CN105777743A - Preparation method and application of pyrazolo[3, 4-b]pyridine compound intermediate - Google Patents
Preparation method and application of pyrazolo[3, 4-b]pyridine compound intermediate Download PDFInfo
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- 0 C*C[C@@](C)N(C1)*(C2C)=I[C@@]2[C@](C)[C@@]1C(*1*2C1CC*2)=* Chemical compound C*C[C@@](C)N(C1)*(C2C)=I[C@@]2[C@](C)[C@@]1C(*1*2C1CC*2)=* 0.000 description 4
- AHIHZCXUWGORQO-UHFFFAOYSA-N CNCc(cccc1)c1F Chemical compound CNCc(cccc1)c1F AHIHZCXUWGORQO-UHFFFAOYSA-N 0.000 description 1
- BESBJLNEDSCYOE-UHFFFAOYSA-N N#Cc1n[n](CC(C=CCC2)=C2F)c2ncccc12 Chemical compound N#Cc1n[n](CC(C=CCC2)=C2F)c2ncccc12 BESBJLNEDSCYOE-UHFFFAOYSA-N 0.000 description 1
- GNPGVZCKAVPTEN-UHFFFAOYSA-O NC(C(c1c([NH2+]Cc(cccc2)c2F)nccc1)=N)=O Chemical compound NC(C(c1c([NH2+]Cc(cccc2)c2F)nccc1)=N)=O GNPGVZCKAVPTEN-UHFFFAOYSA-O 0.000 description 1
- RXTRRIFWCJEMEL-UHFFFAOYSA-N O=C(c1cccnc1Cl)Cl Chemical compound O=C(c1cccnc1Cl)Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 description 1
- IBRSSZOHCGUTHI-UHFFFAOYSA-N OC(c1cccnc1Cl)=O Chemical compound OC(c1cccnc1Cl)=O IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a preparation method and application of a pyrazolo[3, 4-b]pyridine compound intermediate. Specifically, the intermediate structure is shown as formula IV, wherein the groups are defined as the specification and claims. The intermediate can be prepared from a formula (I) compound, and can be used for preparation of Riociguat. The method provided by the invention has the advantages of cheap and easily available raw materials, high total yield, mild reaction condition, simple operation and easy purification, and is suitable for industrial mass production.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to the preparation method and application of pyrazolo [3,4-b] pyridine compounds and their intermediate；It is more particularly to the synthetic method of important intermediate 1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-formonitrile HCN of the western croak of Leo.
Background technology
The western croak of Leo (Riociguat, trade name Adempas) is the activator of the sGC (solubleguanlyasecyclase, sGC) of Bayer Healthcare's exploitation.On October 8th, 2013, it is used for treating pulmonary hypertension (pulmonaryhypertension by FDA approval, PH) medicine, mainly for chronic thromboembolic pulmonary hypertension (chronicthromboembolicpulmonaryhypertension, and pulmonary hypertension (pulmonaryarterialhypertension, PAH) CTEPH).SGC is important signal conduction enzyme, it is possible to is activated catalysis GTP (guanosine triphosphate) (GTP) by nitric oxide (NO) and is converted into second message,second messenger's cyclic guanosine monophosphate (cGMP).SGC is currently the only known NO receptor.The infringement of NO-sGC-cGMP signal path is considered as the pathogenic factor (Chem.Med.Chem.2009,853) causing cardiovascular, lung, endothelium, kidney and hepatic disease.
The western croak of Leo, chemistry N-[4,6-diaminourea-2-[1-[(2-fluorophenyl) methyl]-1H-pyrazolo [3,4-b] pyridin-3-yl]-5-pyrimidine radicals]-N-methylene dicarbamate by name.Structural formula is as follows:
1-(2-luorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-formonitrile HCN (formula 2 compound, also referred to as intermediate (2)) it is the important intermediate synthesizing the western croak of Leo, first its synthetic method is disclosed in WO03095451:
But, the synthetic method of this report has the disadvantage that the dioxane solution domestic market of raw material cyano propanone acetoacetic ester sodium salt (11) is difficult to buy, and price is higher；Intermediate (13) needs column chromatography purification, is not suitable for industrialized production.
