centrifugation, dry, crushing, packaging, obtain Liranaftate fine work.
Compared with prior art, beneficial effects of the present invention are：A kind of preparation method of Liranaftate of the present invention, operation letter
Single, process stabilizing, supplementary material is easily purchased, and cost is relatively low, and the industrial waste gases such as methyl alcohol, pilot process pair are not produced in production process
Product is sodium chloride, is had fewer environmental impacts, environmentally friendly, and product yield is high.
Specific embodiment
The present invention is further described with reference to specific embodiment, so that those skilled in the art do further
Understand, but and be not so limited the present invention.
Embodiment 1
A kind of preparation method of Liranaftate of the present invention, comprises the following steps：
(1) preparation of Liranaftate crude product：
Feed intake：250g absolute ethyl alcohols are added in reaction bulb, by 2- methoxyl group -6- picolilamine 12.5g, Carbon Dioxide
Sodium 8.8g and purified water 31.3g are sequentially added in reaction bulb, are stirred 30 minutes, are slowly added to 2- (5,6,7,8- tetrahydrochysene naphthoxy)
Chlorinated thio formic acid esters 18.8g, adds for 2 hours；
Reaction：20 DEG C of control temperature is reacted 2 hours, plus purified water 125.0g, is stirred 30 minutes；
Suction filtration：By reactant liquor suction filtration, filter cake use purifying water washing three times, the consumption of each purified water is 25.0g；
It is dried：Wet product is put in drying box, control temperature 45 C is dried 4 hours, obtains Liranaftate crude product 24g；
Synthesis yield is 81%；
(2) preparation of Liranaftate fine work：
Removal of impurities：By in 23g Liranaftates crude product and 115g absolute ethyl alcohols input reaction bulb, the medical charcoal of 1.38g, control are added
55 DEG C of decolourings of temperature, removal of impurities 30 minutes, filter, and filtrate is transferred in reaction bulb, 55 DEG C of crystallizations of temperature control, are centrifuged, are dried, crush, wrap
Dress, obtains Liranaftate fine work 22g.
Refined yield is 92%.
Embodiment 2
A kind of preparation method of Liranaftate of the present invention, comprises the following steps：
(1) preparation of Liranaftate crude product：
Feed intake：500g absolute ethyl alcohols are added in reaction bulb, by 2- methoxyl group -6- picolilamine 25g, natrium carbonicum calcinatum
17.6g and purified water 62.6g are sequentially added in reaction bulb, are stirred 30 minutes, are slowly added to 2- (5,6,7,8- tetrahydrochysene naphthoxy)
Chlorinated thio formic acid esters 37.6g, adds for 2.5 hours；
Reaction：25 DEG C of control temperature is reacted 2.5 hours, plus purified water 250g, is stirred 30 minutes；
Suction filtration：By reactant liquor suction filtration, filter cake use purifying water washing three times, each 50g；
It is dried：Wet product is put in drying box, the drying 4 hours of 55 DEG C of temperature is controlled, Liranaftate crude product 49g is obtained；
Synthesis yield is 82%；
(2) preparation of Liranaftate fine work：
Removal of impurities：By in 49g Liranaftates crude product and 245g absolute ethyl alcohols input reaction bulb, the medical charcoal of 2.9g, control are added
55～65 DEG C of decolourings of temperature, removal of impurities 30 minutes, filter, and filtrate is transferred in reaction bulb, 65 DEG C of crystallizations of temperature control, centrifugation, dry, powder
Broken, packaging, obtains Liranaftate fine work 45g.
Refined yield is 92%.
Embodiment 3
A kind of preparation method of Liranaftate of the present invention, comprises the following steps：
(1) preparation of Liranaftate crude product：
Feed intake：250g absolute ethyl alcohols are added in reaction bulb, by 2- methoxyl group -6- picolilamine 12.5g, Carbon Dioxide
Sodium 8.8g and purified water 31.3g are sequentially added in reaction bulb, are stirred 30 minutes, are slowly added to 2- (5,6,7,8- tetrahydrochysene naphthoxy)
Chlorinated thio formic acid esters 18.8g, adds for 2 hours；
Reaction：20 DEG C of control temperature is reacted 2 hours, plus purified water 125.0g, is stirred 30 minutes；
Suction filtration：By reactant liquor suction filtration, filter cake use purifying water washing three times, each 25.0g；
It is dried：Wet product is put in drying box, the drying 4 hours of 45～55 DEG C of temperature is controlled, obtaining crude product, to obtain Liranaftate thick
Product 23.3g；
Synthesis yield is 82%；
(2) preparation of Liranaftate fine work：
Removal of impurities：140g absolute ethyl alcohols are added in reaction bulb, Liranaftate crude product 23.3g, 50 DEG C of stirrings of temperature control are added
30 minutes, 1.5g medical charcoal, the decolouring 30 minutes of 60 DEG C of temperature control is added to filter, 60 DEG C of crystallizations of temperature control, be centrifuged, be dried, crush, wrap
Dress, obtains Liranaftate fine work 23g.
