CN105294686B - Preparation method of riociguat - Google Patents
Preparation method of riociguat Download PDFInfo
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- CN105294686B CN105294686B CN201510857808.6A CN201510857808A CN105294686B CN 105294686 B CN105294686 B CN 105294686B CN 201510857808 A CN201510857808 A CN 201510857808A CN 105294686 B CN105294686 B CN 105294686B
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- leo
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- western croak
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- WXXSNCNJFUAIDG-UHFFFAOYSA-N riociguat Chemical compound N1=C(N)C(N(C)C(=O)OC)=C(N)N=C1C(C1=CC=CN=C11)=NN1CC1=CC=CC=C1F WXXSNCNJFUAIDG-UHFFFAOYSA-N 0.000 title abstract description 6
- 229960000529 riociguat Drugs 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 63
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 239000012043 crude product Substances 0.000 claims abstract description 19
- 229940126214 compound 3 Drugs 0.000 claims abstract description 17
- 229940125898 compound 5 Drugs 0.000 claims abstract description 17
- 239000000047 product Substances 0.000 claims abstract description 16
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims abstract description 10
- -1 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl methyl Chemical group 0.000 claims abstract description 8
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000001953 recrystallisation Methods 0.000 claims abstract description 6
- 238000010992 reflux Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 69
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 37
- 238000003756 stirring Methods 0.000 claims description 27
- 239000000376 reactant Substances 0.000 claims description 23
- 239000012065 filter cake Substances 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 208000035126 Facies Diseases 0.000 claims description 13
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 8
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 229960002587 amitraz Drugs 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 229960004756 ethanol Drugs 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- MPNBXFXEMHPGTK-UHFFFAOYSA-N pyrimidine-4,5,6-triamine Chemical class NC1=NC=NC(N)=C1N MPNBXFXEMHPGTK-UHFFFAOYSA-N 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 238000010025 steaming Methods 0.000 claims 1
- 238000011084 recovery Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- RCKYXYXLIJBCOE-UHFFFAOYSA-N 2-[1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-4,5,6-triamine Chemical compound NC1=C(N)C(N)=NC(C=2C3=CC=CN=C3N(CC=3C(=CC=CC=3)F)N=2)=N1 RCKYXYXLIJBCOE-UHFFFAOYSA-N 0.000 abstract 1
- GFQBSQXXHYLABK-UHFFFAOYSA-N 2-aminopropanediamide Chemical compound NC(=O)C(N)C(N)=O GFQBSQXXHYLABK-UHFFFAOYSA-N 0.000 abstract 1
- DQASIYVADJWVLY-UHFFFAOYSA-N [1-[(2-fluorophenyl)methyl]pyrazolo[3,4-b]pyridine-3-carboximidoyl]azanium;chloride Chemical compound Cl.C12=NC=CC=C2C(C(=N)N)=NN1CC1=CC=CC=C1F DQASIYVADJWVLY-UHFFFAOYSA-N 0.000 abstract 1
- GTCAXTIRRLKXRU-UHFFFAOYSA-N carbamic acid methyl ester Natural products COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000012535 impurity Substances 0.000 description 7
- 208000002815 pulmonary hypertension Diseases 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 3
- 208000026151 Chronic thromboembolic pulmonary hypertension Diseases 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 208000020193 Pulmonary artery hypoplasia Diseases 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011027 product recovery Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses a preparation method of riociguat. The preparation method comprises the steps of firstly, taking 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-formamidine hydrochloride and 2-aminopropanediamide as basic raw materials, adding strong base and a solvent to perform a reflux reaction, so as to prepare 2-[1-(2-fluorobenzyl) -1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidine-4,5,6-triamine, namely a compound 3; then taking the compound 3 and dimethyl carbonate as basic raw materials, dissolving the same into methyl alcohol for reaction, so as to prepare 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyl methyl carbamate, namely a compound 5, finally, dissolving the compound 5 and the strong base into the methyl alcohol, and adding methyl iodide for reacting, so as to prepare a riociguat crude product, and performing recrystallization on the riociguat crude product to obtain a riociguat refined product. The preparation method provided by the invention is relatively high in total recovery, simplified in operation and easy to industrialize.