CN102491974 also reports the process route of a synthetic intermediate (2):
And the existence of this synthetic method is disadvantageous in that: raw material 3-iodo-1H-pyrazolo [3,4-b] pyridine (15) is difficult to buy both at home and abroad, and price is very high；Catalyst tetrakis triphenylphosphine palladium is expensive and consumption big (having reached 33% with the weight ratio of reaction substrate (16))；Double; two (diphenylphosphine) ferrocene (dppf) price of other reagent such as 1,1'-is also costly, therefore this route cost of material is too high, is not suitable for industrialized production.
It addition, the method for the synthetic intermediate (2) of DerPharmaChemica, 2013,5 (4): 232-239 reports is as follows:
But, the method route is oversize, causes production cost high, is also not suitable for industrialized production.
Therefore, this area remain a need for finding that a kind of production cost is low, the preparation method of mild condition, the western croak of Leo easy and simple to handle and intermediate thereof.
Summary of the invention
It is an object of the invention to provide class intermediate preparing the western croak of Leo and preparation method thereof, thus providing, a kind of production cost is low, the western croak preparation method of mild condition, Leo easy and simple to handle.
The preparation method that a first aspect of the present invention provides a kind of Formulas I V compound, comprises the following steps:
At 20～80 DEG C, in organic solvent, compound of formula I is obtained by reacting Formulas I V compound with hydrazine dihydrochloride under desiccant exists；
In formula, R represents fluorine, chlorine, bromine, iodine, mesyl, p-toluenesulfonyl, trifyl, mesyloxy, tolysulfonyl oxygen base or trifluoro-methanesulfonyl oxy；R2For hydrogen, C6-12Arylmethyl, replacement C6-12Arylmethyl or C1-6Alkyl；Referring to of described replacement is optionally substituted by halogen.
In another preference, described organic solvent is selected from DMF, acetonitrile or dimethyl sulfoxide.
In another preference, described desiccant is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, dead plaster, anhydrous calcium chloride or 4A molecular sieve.
The preparation method that a second aspect of the present invention provides the western croak of a kind of Leo, comprises the following steps:
I) formula 2 compound and Feldalat NM are obtained by reacting formula 3 compound；
II) formula 3 compound acetic acid, ammonium chloride existence under be obtained by reacting formula 19 compound；
III) formula 19 compound and formula 5 compound are obtained by reacting formula 6 compound；
IV) formula 6 compound catalyzed hydrogenation in the presence of a catalyst obtains formula 7 compound；
V) formula 7 compound and methylchloroformate are obtained by reacting formula 8 compound；
VI) formula 8 compound and iodomethane reaction obtain formula 9 compound (the western croak of Leo)；
Wherein, the preparation method of formula 2 compound includes step:
At 20～80 DEG C, in organic solvent, compound of formula I is obtained by reacting Formulas I V compound with hydrazine dihydrochloride under desiccant exists；
In various, R is defined as above, R2For 2-fluorobenzyl.
In another preference, step II) in, it is 4～6:1 that acetic acid and formula 3 compound obtain mol ratio.
In another preference, step III) it is specifically described as: in DMF, add formula 19 compound, Feldalat NM, formula 5 compound, react 10～20 hours at 100～110 DEG C；After reaction terminates, remove DMF, and add water and make solid precipitation precipitate out；Filter, obtain formula 6 compound.
In another preference, after filtration, use washing with alcohol filter cake.
In another preference, step IV) in, described catalyst is Pd/C or Raney-Ni.
In another preference, step IV) in, described reaction is carrying out in the solvent of lower group: methanol, ethanol, isopropanol or its combination.
In another preference, step IV) in, described reaction carries out at 20～100 DEG C；It is preferred that carry out at 60-100 DEG C.
A third aspect of the present invention provides compound of formula I, or its salt or hydrate:
In formula, R represents fluorine, bromine, iodine, mesyl, p-toluenesulfonyl, trifyl, mesyloxy, tolysulfonyl oxygen base or trifluoro-methanesulfonyl oxy.
The preparation method that a fourth aspect of the present invention provides compound of formula I described in third aspect present invention, comprises the following steps:
In various, R is defined as above, R1For activated group；
1) at 80～150 DEG C, optionally in organic solvent, the 2-replacement nicotinic acid shown in Formula II is carried out activated carboxylic under the existence of organic reagent and obtain formula III compound；
2) at 0～70 DEG C, in acetonitrile solvent, formula III compound and cyanating reagent are carried out substitution reaction and obtains compound of formula I；
Wherein, described organic solvent is selected from toluene, dichloromethane, chloroform, oxolane or DMF；
Described organic reagent is selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus tribromide, Phosphorous chloride., phosphorus pentachloride, methylchloroformate, ethyl chloroformate or isobutyl chlorocarbonate；
Described cyanating reagent is selected from Cupricin., Cyanogran. or potassium cyanide.
