CN107759574A - A kind of formic acid esters intermediate of 5 fluorine 1H pyrazoles 3 and its synthetic method - Google Patents

A kind of formic acid esters intermediate of 5 fluorine 1H pyrazoles 3 and its synthetic method Download PDF

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CN107759574A
CN107759574A CN201710753540.0A CN201710753540A CN107759574A CN 107759574 A CN107759574 A CN 107759574A CN 201710753540 A CN201710753540 A CN 201710753540A CN 107759574 A CN107759574 A CN 107759574A
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CN107759574B (en
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范海江
管增东
夏爱华
李辉
揭元萍
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PHARMABLOCK (NANJING) R&D CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D231/16—Halogen atoms or nitro radicals

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Abstract

The invention discloses a kind of structural formula IV compound and its synthetic method, and applications of the compound IV in 5 fluorine 1H pyrazoles 3 formic acid esters (compound I) synthesis, belong to organic chemical synthesis field, the 5 fluorine pyrazoles (compound II) that this method is substituted with N is raw materials, reset under catalyst action and obtain compound III, then successfully synthesize the substituted formic acid esters of 1H pyrazoles 3 by carboxylation and esterification can.This method is simple to operate, and route is short, and obtain product yield high, suitable for large-scale production.

Description

A kind of fluoro- 1H- pyrazoles -3- formic acid esters intermediate of 5- and its synthetic method
Technical field
The present invention relates to organic chemical synthesis field, relates in particular to synthesize among the fluoro- 1H- pyrazoles -3- formic acid esters of 5- Body and its synthetic method.
Background technology
1H- pyrazoles -3- the formic acid esters of halogen substitution has a wide range of applications in field of medicaments, such as available for preparing lipid The heterocyclic modulators compound and its pharmaceutically acceptable salt of synthesis, the Class1 suppression of synthesis 11- beta hydroxysteroid dehydrogenases Preparation and V1b Receptor antagonists etc..
The route reported in the A of CN 106061963 is as follows：
Reagent and yield：(a) MeOH, H2SO4, yield 70%；(b) Pd/C, H2, MeOH, yield：73%；(c)NaNO2, KI, H2SO4, H2O, yield 30%.
The method of this report has the following disadvantages：The synthetic route total recovery is 15.3%, and yield is relatively low；Add in b step Hydrogen reaction has certain danger；Diazo-reaction fire-prone in step c, diazol caused by diazo-reaction, Temperature is slightly higher or light in the presence of, i.e., easily decompose, some even can also be decomposed in room temperature, and in the dry state, some are weighed Nitrogen salt is unstable, and vigor is big, is heated or rubs, hits, can decomposition explosion.
Venkat Gaddamidi et al. in J.Agric.Food Chem., 2011,59,9424-9432 document reports with 3- bromines pyrazoles is raw material, N- dimethyl disulfides acyl derivative is first formed with dimethyl disulfide acyl chloride reaction to protect nitrogen, then -70 Act on diisopropylamino lithium at DEG C, and be quenched with carbon dioxide, finally with methanol esterification, obtain the bromo- 1H- pyrazoles -5- first of 3- Sour methyl esters.
The content of the invention
It is an object of the invention to provide a kind of intermediate (compound IV) of the fluoro- 1H- pyrazoles -3- formic acid esters of new 5-, from Compound IV single step reactions obtain the fluoro- 1H- pyrazoles -3- formic acid esters of 5-.The present invention is using compound II as raw material simultaneously, in catalyst The lower rearrangement of effect obtains compound III, then obtains by carboxylation synthesizing compound IV.
A kind of structural formula IV compound：
Compound IV preparation method：It is raw material with compound II,
(1) first reset in the presence of catalyst, obtain compound III
(2) carboxylation and then in the presence of highly basic is carried out with carbon dioxide or dry ice, obtains compound IV
Catalyst may be selected from described in step (1)：Trifluoroacetic acid, p-methyl benzenesulfonic acid monohydrate, trifluoromethanesulfonic acid, benzene Sulfonic acid, methanesulfonic acid；Solvent may be selected from：Dimethylbenzene, toluene, chlorobenzene.Range of reaction temperature is at 110~140 DEG C；Reaction time is 6 ~60 hours.