Description
First, technical field：
The present invention relates to a kind of synthetic method of antithrombotic embolism class diseases medicine, and in particular to a kind of system of the western croak of Leo
Preparation Method.
2nd, background technology：
The western croak of Leo (riociguat) is for treating pulmonary hypertension (pulmonary hypertension, PH) medicine
Thing, mainly for chronic thromboembolic pulmonary hypertension (chronic throm-boembolic pulmonary
Hypertension, CTEPH) and pulmonary hypertension (pulmonary arterial hypertension, PAH), its chemical name
Referred to as：N- [4,6- diaminourea -2- [1- [(2- fluorophenyls) methyl] -1H- pyrazolos [3,4-b] pyridin-3-yl] -5- pyrimidines
Base]-N- methylene dicarbamates, its structural formula is as follows.
At present, the synthetic method of the western croak of existing Leo is with 1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- first
Used as double nucleophile, and phenylazo Cyanoacetyl-Cyacetazid is straight under conditions of Feldalat NM highly basic for two nitrogen-atoms on amidine hydrochlorate
It is bonded into pyrimidine ring and obtains intermediate 3, intermediate 3 palladium carbon or Raney's nickel does catalyst hydrogenation reduction and obtain triamine intermediate 4,
The amino of the 5- positions of intermediate 4 has stronger nucleophilicity, directly obtains centre with methylchloroformate reaction in the basic conditions
Body 5, intermediate 5 are methylated with iodomethane again with sodium hydrogen or LHMDS dehydrogenation, obtain the western croak of Leo (referring to
CN1665811A；US7173037B2), its synthetic route is as follows：
There is following defect in existing synthetic method：(1) first step dimethylformamide DMF does reaction dissolvent, and solvent is returned
Receive difficult, a large amount of contaminated wastewaters containing DMF are serious；(2) second step product content is low, and impurity is more, and some impurity easily take to most
Finished product, causes the newly-increased impurity of final products many, purification difficult；(3) the 3rd step pyridines make solvent, and taste is big, and toxicity is big；
In (4) the 4th steps, intermediate 5 always has part residual, it is difficult to react complete, becomes a main big impurity in final products
(original is ground about 0.04% in medicine, caused by this is by synthetic method, increases the amount meeting of LHMDS and iodomethane
Cause hydrolysis and other impurity to generate, and increase larger cost, cross raw material residual at least more, it is impossible to refined qualified or multiple
Crystallization loss is larger), this impurity and the western croak property of purpose product Leo it is close, cause refined difficulty, it is single miscellaneous to be difficult to control to
Less than 0.1%.Existing document typically improves the purity of purpose product using the method for column chromatography, which increases production cost, difficult
To adapt to industrial amplification production, or crystallized using multi-solvents system, this can cause product recovery rate extremely low, also not have
Using value in standby commercial production.
Therefore, to by existing synthetic process obtain content more than 99%, it is single it is miscellaneous be less than 0.05% it is medicinal
The western croak sterling of Leo of rank, production cost are very high, and amplification production even more has many technical problems and will solve.Due to
There is drawbacks described above so that for the synthetic method and production technology of the western croak of existing Leo is in the urgent need to further being improved
And optimization, so as on a large scale, the western croak of Leo of inexpensive synthesis of high purity, this is also the study hotspot in the technical field
One of with emphasis, the power and starting point that even more present invention is accomplished is located.
3rd, the content of the invention：
The technical problem to be solved in the present invention is：In order to overcome total recovery present in the existing synthetic technology of the western croak of Leo
The technical problem such as low, troublesome poeration and purification difficult, a kind of total recovery of present invention offer is higher, operation simplifies, is easy to industrialization
The preparation method of the western croak of Leo of production.