In another preference, described organic reagent is thionyl chloride and oxalyl chloride.
In another preference, described cyanating reagent is Cupricin..
In another preference, in step 2) in add sodium iodide as auxiliary agent.Preferably, formula III compound: Cupricin.: the mol ratio of sodium iodide is 1: 1.0～1.5: 1.5～3.0.
In another preference, described method also includes the purification step of compound of formula I: at-20 DEG C～20 DEG C, by step 2) mixed solvent of the compound of formula I dichloromethane that obtains and petroleum ether pulls an oar, and is filtrated to get purified compound of formula I；In described mixed solvent, the volume ratio of dichloromethane and petroleum ether is 1: 100～1: 1.
In another preference, in described mixed solvent, the volume ratio of dichloromethane and petroleum ether is 1:100～1:5.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus constituting new or preferred technical scheme.As space is limited, tired no longer one by one state at this.
Detailed description of the invention
The present inventor is through extensive and deep research, the preparation method having had been surprisingly found that a kind of key intermediate (i.e. compound 2) preparing the western croak of Leo, as long as the method can prepare this key intermediate and mild condition by a step, raw material is cheap, be easy to get.On this basis, inventor completes the present invention.
Pyrazolo of the present invention [3,4-b] pyridine compounds and their intermediate refers to Formulas I V compound, in formula, and R2For hydrogen, C6-12Arylmethyl, replacement C6-12Arylmethyl or C1-6Alkyl；Described replacement refer to that the substituent group being selected from lower group is replaced: halogen (such as fluorine, chlorine, bromine, iodine).
The invention provides a kind of preparation method operating extremely simple Formulas I V compound, comprise the following steps:
At 20～80 DEG C, in organic solvent, by compound of formula I and hydrazine dihydrochloride (NH2NHR2.2HCl) under desiccant exists, it is obtained by reacting Formulas I V compound；In Formulas I, R represents fluorine, chlorine, bromine, iodine, mesyl, p-toluenesulfonyl, trifyl, mesyloxy, tolysulfonyl oxygen base or trifluoro-methanesulfonyl oxy；R2As defined above.The method only need to can prepare pyrazolo [3,4-b] the pyridine compounds and their intermediate shown in Formulas I V by a step, and compared with prior art, the method highly shortened operating procedure, thus greatly reducing production cost, is especially suitable for industrialized production.
Compound shown in Formulas I V is the critically important intermediate of a class at field of medicaments, such as, when the R2 in Formulas I V compound is the benzyl that 2-fluorine replaces, this midbody compound can be used for preparing the western croak of Leo, and the preparation method of the western croak of Leo such as comprises the following steps:
I) formula 2 compound and Feldalat NM are obtained by reacting formula 3 compound；
II) formula 3 compound acetic acid, ammonium chloride existence under be obtained by reacting formula 19 compound；
III) formula 19 compound and formula 5 compound are obtained by reacting formula 6 compound；
IV) formula 6 compound catalyzed hydrogenation in the presence of a catalyst obtains formula 7 compound；
V) formula 7 compound and methylchloroformate are obtained by reacting formula 8 compound；
VI) formula 8 compound and iodomethane reaction obtain formula 9 compound (the western croak of Leo).
If based on the preparation method of formula 2 compound provided by the invention, producing the western croak of Leo further, it is possible to be substantially reduced the production cost of the western croak of Leo.
The preparation method of described formula 2 compound is namely at 20～80 DEG C, in organic solvent, compound of formula I and hydrazine dihydrochloride are obtained by reacting under desiccant exists Formulas I V compound (in Formulas I V, R2For 2-fluorobenzyl)；
In formula, R is defined as above.
Usefulness of the present invention specifically includes that
(1) preparation method providing a kind of pyrazolo [3,4-b] pyridine compounds and their, and provide the midbody compound for preparing this pyrazolo [3,4-b] pyridine compounds and their that a class formation is novel.
(2) preparation method providing a kind of western croak of new Leo.
(3) method of the present invention, reaction reagent is cheap and easy to get, and reaction condition is gentle, easy and simple to handle.
(4) method of the present invention, can obtain the product of high yield.
(5) method of the present invention, is suitable for industrialized production.