Highly basic described in step (2) may be selected from n-BuLi, tert-butyl lithium, lithium diisopropylamine (LDA), two (front threes Base silicon substrate) lithium amide (LiHMDS), two (trimethyl silicon substrate) Sodamides (NaHMDS), magnesium dichloride (2,2,6,6- tetramethyl piperazines Pyridine) lithium salts, phenyl lithium.The mol ratio of compound III and highly basic is 1.0: 1.0~1.0: 3.0.Reaction temperature is -78~-30 ℃.Reaction dissolvent is selected from tetrahydrofuran, ether, 2- methyltetrahydrofurans, cyclopentyl methyl ether.
By compound IV prepare compounds I method, compound IV
In the presence of thionyl chloride, esterification occurs with ROH and obtains compound I
Wherein R is methyl or ethyl.The mol ratio of compound IV and thionyl chloride is 1.0: 1.5~1.0: 3.5.
By compound II prepare compounds I method：It is raw material with compound II,
(1) first reset in the presence of catalyst, obtain compound III
(2) carboxylation and then in the presence of highly basic is carried out with carbon dioxide or dry ice, obtains compound IV
(3) in the presence of thionyl chloride, esterification occurs with ROH and obtains compound I
Wherein R is methyl or ethyl.The mol ratio of compound IV and thionyl chloride is 1.0: 1.5~1.0: 3.5.
Beneficial effect：
Although the existing a certain degree of research of 1H- pyrazoles -3- formic acid esters that prior art substitutes to halogen, fluoro 1H- pyrazoles -3- formic acid esters has not yet to see report in the art.In terms of medicine, aromatic fluorine compound is active group A kind of medicine plays the role of very important.When fluorine atom or fluoro-containing group are introduced into compound, its electrical effect and mimic effect The distribution of intramolecule electron density is changed, have impact on the acid-base property of compound internal structure, and then changes its activity, and And the fat-soluble of compound can also be improved.Fluorine atom instead of the hydrogen atom in compound, and its ester type compound is on biomembrane Dissolubility strengthened, the transmission speed for promoting it to absorb in vivo, physiological action is changed.It is so many Fluorochemical than not fluorochemical on the pharmaceutical properties such as medicine, agricultural chemicals have dosage is few, toxicity is low, drug effect is high, metabolism The advantages of ability is strong.
The present invention provides a kind of intermediate (compound IV) of the fluoro- 1H- pyrazoles -3- formic acid esters of new 5-, from compound IV Single step reaction obtains the fluoro- 1H- pyrazoles -3- formic acid esters of 5-.The present invention is using compound II as raw material simultaneously, the weight under catalyst action Row obtains compound III, then obtains by carboxylation synthesizing compound IV.The step of route involves is short, simple to operate, work Skill is reproducible, is easy to purify, and total recovery is up to 61.1%, is easy to produce in batches.
The abbreviation for the reaction reagent being related in specification is as follows：
LiHMDS bis- (trimethyl silicon substrate) lithium amide；
LDA lithium diisopropylamines；
NaHMDS bis- (trimethyl silicon substrate) Sodamide；
LTMPMgCl2Magnesium dichloride (2,2,6,6- tetramethyl piperidines) lithium salts；
THF tetrahydrofurans；
TsOH·H2O p-methyl benzenesulfonic acid monohydrates.
Embodiment
The present invention further illustrates the present invention with the following example, but protection scope of the present invention is not limited to implement Example.Those skilled in the art can make many other changes in the case of without departing from the spirit and scope of protection of the present invention And modification, these, which are changed and modifications, is included in claims in the range of protection.
Embodiment 1
Compound II prepare compounds III：
Compound II (120.0g, 0.705mol, 1.0e.q.) is added into dimethylbenzene (1200mL), adds trifluoroacetic acid (4.02g, 0.0353mol, 0.05e.q.), 140 DEG C are warming up to after adding, reacted 6 hours, GC detection raw materials have reacted, and add Saturated aqueous sodium carbonate washs, and (3 × 900mL) is extracted with ethyl acetate, is dried with anhydrous magnesium sulfate, filters, filtrate concentration Do to obtain compound III yellow liquid 108.0g, yield 90.0%.
Compound III prepare compounds IV：
Compound III (70.0g, 0.411mol, 1.0e.q.) is dissolved in THF (700mL), under nitrogen protection, -78 DEG C 2.5M n-BuLis/normal hexane (197mL, 0.494mol, 1.2e.q.) is added dropwise, drop finishes -78 DEG C and is incubated 20 minutes, slowly logical After entering dry carbon dioxide about 15 minutes, stopping is passed through carbon dioxide, starts that 1N aqueous hydrochloric acid solution is added dropwise, adjusts pH =2,1L ethyl acetate extraction is added, drying is concentrated to give yellow oil, adds 500mL petroleum ether mashing, separates out solid, Filtering, obtains compound IV white solid 70.5g, yield 80.0%.