Refined yield is 92%.
Claims (3)
1. a kind of preparation method of Liranaftate, it is characterised in that comprise the following steps：
(1) preparation of Liranaftate crude product：By 2- methoxyl group -6- picolilamines and the mixing of 15-20 times of absolute ethyl alcohol and stirring
Afterwards, 0.3-0.6 times of natrium carbonicum calcinatum, 2-2.5 times of purified water are added, is then slowly added into 1-2 times of 2- (5,6,7,8- naphthanes
Epoxide) chlorinated thio formic acid esters, 10～30 DEG C of temperature control reaction 2-3 hours, plus 10 times of purified water stirs 30 minutes, centrifugation,
It is dried at 45-55 DEG C, obtains Liranaftate crude product；
(2) preparation of Liranaftate fine work：Absolute ethyl alcohol is with Liranaftate crude product according to 1:(5-6) after feeding intake, profit is added to draw naphthalene
The medical charcoal of ester crude product quality 0.05-0.07 times, 55～65 DEG C of decolourings of temperature control, removal of impurities 30 minutes, aseptic filtration to stainless steel is anti-
Answer in kettle, 55-65 DEG C of crystallization of temperature control, centrifugation, dry, crushing, packaging obtain Liranaftate fine work.
2. a kind of preparation method of Liranaftate according to claim 1, it is characterised in that step 2) aseptic filtration process
Used in 0.22 μm of filter core and 10 μm of titanium rods.
3. the preparation method of a kind of Liranaftate according to claim 1, it is characterised in that comprise the following steps：
(1) preparation of Liranaftate crude product：After by 2- methoxyl group -6- picolilamines and the mixing of 20 times of absolute ethyl alcohol and stirring,
0.5 times of natrium carbonicum calcinatum, 2.5 times of purified waters are added, 1.5 times of 2- (5,6,7,8- tetrahydrochysene naphthoxy) chlorination is then slowly added into
Thiocarboxylic, 15-25 DEG C of temperature control reacts 2.5 hours, plus 10 times of purified water is stirred 30 minutes, is centrifuged, dry at 45-55 DEG C
It is dry, obtain Liranaftate crude product；
(2) preparation of Liranaftate fine work：Absolute ethyl alcohol is with Liranaftate crude product according to 1:After 5 feed intake, add Liranaftate thick
The medical charcoal that 0.06 times of quality, 60 DEG C of decolourings of temperature control, removal of impurities 30 minutes, in aseptic filtration to stainless steel cauldron, temperature control 60
DEG C crystallization, centrifugation, be dried, crush, packaging, obtain Liranaftate fine work.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611250807.6A CN106632018A (en) | 2016-12-30 | 2016-12-30 | Preparation method of liranaftate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611250807.6A CN106632018A (en) | 2016-12-30 | 2016-12-30 | Preparation method of liranaftate |
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| CN106632018A true CN106632018A (en) | 2017-05-10 |
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| CN201611250807.6A Pending CN106632018A (en) | 2016-12-30 | 2016-12-30 | Preparation method of liranaftate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1696116A (en) * | 2004-05-12 | 2005-11-16 | 东曹株式会社 | 0-(5,6,7,8-tetrahydro-2-naphthyl)-N-(6-methoxy group-2-pyridyl)-N-methyl methyl thiocarbamate and its prepn. |
| JP2006298832A (en) * | 2005-04-21 | 2006-11-02 | Tosoh Corp | High-purity o-(5,6,7,8-tetrahydro-2-naphthyl)-n-(6-methoxy-2-pyridyl)-n-methylthiocarbamate and its preparation method |
| CN104402810A (en) * | 2014-11-27 | 2015-03-11 | 天方药业有限公司 | Preparation method of liranaftate |
-
2016
- 2016-12-30 CN CN201611250807.6A patent/CN106632018A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1696116A (en) * | 2004-05-12 | 2005-11-16 | 东曹株式会社 | 0-(5,6,7,8-tetrahydro-2-naphthyl)-N-(6-methoxy group-2-pyridyl)-N-methyl methyl thiocarbamate and its prepn. |
| JP2006298832A (en) * | 2005-04-21 | 2006-11-02 | Tosoh Corp | High-purity o-(5,6,7,8-tetrahydro-2-naphthyl)-n-(6-methoxy-2-pyridyl)-n-methylthiocarbamate and its preparation method |
| CN104402810A (en) * | 2014-11-27 | 2015-03-11 | 天方药业有限公司 | Preparation method of liranaftate |
Non-Patent Citations (3)
| Title |
|---|
| 李飞等: "利拉萘酯合成工艺的研究", 《南京医科大学学报(自然科学版)》 * |
| 金荣庆等: "利拉萘酯的合成方法改进", 《中南药学》 * |
| 陶琼华等: "利拉萘酯的合成", 《中国医药工业杂志》 * |
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Application publication date: 20170510 |
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