In order to solve the above problems, the technical scheme that the present invention takes is：
The present invention provides a kind of preparation method of the western croak of Leo, and the preparation method is comprised the following steps：
A, it is that compound 1 is added instead first by 1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- amitraz hydrochlorides
In answering container, it is subsequently adding solvent and highly basic is heated to backflow；Deca 2- amino Malondiamide is compound 2 at reflux
Solution, time for adding are 20～40min, and 2～4h of back flow reaction is carried out after dripping；After reaction, gained reactant liquor is through processing
It is compound 3 to 2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,5,6- triamines；
Mol ratio between the compound 1, compound 2 and highly basic three is 1：0.9～1.1:1～1.5；The chemical combination
The ratio of thing 1 and solvent addition therebetween is 1g：5～10mL；2 solution of the compound be by compound 2 and solvent by
According to 1g：The ratio mixed dissolution of 5mL is formulated；
The chemical equation of the step is as follows：
B, by step a gained compound 3 and dimethyl carbonate be that compound 4 is dissolved in methanol, then at 20～30 DEG C
5～8h of lower stirring reaction；Reactant liquor obtained by after reaction is concentrated, crystallize, obtains i.e. 4, the 6- diaminourea -2- [1- (2- of compound 5
Luorobenzyl) -1H- pyrazolos [3,4-b] pyridin-3-yl] (compound 5 refers to list of references to -5- pyrimidinyl-amino methyl formates
WO2003095451A1)；
Mol ratio between the compound 3 and compound 4 is 1：0.9～1.3；The compound 3 and both methanol it
Between addition ratio be 1g：5～10mL；
The chemical equation of the step is as follows：
C, compound obtained by step b 5 and highly basic are dissolved in methanol, then Deca iodomethane, Deca at -10～0 DEG C
Time is 10～30min；After dripping at -5～5 DEG C 2～5h of stirring reaction, be then warming up to 20～30 DEG C continue reaction 1
～3h；After reaction gained reactant liquor it is layered, extraction, concentration and crystallize, obtain the western croak crude product of Leo；
Between the compound 5, iodomethane and highly basic three, the mole ratio of addition is 1：0.9～1.1:1.5～
2.0；The ratio of the compound 5 and methanol addition therebetween is 1g：5～10mL；
The chemical equation of the step is as follows：
D, Leo obtained by step c western croak crude product is carried out into recrystallization using ethanol and dimethyl sulfoxide DMSO system, obtained
The western croak highly finished product of Leo.
According to the preparation method of the above-mentioned western croak of Leo, solvent described in step a is methanol or ethanol.
According to the preparation method of the above-mentioned western croak of Leo, highly basic described in step a is Feldalat NM, Sodium ethylate or sodium hydride.
According to the preparation method of the above-mentioned western croak of Leo, the temperature that back flow reaction is carried out in step a is 60～65 DEG C.
According to the preparation method of the above-mentioned western croak of Leo, after reacting described in step a, gained reactant liquor is obtained through process
Compound 3, processing concrete operations is：Gained reactant liquor is down to into room temperature, solvent is then removed under reduced pressure, is added in gained residue
Ethyl acetate, precipitation solid of the volume number for 2～4 times of residue mass number；Then filtered, gained filter cake adopts water successively
Carry out washing with ethyl acetate, filter, gained solid is in the condition that 60～80 DEG C, vacuum are 0.08～0.095MPa after filtration
Under be dried 5h, obtain compound 3.
According to the preparation method of the above-mentioned western croak of Leo, concentration described in step b, the specific operation process of crystallization are：Will
After reaction, gained reactant liquor removes solvent under reduced pressure under the conditions of 40～60 DEG C, 0.08～0.095MPa of vacuum, adds in residue
Enter ethyl acetate to be stirred, separate out solid and filter, gained filter cake is to do under 0.08～0.095MPa in 60～80 DEG C, vacuum
Dry 5h, obtains compound 5.
According to the preparation method of the above-mentioned western croak of Leo, highly basic described in step c is Feldalat NM, Sodium ethylate or sodium hydride.
According to the preparation method of the above-mentioned western croak of Leo, reactant liquor described in step c is layered, extraction, concentration and crystallize,
Specific operation process is：
Add saturated ammonium chloride that reaction, layering is quenched in gained reactant liquor, take organic faciess, water is mutually extracted with ethyl acetate two
It is secondary；Merge gained organic faciess, organic faciess are removed under reduced pressure solvent, gained under 60～70 DEG C, 0.08～0.095MPa of vacuum
Add water to be stirred in residue, separate out solid and filtered, gained filter cake in 60～80 DEG C, vacuum 0.08～
12～20h is dried under 0.095MPa.