Compound IV prepare compounds I-1：
Compound IV (70.0g, 0.327mol, 1.0e.q.) is dissolved in methanol (500mL), under the conditions of ice-water bath, is added dropwise Thionyl chloride (77.8g, 0.654mol, 2.0e.q.), Bi Huiliu 10h are dripped, concentration of reaction solution, pH are adjusted with saturated sodium bicarbonate =8, then extracted with ethyl acetate (500mL × 2), dry concentration, concentrate ethyl acetate and petroleum ether (volume：Volume= 1:50) it is beaten, obtains compound I-1 white solid 36.9g, yield 78.2%.
Embodiment 2
Compound II prepare compounds III：
Compound II (125.4g, 0.737mol, 1.0e.q.) is added into toluene (1200mL), added to methylbenzene sulphur Sour monohydrate (7.00g, 0.0369mol, 0.05e.q.), 110 DEG C are warming up to after adding, reacted 60 hours, GC detection raw materials It has been reacted that, add saturated aqueous sodium carbonate washing, (3 × 900mL) is extracted with ethyl acetate, is dried with anhydrous magnesium sulfate, mistake Compound III yellow liquid 117.0g, yield 93.3% are done to obtain in filter, filtrate concentration.
Compound III prepare compounds IV：
Compound III (75.1g, 0.441mol, 1.0e.q.) is dissolved in ether (650mL), under nitrogen protection, -78 DEG C 1.3M tert-butyl lithiums/heptane (407mL, 0.529mol, 1.2e.q.) is added dropwise, drop finishes -78 DEG C and is incubated 35 minutes, is slowly introducing After dry carbon dioxide about 20 minutes, stopping is passed through carbon dioxide, starts that 1N hydrochloride aqueous solution is added dropwise, adjusts pH =2,1L ethyl acetate extraction is added, drying is concentrated to give yellow oil, adds 500mL petroleum ether mashing, separates out solid, Filtering, obtains compound IV white solid 77.4g, yield 81.9%.
Compound IV prepare compounds I-1：
Compound IV (70.0g, 0.327mol, 1.0e.q.) is dissolved in methanol (500mL), under the conditions of ice-water bath, is added dropwise Thionyl chloride (58.4g, 0.491mol, 1.5e.q.), Bi Huiliu 10h are dripped, concentration of reaction solution, pH are adjusted with saturated sodium bicarbonate =8, then extracted with ethyl acetate (500mL × 2), dry concentration, concentrate ethyl acetate and petroleum ether (volume：Volume= 1:50) it is beaten, obtains compound I-1 white solid 37.7g, yield 80.1%.
Embodiment 3
Compound II prepare compounds III：
Compound II (122.6g, 0.720mol, 1.0e.q.) is added into chlorobenzene (1200mL), adds benzene sulfonic acid (5.69g, 0.0360mol, 0.05e.q.), 130 DEG C are warming up to after adding, reacted 20 hours, GC detection raw materials have reacted, and add Saturated aqueous sodium carbonate washs, and (3 × 900mL) is extracted with ethyl acetate, is dried with anhydrous magnesium sulfate, filters, filtrate concentration Do to obtain compound III yellow liquid 112.5g, yield 91.8%.
Compound III prepare compounds IV：
Compound III (80.3g, 0.472mol, 1.0e.q.) is dissolved in 2- methyltetrahydrofurans (800mL), nitrogen Under protection, -60 DEG C are added dropwise 2.0M LDA/ normal hexanes (283mL, 0.566mol, 1.2e.q.), and drop finishes -60 DEG C and is incubated 60 minutes, After being slowly introducing dry carbon dioxide about 30 minutes, stopping is passed through carbon dioxide, and the hydrogen chloride for starting to be added dropwise 1N is water-soluble Liquid, pH=2 being adjusted, add 1L ethyl acetate extraction, drying is concentrated to give yellow oil, adds 500mL petroleum ether mashing, Solid is separated out, filtering, obtains compound IV white solid 81.2g, yield 80.3%.