Below in conjunction with specific embodiment, the present invention is expanded on further.Should be understood that these embodiments are merely to illustrate the present invention rather than restriction the scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, generally conventionally condition, or according to manufacturer it is proposed that condition.Unless otherwise indicated, otherwise percentage ratio and number are calculated by weight.
The synthesis of embodiment 1 Formula II-c compound
In there-necked flask, add dichloromethane (20mL), 2-methyl mercapto nicotinic acid (2.0g, 11.8mmol, 1eq), at 0 DEG C, metachloroperbenzoic acid (m-CPBA, 4.6g, 26mmol are added, 2.2eq), it is warming up to 30 DEG C, continues stirring 3 hours.After reaction terminates, wash three times with saturated sodium bicarbonate, organic layer concentrating under reduced pressure, obtain white solid (1.6g, 67%), be directly used in next step.
The synthesis of embodiment 2 compound (18)
In there-necked flask, add thionyl chloride (250mL), at 0 DEG C, add 2-chlorine apellagrin (100.0g, 0.64mol, 1.0eq), be warming up to 90 DEG C, continue stirring to solid and be completely dissolved.After reaction terminates, concentrating under reduced pressure.Residue toluene (100mL) dissolves, then concentrating under reduced pressure, repeats twice, obtains rufous grease (120.1g), is directly used in next step reaction.
The synthesis of embodiment 3 formula III-b compound
In there-necked flask, add toluene (15mL), 2-bromo-nicotinic acid (2.0g, 10mmol, 1eq), oxalyl chloride (1.1ml, 13mmol, 1.3eq) is added at 0 DEG C, dropping N, dinethylformamide (1mL), is warming up to 130 DEG C, continues stirring to solid and is completely dissolved.After reaction terminates, concentrating under reduced pressure.Residue toluene (10mL) dissolves, then concentrating under reduced pressure, repeats twice, obtains rufous grease (2.3g), be directly used in next step.
The synthesis of embodiment 4 formula III-c compound
In there-necked flask, add thionyl chloride (10mL), at 0 DEG C, add 2-mesyl nicotinic acid (2.0g, 10.0mmol, 1.0eq), be warming up to 90 DEG C, continue stirring to solid and be completely dissolved.After reaction terminates, concentrating under reduced pressure.Residue toluene (10mL) dissolves, then concentrating under reduced pressure, repeats twice, obtains rufous grease (2.3g), is directly used in next step reaction.
The synthesis of embodiment 5 compound (1)
In there-necked flask, add acetonitrile (300mL), at 0 DEG C, add Cupricin. (86.4g, 0.96mol, 1.5eq) and sodium iodide (240.0g, 1.6mol, 2.5eq), be stirred at room temperature 30 minutes.Dropping compound 18 (111.0g, 0.64mol, 1.0eq), drips off for 30 minutes.It is warming up to 50 DEG C, continues reaction 2 hours.TLC monitoring reacts completely.Cool to room temperature, filter, use acetonitrile wash.Filtrate reduced in volume, residue dichloromethane (200mL) dilutes, and stirs dissolving in 1 hour, is filtered to remove insoluble matter.Filtrate reduced in volume, residue petroleum ether: dichloromethane=50:1 pulls an oar at 0 DEG C, it is filtrated to get faint yellow solid (100.2g), yield: 94.6%.
1HNMR (400MHz, CDCl3) δ 8.73 (dd, J=4.8,1.9Hz, 1H), 8.47 (dd, J=7.8,1.9Hz, 1H), 7.58 (dd, J=7.8,4.8Hz, 1H).
The synthesis of embodiment 6 Formulas I-b compound
In there-necked flask, add acetonitrile (10mL), at 0 DEG C, add Cupricin. (675mg, 7.5mmol, 1.1eq) and sodium iodide (2.0g, 13.6mmol, 2.0eq), be stirred at room temperature 30 minutes under nitrogen protection.Dropping formula III-b compound (1.5g, 6.8mmol, 1eq), drips off for 30 minutes.It is warming up to 30 DEG C, continues reaction 2 hours.TLC monitoring reacts completely.Cool to room temperature, filter, use acetonitrile wash.Filtrate reduced in volume, residue dichloromethane (20mL) dilutes, and stirs dissolving in 1 hour, is filtered to remove insoluble matter.Filtrate reduced in volume, residue petroleum ether: dichloromethane=20:1 pulls an oar at 20 DEG C, filters.Obtain faint yellow solid (819mg), yield: 57.4%.