According to the preparation method of the above-mentioned western croak of Leo, the concrete operations of recrystallization in step d are：
Leo western croak crude product is added in reactor, dehydrated alcohol is subsequently adding and is heated to 75～80 DEG C, be subsequently added into two
Methyl sulfoxide DMSO is to solid dissolving, and adds activated carbon back flow reaction 30min, and heat filtering is carried out after reaction, and gained filtrate is cold
But to 20 DEG C, stirring and crystallizing 5h；Filter after crystallize, gained filter cake is dried under 60～80 DEG C, 0.08～0.095MPa of vacuum
12～20h, obtains the western croak finished product of Leo；
Between the western croak crude product of the Leo and dehydrated alcohol, DMSO, the ratio of addition is 1g：20mL：10mL；The profit
The mass ratio added between western croak crude product difficult to understand and activated carbon is 20：0.8～1.2.
The positive beneficial effect of the present invention：
1st, the present invention with 1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- amitraz hydrochlorides be initiation material, Jing
Single step reaction is directly obtained triamine intermediate, it is to avoid is reacted using Hydrogenation, so as to reduce process conditions, is greatly simplified
Technological operation, improves reaction yield, is improved total recovery, makes synthesis technique of the present invention be more suitable for industrialized great production.
2nd, replace the methylchloroformate of severe toxicity in synthesis technique of the present invention using nontoxic, environmentally friendly dimethyl carbonate, so as to
The pollution to environment is reduced to a great extent, processing safety is improve, it is easier to industrialized great production.
3rd, recrystallization is carried out to the western croak crude product of Leo using ethanol/DMSO mixed solvent systems in synthesis technique of the present invention,
The western croak highly finished product of highly purified Leo can be obtained, its purity is more than 99.5%, and single impurity is less than 0.1%.
4th, all step reaction mild conditions of synthesis technique of the present invention, effectively reduce the consumption to the energy, while total receive
Rate is high, and finished product purity is good, simple to operate, is suitable for the large-scale industrial production application of the western croak of high-purity Leo.
4th, illustrate：
The liquid chromatograph collection of illustrative plates of the western croak of 1 gained Leo of Fig. 1 embodiment of the present invention；
The H-NMR collection of illustrative plates of the western croak of 1 gained Leo of Fig. 2 embodiment of the present invention.
5th, specific embodiment：
Below in conjunction with specific embodiment, the present invention is described in detail, but is not intended to limit present disclosure.
Embodiment 1：
The preparation method of the western croak of Leo of the present invention, detailed step are as follows：
A, first 31g (0.1mol) 1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- amitraz hydrochlorides are changed
During compound 1 adds 500mL reaction bulbs, 150mL methanol and 5.4g (0.1mol) Feldalat NM are subsequently adding, are heated to backflow；65
At DEG C, Deca 2- amino Malondiamide is that (solution is dissolved in 2 solution of compound by 11.7g (0.1mol) 2- amino Malondiamides
It is formulated in 50mL methanol), time for adding is 30min, and back flow reaction 2h, stopped reaction are carried out after dripping；Gained is anti-
Answer liquid to be down to room temperature, then remove solvent under reduced pressure, in gained residue, add 100mL ethyl acetate, have a large amount of solids generations, mistake
Filter, gained filter cake are carried out washing, are filtered with 100mL water and 100mL ethyl acetate successively, and gained solid is in 65 DEG C, vacuum
0.09MPa is dried 5h, obtains 28.4g 2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4, and 5,6-
Triamine is compound 3 (yield is 80%)；
B, 28.4g (0.08mol) compound 3,150mL methanol in 500mL reaction bulbs obtained by addition step a, 7.3g
(0.08mol) dimethyl carbonate (compound 4), stirring reaction 6h at 25 DEG C；After reaction terminates, by gained reactant liquor 50
DEG C, remove solvent under reduced pressure under vacuum 0.09MPa, 150mL ethyl acetate stirring 15min is added in gained residue, is filtered, institute
Obtain filter cake and 5h is dried under 65 DEG C, vacuum 0.09MPa, obtain 28.5g 4,6- diaminourea -2- [1- (2- luorobenzyls) -1H- pyrroles
Azoles simultaneously [3,4-b] pyridin-3-yl] -5- pyrimidinyl-amino methyl formates (compound 5) (yield 86%)；