Compound IV prepare compounds I-1：
Compound IV (70.0g, 0.327mol, 1.0e.q.) is dissolved in methanol (500mL), under the conditions of ice-water bath, is added dropwise Thionyl chloride (97.3g, 0.818mol, 2.5e.q.), Bi Huiliu 10h are dripped, concentration of reaction solution, pH are adjusted with saturated sodium bicarbonate =8, then extracted with ethyl acetate (500mL × 2), dry concentration, concentrate ethyl acetate and petroleum ether (volume：Volume= 1:50) it is beaten, obtains compound I-1 white solid 37.5g, yield 79.5%.
Embodiment 4
Compound II prepare compounds III：
Compound II (123.3g, 0.724mol, 1.0e.q.) is added into chlorobenzene (1200mL), adds methanesulfonic acid (3.48g, 0.0362mol, 0.05e.q.), 120 DEG C are warming up to after adding, reacted 40 hours, GC detection raw material reactions are over, and add Enter saturated aqueous sodium carbonate washing, (3 × 900mL) is extracted with ethyl acetate, is dried with anhydrous magnesium sulfate, filter, filtrate is dense Compound III yellow liquid 111.9g, yield 90.8% are done to obtain in contracting.
Compound III prepare compounds IV：
Compound III (81.6g, 0.479mol, 1.0e.q.) is dissolved in cyclopentyl methyl ether (550mL), nitrogen protection Under, -60 DEG C are added dropwise 1.5M phenyl lithiums/tetrahydrofuran (383mL, 0.575mol, 1.2e.q.), and drop finishes -60 DEG C and is incubated 45 minutes, After being slowly introducing dry carbon dioxide about 25 minutes, stopping is passed through carbon dioxide, and the hydrogen chloride for starting to be added dropwise 1N is water-soluble Liquid, pH=2 being adjusted, add 1L ethyl acetate extraction, drying is concentrated to give yellow oil, adds 500mL petroleum ether mashing, Solid is separated out, filtering, obtains compound IV white solid 82.2g, yield 80.1%.
Compound IV prepare compounds I-1：
Compound IV (70.0g, 0.327mol, 1.0e.q.) is dissolved in methanol (500mL), under the conditions of ice-water bath, is added dropwise Thionyl chloride (136.2g, 1.15mol, 3.5e.q.), Bi Huiliu 10h are dripped, concentration of reaction solution, pH are adjusted with saturated sodium bicarbonate =8, then extracted with ethyl acetate (500mL × 2), dry concentration, concentrate ethyl acetate and petroleum ether (volume：Volume= 1:50) it is beaten, obtains compound I-1 white solid 37.2g, yield 79.0%.
Embodiment 5
Compound II prepare compounds III：
Compound II (122.1g, 0.717mol, 1.0e.q.) is added into toluene (1200mL), adds trifluoromethanesulfonic acid (5.38g, 0.0359mol, 0.05e.q.), 110 DEG C are warming up to after adding, reacted 60 hours, GC detection raw material reactions are over, and add Enter saturated aqueous sodium carbonate washing, (3 × 900mL) is extracted with ethyl acetate, is dried with anhydrous magnesium sulfate, filter, filtrate is dense Compound III yellow liquid 111.5g, yield 91.3% are done to obtain in contracting.
Compound III prepare compounds IV：
Compound III (76.9g, 0.452mol, 1.0e.q.) is dissolved in tetrahydrofuran (600mL), nitrogen protection Under, -65 DEG C are added dropwise 2.0M LDA/ normal hexanes (271mL, 0.542mol, 1.2e.q.), and drop finishes -65 DEG C and is incubated 45 minutes, 30 points Dry ice is added portionwise in clock, then starts that 1N hydrochloride aqueous solution is added dropwise, adjusts pH=2, adds 1L ethyl acetate extraction, Drying is concentrated to give yellow oil, adds 500mL petroleum ether mashing, separates out solid, filtering, obtain compound IV white solids 78.8g, yield 81.4%.
Compound IV prepare compounds I-1：
Compound IV (70.0g, 0.327mol, 1.0e.q.) is dissolved in methanol (500mL), under the conditions of ice-water bath, is added dropwise Thionyl chloride (58.4g, 0.491mol, 1.5e.q.), Bi Huiliu 10h are dripped, concentration of reaction solution, pH are adjusted with saturated sodium bicarbonate =8, then extracted with ethyl acetate (500mL × 2), dry concentration, concentrate ethyl acetate and petroleum ether (volume：Volume= 1:50) it is beaten, obtains compound I-1 white solid 38.4g, yield 81.5%.