The synthesis of embodiment 7 Formulas I-c compound
In there-necked flask, add acetonitrile (10mL), at 0 DEG C, add Cupricin. (675mg, 7.5mmol, 1.1eq) and sodium iodide (2.0g, 13.6mmol, 2.0eq), be stirred at room temperature 30 minutes under nitrogen protection.Dropping formula III-c compound (1.5g, 6.8mmol, 1eq), drips off for 30 minutes.It is warming up to 30 DEG C, continues reaction 2 hours.TLC monitoring reacts completely.Cool to room temperature, filter, use acetonitrile wash.Filtrate reduced in volume, residue dichloromethane (20mL) dilutes, and stirs dissolving in 1 hour, is filtered to remove insoluble matter.Filtrate reduced in volume, residue petroleum ether: dichloromethane=5:1 pulls an oar at 20 DEG C, filters.Obtain pale white solid (564mg), yield: 39.5%.
The synthesis of embodiment 8 compound (2)
In there-necked flask, adding DMF (200mL), add adjacent fluorine benzyl hydrazine hydrochloride (16.4g, 0.066mmol, 1.1eq), at 30 DEG C, stirring is until being completely dissolved.Add the 4A molecular sieve (5g) of activation, after stirring 30 minutes, add compound 1 (10.0g, 0.060mmol, 1.0eq), react 16 hours at 30 DEG C.After reaction terminates, filtering, filtrate is poured into water, and is then extracted with ethyl acetate three times.Merging organic layer, saturated sodium bicarbonate washs, and anhydrous sodium sulfate dries.Concentrating under reduced pressure, residue petroleum ether: dichloromethane=20:1 recrystallization obtains pale white solid (11.7g), yield: 77.7%.
1HNMR (400MHz, CDCl3) δ 8.39 (dd, J=4.7,1.9Hz, 1H), 7.93 (dd, J=7.8,1.9Hz, 1H), 7.36 (t, J=6.9Hz, 2H), 7.33 7.29 (m, 1H), 7.22 7.10 (m, 2H), 4.86 (d, J=4.6Hz, 2H).
The synthesis of embodiment 9 compound (2)
In there-necked flask, add acetonitrile (20mL), add adjacent fluorine benzyl hydrazine hydrochloride (572mg, 2.7mmol, 1.1eq), stir 2 hours under room temperature.Add anhydrous magnesium sulfate (0.5g), after stirring 30 minutes, add Formulas I-b compound (500mg, 2.4mol, 1.0eq), react 16 hours at 70 DEG C.After reaction terminates, filtering, filtrate is poured into water, and is then extracted with ethyl acetate three times.Merging organic layer, saturated sodium bicarbonate washs, and anhydrous sodium sulfate dries.Concentrating under reduced pressure, residue petroleum ether: dichloromethane=17:1 recrystallization obtains pale white solid (275mg), yield: 45.8%.1HNMR nuclear magnetic data is basically identical with embodiment 8.
The synthesis of embodiment 10 compound (2)
In there-necked flask, add acetonitrile (20mL), add adjacent fluorine benzyl hydrazine hydrochloride (572mg, 2.7mmol, 1.1eq), stir 2 hours under room temperature.Add anhydrous magnesium sulfate (0.5g), after stirring 30 minutes, add Formulas I-c compound (500mg, 2.4mol, 1.0eq), react 16 hours at 50 DEG C.After reaction terminates, filtering, filtrate is poured into water, and is then extracted with ethyl acetate three times.Merging organic layer, saturated sodium bicarbonate washs, and anhydrous sodium sulfate dries.Concentrating under reduced pressure, residue petroleum ether: dichloromethane=17:1 recrystallization obtains pale white solid (235mg), yield: 38.9%.1HNMR nuclear magnetic data is basically identical with embodiment 8.
The synthesis of embodiment 11 compound (2)
In there-necked flask, adding dimethyl sulfoxide (10mL), add adjacent fluorine benzyl hydrazine hydrochloride (1.3g, 6.3mmol, 1.1eq), at 30 DEG C, stirring is until being completely dissolved.Add anhydrous sodium sulfate (1g), after stirring 30 minutes, add compound 1 (1.0g, 5.7mmol, 1.0eq), react 16 hours at 30 DEG C.After reaction terminates, filtering, filtrate is poured into water, and is then extracted with ethyl acetate three times.Merging organic layer, saturated sodium bicarbonate washs, and anhydrous sodium sulfate dries.Concentrating under reduced pressure, residue petroleum ether: dichloromethane=20:1 recrystallization obtains pale white solid (0.9g), yield: 62.7%.1HNMR nuclear magnetic data is basically identical with embodiment 8.