C, 250mL reaction bulbs are taken, add 28.5g (0.07mol) 4,6- diaminourea -2- [1- (2- luorobenzyls) -1H- pyrazoles
And [3,4-b] pyridin-3-yl] -5- pyrimidinyl-amino methyl formates (compound 5), 150mL DMF and 2.5g sodium hydrides, stirring
Under be cooled to -5 DEG C, be then slowly added dropwise 4.3mL (0.069mol) iodomethane, time for adding is 10min；Drip after 0 DEG C
Lower stirring reaction 3h, then rises to 25 DEG C of stirring reactions 2h；50mL saturated ammonium chlorides are added to be quenched in gained reactant liquor after reaction
Reaction, layering, take organic faciess, and water is mutually extracted with ethyl acetate twice, uses ethyl acetate 50mL every time；Merge organic faciess, will have
Machine removes solvent under 65 DEG C, vacuum 0.09MPa under reduced pressure, adds 100mL water stirring 20min, filters in gained residue,
Gained filter cake is dried overnight under 65 DEG C, vacuum 0.09MPa, obtains the western croak crude product 23.3g of Leo；
D, Leo western croak crude product 23.3g is added in reaction bulb, adds 500mL dehydrated alcohol, be heated to 78 DEG C, then plus
Enter 230mL DMSO to solid dissolving, be subsequently adding 1.2g activated carbons backflow 30min, heat filtering, gained filtrate are naturally cooled to
20 DEG C, stirring and crystallizing 5h is filtered after crystallize, and gained filter cake is dried overnight under 65 DEG C, vacuum 0.09MPa, obtains 19.8g Leos
Western croak finished product (purity is 99.9%).
Embodiment 2：
The preparation method of the western croak of Leo of the present invention, detailed step are as follows：
A, first 31g (0.1mol) 1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- amitraz hydrochlorides are changed
During compound 1 adds 500mL reaction bulbs, 150mL methanol and 5.94g (0.11mol) Feldalat NM are subsequently adding, are heated to backflow；
At 60 DEG C, Deca 2- amino Malondiamide is that (solution is molten by 10.5g (0.09mol) 2- amino Malondiamides for 2 solution of compound
It is formulated in 50mL methanol), time for adding is 30min, and back flow reaction 2h, stopped reaction are carried out after dripping；By gained
Reactant liquor removes solvent under reduced pressure after being down to room temperature, 100mL ethyl acetate is added in gained residue, has a large amount of solids generations, mistake
Filter, gained filter cake are carried out washing, are filtered with 100mL water and 100mL ethyl acetate successively, and gained solid is in 65 DEG C, vacuum
0.09MPa is dried 5h, obtains 27.7g 2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4, and 5,6-
Triamine is compound 3 (yield is 78%)；
B, in 500mL reaction bulbs add step a obtained by 27.7g (0.079mol) compound 3,150mL methanol, 6.7g
(0.071mol) dimethyl carbonate (compound 4), stirring reaction 6h at 20 DEG C；After reaction terminates, by gained reactant liquor 50
DEG C, remove solvent under reduced pressure under vacuum 0.09MPa, 150mL ethyl acetate stirring 15min is added in gained residue, is filtered, institute
Obtain filter cake and 5h is dried under 65 DEG C, vacuum 0.09MPa, obtain 26.75g 4,6- diaminourea -2- [1- (2- luorobenzyls) -1H-
Pyrazolo [3,4-b] pyridin-3-yl] -5- pyrimidinyl-amino methyl formates (compound 5) (yield 83%)；
C, 250mL reaction bulbs are taken, add 26.75g (0.065mol) 4,6- diaminourea -2- [1- (2- luorobenzyls) -1H- pyrroles
Azoles simultaneously [3,4-b] pyridin-3-yl] -5- pyrimidinyl-amino methyl formates (compound 5), 150mL DMF and 2.34g
(0.098mol) -5 DEG C are cooled under sodium hydride, stirring, 3.6mL (0.059mol) iodomethane, time for adding is then slowly added dropwise
For 10min；Stirring reaction 3h at 0 DEG C is dripped, 25 DEG C of stirring reactions 2h are then risen to；Add in gained reactant liquor after reaction
Enter 50mL saturated ammonium chlorides and reaction, layering is quenched, take organic faciess, water is mutually extracted with ethyl acetate twice, uses ethyl acetate every time
50mL；Merge organic faciess, remove organic faciess under reduced pressure solvent under 65 DEG C, vacuum 0.09MPa, add in gained residue
100mL water stirring 20min, filtration, gained filter cake are dried overnight under 65 DEG C, vacuum 0.09MPa, obtain the western croak crude product of Leo
20.3g；
D, Leo western croak crude product 20.3g is added in reaction bulb, adds 400mL dehydrated alcohol, be heated to 78 DEG C, then plus
Enter 200mL DMSO to solid dissolving, be subsequently adding 1.0g activated carbons backflow 30min, heat filtering, gained filtrate are naturally cooled to
20 DEG C, then stirring and crystallizing 5h filters, and gained filter cake is dried overnight under 65 DEG C, vacuum 0.09MPa, obtains 17.3g Leos west
Croak finished product (purity is 99.7%).