Embodiment 6
Compound II prepare compounds III：
Prepared with method same in embodiment 1, finally obtain compound III yellow liquid 112.2g, yield 92.1%.
Compound III prepare compounds IV：
III (82.0g, 0.482mol, 1.0e.q.) is dissolved in THF (550mL), under nitrogen protection, -65 DEG C of dropwise additions 1.0M LiHMDS/ tetrahydrofurans (578mL, 0.578mol, 1.2e.q.), drop finish -65 DEG C and are incubated 20 minutes, are slowly introducing drying Carbon dioxide after about 25 minutes, stopping is passed through carbon dioxide, starts that 1N aqueous hydrochloric acid solution is added dropwise, adjust pH=2, add Entering 1L ethyl acetate extraction, drying is concentrated to give yellow oil, adds 500mL petroleum ether mashing, separates out solid, filter, Obtain compound IV white solid 83.9g, yield 81.3%.
Compound IV prepare compounds I-2：
Prepared with method same in embodiment 1, only change is to replace methanol to join as solvent by the use of 500mL ethanol
With reaction, compound I-2 white solid 42.2g, yield 81.6% are obtained.
Embodiment 7
Compound II prepare compounds III：
Prepared with method same in embodiment 2, finally obtain compound III yellow liquid 117.0g, yield 92.5%.
Compound III prepare compounds IV：
III (77.3g, 0.454mol, 1.0e.q.) is dissolved in ether (600mL), under nitrogen protection, -30 DEG C of dropwise additions 1.0M magnesium dichlorides (2,2,6,6- tetramethyl piperidine) lithium salts/THF (545mL, 0.545mol, 1.0e.q.), drop finish, -60 DEG C of guarantors Temperature 20 minutes, after being slowly introducing dry carbon dioxide about 30 minutes, stopping is passed through carbon dioxide, starts that 1N chlorine is added dropwise Change aqueous solution of hydrogen, adjust pH=2, add 1L ethyl acetate extraction, drying is concentrated to give yellow oil, adds 500mL stone Oily ether mashing, separates out solid, filtering, obtains compound IV white solid 76.4g, yield 80.8%.
Compound IV prepare compounds I-1：
Prepared with method same in embodiment 2, only change is to replace methanol to be participated in as solvent by the use of 500mL ethanol Reaction, obtains compound I-2 white solid 41.8g, yield 80.9%.
Embodiment 8
Compound II prepare compounds III：
Prepared with method same in embodiment 3, only change is to replace toluene finally to be obtained as solvent by the use of dimethylbenzene Compound III yellow liquid 115.3g, yield 90.9%.
Compound III prepare compounds IV：
III (82.1g, 0.482mol, 1.0e.q.) is dissolved in 2- methyltetrahydrofurans (550mL), nitrogen protection Under, -60 DEG C are added dropwise 1.2M LDA/THF (482mL, 0.578mol, 1.2e.q.), and drop finishes -60 DEG C and is incubated 35 minutes, is slowly introducing After dry carbon dioxide about 35 minutes, stopping is passed through carbon dioxide, starts that 1N hydrochloride aqueous solution is added dropwise, adjusts pH =2,1L ethyl acetate extraction is added, drying is concentrated to give yellow oil, adds 500mL petroleum ether mashing, separates out solid, Filtering, obtains compound IV white solid 83.9g, yield 81.3%.
Compound IV prepare compounds I-1：
Prepared with method same in embodiment 3, only change is to replace methanol to be participated in as solvent by the use of 500mL ethanol Reaction, obtains compound I-2 white solid 42.4g, yield 82.0%.
Embodiment 9
Compound II prepare compounds III：
Prepared with method same in embodiment 1, finally obtain compound III yellow liquid 114.1g, yield 91.3%.Change Compound III prepare compounds IV：
III (83.1g, 0.488mol, 1.0e.q.) is dissolved in cyclopentyl methyl ether (800mL), under nitrogen protection, -78 DEG C 2.5M n-BuLis/n-hexane (234mL, 0.586mol, 1.2e.q.) is added dropwise, drop finishes -60 DEG C and is incubated 30 minutes, 20 minutes Dry ice is inside added portionwise, then starts that 1N hydrochloride aqueous solution is added dropwise, adjusts pH=2, adds 1L ethyl acetate extraction, does It is dry to be concentrated to give yellow oil, 500mL petroleum ether mashing is added, solid is separated out, filtering, obtains compound IV white solids 81.2g, yield 81.1%.