The synthesis of embodiment 12 compound (2)
In there-necked flask, add acetonitrile (10mL), add adjacent fluorine benzyl hydrazine hydrochloride (1.3g, 6.3mmol, 1.1eq), stir at 30 DEG C.Add anhydrous sodium sulfate (1g), after stirring 30 minutes, add compound 1 (1.0g, 5.7mmol, 1.0eq), react 16 hours at 30 DEG C.After reaction terminates, filtering, filtrate is poured into water, and is then extracted with ethyl acetate three times.Merging organic layer, saturated sodium bicarbonate washs, and anhydrous sodium sulfate dries.Concentrating under reduced pressure, residue petroleum ether: dichloromethane=20:1 recrystallization obtains pale white solid (602mg), yield: 41.9%.1HNMR nuclear magnetic data is basically identical with embodiment 8.
The synthesis of embodiment 13 compound (19)
In there-necked flask, add methanol (50mL), Feldalat NM (3.2g, 0.060mol, 1.5eq), stir to being completely dissolved at 30 DEG C.Add compound 2 (10.0g, 0.040mol, 1.0eq), react 16 hours at 30 DEG C.Adding acetic acid (9.6g, 0.16mol, 4.0eq), ammonium chloride (3.2g, 0.060mol, 1.5eq), be warming up to 70 DEG C, backflow is overnight.After reaction terminates, concentrating under reduced pressure, residue adds acetone, has white solid to precipitate out.Sucking filtration, filter cake washing with acetone, dry to obtain pale white solid (11.9g), yield: 90.7%.
1HNMR (400MHz, DMSO) δ 8.73 (d, J=4.2Hz, 1H), 8.62 (d, J=8.1Hz, 1H), 7.49 (dd, J=8.2,4.5Hz, 1H), 7.38 7.34 (m, 1H), 7.25 (t, J=9.2Hz, 2H), 7.14 (t, J=7.4Hz, 1H), 5.87 (s, 2H), 1.81 (s, 3H).
The synthesis of embodiment 14 compound (5)
In there-necked flask, add aniline (46.6g, 0.50mol, 1eq), add ice cube, under stirring, drip concentrated hydrochloric acid (85mL).Drip and finish, add a small amount of ice cube.Keep temperature 0-5 DEG C, water (50mL) solution of dropping sodium nitrite (29.0g, 0.42moll, 0.8eq).Drip and finish, continue stirring 30 minutes.Add water (100mL) solution of sodium acetate (51.0g, 0.62mol, 1.2eq), after stirring 30 minutes, add Cyanoacetyl-Cyacetazid (33.0g, 0.50mol, ethanol (25mL) solution 1eq), continues stirring reaction 1 hour.After reaction terminates, sucking filtration, filter cake distilled water wash, dry to obtain yellow solid (70.2g), yield: 82.0%.
1HNMR (301MHz, CDCl3) δ 10.02 (s, 1H), 7.47 7.40 (m, 2H), 7.33 (d, J=7.8Hz, 2H), 7.27 (d, J=7.5Hz, 1H).
The synthesis of embodiment 15 compound (6)
In there-necked flask, add DMF (50mL), add compound 19 (3.3g, 0.010mol, 1.0eq), under stirring, add Feldalat NM (1.1g, 0.020mol, 2.0eq).It is subsequently adding compound 5 (1.9g, 0.011mol, 1.1eq), is warming up to 110 DEG C and reacts 16 hours.After reaction terminates, concentrating under reduced pressure, residue adds water and makes to precipitate completely.Sucking filtration, filter cake washing with alcohol, obtain brown-red solid (4.0g), yield 90.1%.
1HNMR (400MHz, DMSO) δ 9.21 (dd, J=8.1,1.6Hz, 1H), 8.66 (dd, J=4.5,1.6Hz, 1H), 8.51 (s, 2H), 8.03 (d, J=7.4Hz, 2H), 7.90 (s, 2H), 7.50 (t, J=7.7Hz, 2H), 7.43 7.34 (m, 2H), 7.28 7.09 (m, 3H), 5.85 (s, 2H).