Embodiment 3：
The preparation method of the western croak of Leo of the present invention, detailed step are as follows：
A, first 31g (0.1mol) 1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- amitraz hydrochlorides are changed
During compound 1 adds 500mL reaction bulbs, 150mL methanol and 8.1g (0.15mol) Feldalat NM are subsequently adding, are heated to backflow；65
At DEG C, Deca 2- amino Malondiamide is that (solution is dissolved in 2 solution of compound by 12.9g (0.11mol) 2- amino Malondiamides
It is formulated in 50mL methanol), time for adding is 30min, and back flow reaction 2h, stopped reaction are carried out after dripping；Gained is anti-
Answer liquid after being down to room temperature, to remove solvent under reduced pressure, in gained residue, add 100mL ethyl acetate, there are a large amount of solids to generate, filter,
Gained filter cake is carried out washing, is filtered with 100mL water and 100mL ethyl acetate successively, and gained solid is in 65 DEG C, vacuum
0.09MPa is dried 5h, obtains 29.0g 2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4, and 5,6-
Triamine is compound 3 (yield is 83%)；
B, in 500mL reaction bulbs add step a obtained by 29.0g (0.083mol) compound 3,150mL methanol, 9.7g
(0.1mol) dimethyl carbonate (compound 4), stirring reaction 6h at 30 DEG C；Reaction terminate after, by gained reactant liquor 50 DEG C,
Remove solvent under vacuum 0.09MPa under reduced pressure, 150mL ethyl acetate stirring 15min is added in gained residue, is filtered, gained
Filter cake is dried 5h under 65 DEG C, vacuum 0.09MPa, obtain 4,6- diaminourea -2- [1- (2- luorobenzyls) -1H- pyrazolos [3,
4-b] pyridin-3-yl] -5- pyrimidinyl-amino methyl formates (compound 5) 29.8g (yield 88%)；
C, 250mL reaction bulbs are taken, add 29.8g (0.073mol) 4,6- diaminourea -2- [1- (2- luorobenzyls) -1H- pyrazoles
And [3,4-b] pyridin-3-yl] -5- pyrimidinyl-amino methyl formates (compound 5), 150mL DMF and 3.5g (0.15mol) hydrogen
Change sodium, -5 DEG C are cooled under stirring, 6.0mL (0.08mol) iodomethane is then slowly added dropwise, time for adding is 10min；Drip
Stirring reaction 3h at 0 DEG C, then rises to 25 DEG C of stirring reactions 2h；50mL saturation chlorinations are added in gained reactant liquor after reaction
Ammonium is quenched reaction, layering, takes organic faciess, and water is mutually extracted with ethyl acetate twice, uses ethyl acetate 50mL every time；Merge organic
Phase, removes organic faciess under reduced pressure solvent under 65 DEG C, vacuum 0.09MPa, and the stirring of 100mL water is added in gained residue
20min, filtration, gained filter cake are dried overnight under 65 DEG C, vacuum 0.09MPa, obtain the western croak crude product 24.7g of Leo；
D, Leo western croak crude product 24.7g is added in reaction bulb, adds 500mL dehydrated alcohol, be heated to 78 DEG C, then plus
Enter 247mL DMSO to solid dissolving, be subsequently adding 1.2g activated carbons backflow 30min, heat filtering, gained filtrate are naturally cooled to
20 DEG C, then stirring and crystallizing 5h filters, and gained filter cake is dried overnight under 65 DEG C, vacuum 0.09MPa, obtains 21.5g Leos west
Croak finished product (purity is 99.9%).