Compound IV prepare compounds I-2：
Prepared with method same in embodiment 4, only change is to replace methanol to be participated in as solvent by the use of 500mL ethanol Reaction, obtains compound I-2 white solid 41.2g, yield 79.8%.
Embodiment 10
Compound II prepare compounds III：
Being prepared with method same in embodiment 1, only change is to substitute trifluoroacetic acid with trifluoromethanesulfonic acid, finally Compound III yellow liquid 113.6g, yield 90.8%.
Compound III prepare compounds IV：
Compound III (75.3g, 0.442mol, 1.0e.q.) is dissolved in 2- methyltetrahydrofurans (600mL), nitrogen Under protection, -65 DEG C of 1.0M LiHMDS/ tetrahydrofurans (530mL, 0.530mol, 1.2e.q.), drop finishes -65 DEG C and is incubated 45 minutes, After being slowly introducing dry carbon dioxide about 35 minutes, stopping is passed through carbon dioxide, and the hydrogen chloride for starting to be added dropwise 1N is water-soluble Liquid, pH=2 being adjusted, add 1L ethyl acetate extraction, drying is concentrated to give yellow oil, adds 500mL petroleum ether mashing, Solid is separated out, filtering, obtains compound IV white solid 76.1g, yield 80.4%.
Compound IV prepare compounds I-2：
Prepared with method same in embodiment 6, obtain compound I-2 white solid 42.4g, yield 82.1%.
Table one, compound structure parsing

Claims (11)

  1. A kind of 1. structural formula IV compound：
  2. A kind of 2. compound IV of claim 1 preparation method, it is characterised in that：
    It is raw material with compound II
    (1) first reset in the presence of catalyst, obtain compound III
    (2) carboxylation and then in the presence of highly basic is carried out with carbon dioxide or dry ice, obtains compound IV
  3. 3. compound IV synthetic method according to claim 2, the institute in compound II prepare compound III steps (1) Catalyst is stated to may be selected from：Trifluoroacetic acid, p-methyl benzenesulfonic acid monohydrate, trifluoromethanesulfonic acid, benzene sulfonic acid, methanesulfonic acid.
  4. 4. compound IV synthetic method according to claim 2, molten in compound II prepare compound III steps (1) Agent may be selected from：Dimethylbenzene, toluene, chlorobenzene.
  5. 5. compound IV synthetic method according to claim 2, anti-in compound II prepare compound III steps (1) Temperature range is answered at 110~140 DEG C；Reaction time was at 6~60 hours.
  6. 6. compound IV synthetic method according to claim 2, the institute in compound III prepare compound IV steps (2) State highly basic and may be selected from n-BuLi, tert-butyl lithium, lithium diisopropylamine, two (trimethyl silicon substrate) lithium amides, two (trimethyl silicanes Base) Sodamide, magnesium dichloride (2,2,6,6- tetramethyl piperidines) lithium salts, phenyl lithium.
  7. 7. according to the synthetic method of compound IV described in claim 2 or claim 6, in compound III prepare compounds The mol ratio of compound III and highly basic is 1.0: 1.0~1.0: 3.0 in IV steps (2).
  8. 8. according to the synthetic method of compound IV described in claim 2 or claim 6, in compound III prepare compounds Reaction temperature described in IV steps (2) is -78~-30 DEG C.
  9. 9. according to the synthetic method of compound IV described in claim 2 or claim 6, in compound III prepare compounds Reaction dissolvent is selected from tetrahydrofuran, ether, 2- methyltetrahydrofurans, cyclopentyl methyl ether in IV steps (2).
  10. A kind of 10. preparation method of structural formula I compound, it is characterised in that compound IV
    In the presence of thionyl chloride, esterification occurs with ROH and obtains compound I
    Wherein R is methyl or ethyl.
  11. 11. the mol ratio of compound I synthetic method according to claim 10, compound IV and thionyl chloride is 1.0: 1.5~1.0: 3.5.
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WO2017136727A2 (en) * 2016-02-05 2017-08-10 Denali Therapeutics Inc. Compounds, compositions and methods

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103068813A (en) * 2010-06-15 2013-04-24 拜耳知识产权有限责任公司 Anthranilic acid diamide derivatives
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