The synthesis of embodiment 16 compound (7)
In there-necked flask, add methanol (20mL), add compound 6 (1.0g, 2.3mmol, 1.0eq), add the Pd/C (0.1g) of 10%, pass into hydrogen, in 60 DEG C of stirring reactions 3 hours.After reaction terminates, kieselguhr filters, methanol washing leaching cake.Filtrate concentrates to obtain yellow solid (0.7g), yield 85.2%.
The synthesis of embodiment 17 compound (7)
In there-necked flask, add isopropanol (20mL), add compound 6 (1.0g, 2.3mmol, 1.0eq), add the Pd/C (0.2g) of 5%, pass into hydrogen, in 25 DEG C of stirring reactions 5 hours.After reaction terminates, kieselguhr filters, washed with isopropyl alcohol filter cake.Filtrate concentrates to obtain yellow solid (0.6g), yield 76.2%.
The synthesis of embodiment 18 compound (7)
In there-necked flask, add isopropanol (20mL), add compound 6 (1.0g, 2.3mmol, 1.0eq), add the Pd/C (0.1g) of 10%, pass into hydrogen, in 90 DEG C of stirring reactions 2 hours.After reaction terminates, kieselguhr filters, washed with isopropyl alcohol filter cake.Filtrate concentrates to obtain yellow solid (0.58g), yield 72.0%.
The synthesis of embodiment 19 compound (8)
In there-necked flask, add pyridine (5mL), add compound 7 (350mg, 1mmol, 1.0eq), stir 20 minutes in ice bath, add methylchloroformate (162mg, 1.5mmol, 1.5eq), continue to stir 1 hour in ice bath.It is warming up to room temperature, continues stirring 2 hours.After reaction terminates, concentrating under reduced pressure, residue ethanol dissolves, then concentrating under reduced pressure, repeats twice, obtains yellow solid (390mg), yield 95.7%.
1HNMR (400MHz, DMSO) δ 9.06 (d, J=8.1Hz, 1H), 8.60 (d, J=4.4Hz, 1H), 8.12 (brs, 1H), 7.33 (dd, J=8.0,4.4Hz, 2H), 7.25 7.19 (m, 1H), 7.11 (dd, J=14.5,7.7Hz, 2H), 6.37 (s, 4H), 5.80 (s, 2H), 3.65 (s, 0.8H), 3.53 (s, 2.2H).
The synthesis of the western croak of embodiment 20 Leo (9)
In there-necked flask, add anhydrous hydrogen furan (5mL), add compound 8 (100mg, 0.24mmol, 1.0eq), stir 10 minutes in ice bath, then the LHMDS tetrahydrofuran solution (0.26mL of 1M it is added dropwise at leisure, 0.26mmol, 1.1eq), continue to stir 30 minutes in ice bath.Add iodomethane (41mg, 0.29mmol, 1.2eq), continue stirring 1 hour in ice bath.It is warming up to room temperature, continues stirring 3 hours.Adding the aqueous ammonium chloride solution cancellation reaction of 5%, be extracted with ethyl acetate three times, merge organic facies, anhydrous sodium sulfate dries.Concentrating under reduced pressure, obtains yellow foamy solid, then obtains white solid (71mg), yield 70.7% with acetone recrystallization.
1HNMR (400MHz, DMSO) δ 9.06 (d, J=8.1Hz, 1H), 8.60 (d, J=4.4Hz, 1H), 7.33 (dd, J=8.0,4.4Hz, 2H), 7.25 7.19 (m, 1H), 7.11 (dd, J=14.5,7.7Hz, 2H), 6.37 (s, 4H), 5.80 (s, 2H), 3.65 (s, 0.8H), 3.53 (s, 2.2H), 3.00 (s, 3H).
The all documents mentioned in the present invention are incorporated as reference all in this application, are individually recited as reference such just as each section of document.In addition, it is to be understood that after the above-mentioned teachings having read the present invention, the present invention can be made various changes or modifications by those skilled in the art, these equivalent form of values fall within the application appended claims limited range equally.
Claims (10)
1. the preparation method of a Formulas I V compound, it is characterised in that comprise the following steps:
At 20～80 DEG C, in organic solvent, compound of formula I is obtained by reacting Formulas I V compound with hydrazine dihydrochloride under desiccant exists；
In formula, R represents fluorine, chlorine, bromine, iodine, mesyl, p-toluenesulfonyl, trifyl, mesyloxy, tolysulfonyl oxygen base or trifluoro-methanesulfonyl oxy；R2For hydrogen, C6-12Arylmethyl, replacement C6-12Arylmethyl or C1-6Alkyl；Referring to of described replacement is optionally substituted by halogen.
2. preparation method according to claim 1, it is characterised in that described desiccant is selected from anhydrous sodium sulfate, anhydrous magnesium sulfate, dead plaster, anhydrous calcium chloride or 4A molecular sieve.
3. the preparation method of the western croak of Leo, it is characterised in that comprise the following steps:
I) formula 2 compound and Feldalat NM are obtained by reacting formula 3 compound；
II) formula 3 compound acetic acid, ammonium chloride existence under be obtained by reacting formula 19 compound；
III) formula 19 compound and formula 5 compound are obtained by reacting formula 6 compound；
IV) formula 6 compound catalyzed hydrogenation in the presence of a catalyst obtains formula 7 compound；
V) formula 7 compound and methylchloroformate are obtained by reacting formula 8 compound；
VI) formula 8 compound and iodomethane reaction obtain formula 9 compound (the western croak of Leo)；
Wherein, the preparation method of formula 2 compound includes step:
At 20～80 DEG C, in organic solvent, compound of formula I is obtained by reacting Formulas I V compound with hydrazine dihydrochloride under desiccant exists；
In various, R is defined as above, R2For 2-fluorobenzyl.
4. preparation method according to claim 3, it is characterised in that step II) in, it is 4～6:1 that acetic acid and formula 3 compound obtain mol ratio.
5. preparation method according to claim 3, it is characterised in that step III) it is specifically described as: in DMF, add formula 19 compound, Feldalat NM, formula 5 compound, react 10～20 hours at 100～110 DEG C；After reaction terminates, remove DMF, and add water and make solid precipitation precipitate out；Filter, obtain formula 6 compound.
6. preparation method according to claim 3, it is characterised in that step IV) in, described catalyst is Pd/C or Raney-Ni；And/or described reaction is carrying out in the solvent of lower group: methanol, ethanol, isopropanol or its combination.
7. preparation method according to claim 3, it is characterised in that step IV) in, described reaction carries out at 20～100 DEG C.
8. compound of formula I, or its salt or hydrate:
In formula, R represents fluorine, bromine, iodine, mesyl, p-toluenesulfonyl, trifyl, mesyloxy, tolysulfonyl oxygen base or trifluoro-methanesulfonyl oxy.
9. the preparation method of compound of formula I according to claim 8, it is characterised in that comprise the following steps:
In various, R is defined as above, R1For activated group；
1) at 80～150 DEG C, optionally in organic solvent, the 2-replacement nicotinic acid shown in Formula II is carried out activated carboxylic under the existence of organic reagent and obtain formula III compound；
2) at 0～70 DEG C, in acetonitrile solvent, formula III compound and cyanating reagent are carried out substitution reaction and obtains compound of formula I；
Wherein, described organic solvent is selected from toluene, dichloromethane, chloroform, oxolane or DMF；
Described organic reagent is selected from thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus tribromide, Phosphorous chloride., phosphorus pentachloride, methylchloroformate, ethyl chloroformate or isobutyl chlorocarbonate；
Described cyanating reagent is selected from Cupricin., Cyanogran. or potassium cyanide.
10. preparation method according to claim 9, it is characterized in that, also including the purification step of compound of formula I: at-20 DEG C～20 DEG C, by step 2) mixed solvent of the compound of formula I dichloromethane that obtains and petroleum ether pulls an oar, and is filtrated to get purified compound of formula I；In described mixed solvent, the volume ratio of dichloromethane and petroleum ether is 1: 100～1: 1.
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Cited By (2)
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| CN107118211A (en) * | 2017-05-24 | 2017-09-01 | 南京斯贝源医药科技有限公司 | The preparation method of the western croak of Leo |
| CN108069960A (en) * | 2016-11-15 | 2018-05-25 | 江苏豪森药业集团有限公司 | The preparation method of the western croak intermediate of Leo |
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| WO2011049722A1 (en) * | 2009-10-19 | 2011-04-28 | Merck Sharp & Dohme Corp. | PYRAZOLO [3,4-b] PYRIDIN-4-ONE KINASE INHIBITORS |
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| CN108069960A (en) * | 2016-11-15 | 2018-05-25 | 江苏豪森药业集团有限公司 | The preparation method of the western croak intermediate of Leo |
| CN107118211A (en) * | 2017-05-24 | 2017-09-01 | 南京斯贝源医药科技有限公司 | The preparation method of the western croak of Leo |
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