Claims (6)
1. the preparation method of the western croak of a kind of Leo, it is characterised in that the preparation method is comprised the following steps：
A, first by 1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridine -3- amitraz hydrochlorides be compound 1 add reaction hold
In device, it is subsequently adding solvent and highly basic is heated to backflow；Deca 2- amino Malondiamide is that compound 2 is molten at reflux
Liquid, time for adding are 20～40min, and 2～4h of back flow reaction is carried out after dripping；After reaction, gained reactant liquor is obtained through process
2- [1- (2- luorobenzyls) -1H- pyrazolos [3,4-b] pyridin-3-yl] pyrimidine -4,5,6- triamines are compound 3；
The solvent is methanol or ethanol, and the highly basic is Feldalat NM, Sodium ethylate or sodium hydride；
Mol ratio between the compound 1, compound 2 and highly basic three is 1：0.9～1.1:1～1.5；The compound 1
With solvent therebetween addition ratio be 1g：5～10mL；2 solution of the compound be by compound 2 and solvent according to
1g：The ratio mixed dissolution of 5mL is formulated；
B, by step a gained compound 3 and dimethyl carbonate be that compound 4 is dissolved in methanol, then stir at 20～30 DEG C
Mix 5～8h of reaction；Reactant liquor obtained by after reaction is concentrated, crystallize, obtains i.e. 4, the 6- diaminourea -2- of compound 5 [1- (2- fluorine benzyls
Base) -1H- pyrazolos [3,4-b] pyridin-3-yl] -5- pyrimidinyl-amino methyl formates；
Mol ratio between the compound 3 and compound 4 is 1：0.9～1.3；The compound 3 is added with methanol therebetween
The ratio for entering amount is 1g：5～10mL；
C, compound obtained by step b 5 and highly basic are dissolved in methanol, then Deca iodomethane, time for adding at -10～0 DEG C
For 10～30min；After dripping at -5～5 DEG C 2～5h of stirring reaction, be then warming up to 20～30 DEG C continue reaction 1～3h；
After reaction gained reactant liquor it is layered, extraction, concentration and crystallize, obtain the western croak crude product of Leo；
The highly basic is Feldalat NM, Sodium ethylate or sodium hydride；
Between the compound 5, iodomethane and highly basic three, the mole ratio of addition is 1：0.9～1.1:1.5～2.0；Institute
The ratio for stating compound 5 and methanol addition therebetween is 1g：5～10mL；
D, Leo obtained by step c western croak crude product is carried out into recrystallization using ethanol and dimethyl sulfoxide DMSO system, obtain Leo
Western croak highly finished product.
2. the preparation method of the western croak of Leo according to claim 1, it is characterised in that：Back flow reaction is carried out in step a
Temperature is 60～65 DEG C.
3. the preparation method of the western croak of Leo according to claim 1, it is characterised in that gained after reacting described in step a
Reactant liquor obtains compound 3 through process, processes concrete operations and is：Gained reactant liquor is down to into room temperature, is then removed under reduced pressure molten
Agent, adds ethyl acetate, precipitation solid that volume number is 2～4 times of residue mass number in gained residue；Then carried out
Filter, gained filter cake are carried out washing, are filtered using water and ethyl acetate successively, and after filtration, gained solid is in 60～80 DEG C, vacuum
5h to be dried under conditions of 0.08～0.095MPa, obtain compound 3.
4. the preparation method of the western croak of Leo according to claim 1, it is characterised in that：Concentration, crystallize described in step b
Specific operation process is：Gained reactant liquor will reduce pressure under the conditions of 40～60 DEG C, 0.08～0.095MPa of vacuum steaming after reaction
Except solvent, add ethyl acetate to be stirred in residue, separate out solid and filter, gained filter cake in 60～80 DEG C, vacuum is
5h is dried under 0.08～0.095MPa, compound 5 is obtained.
5. the preparation method of the western croak of Leo according to claim 1, it is characterised in that：Reactant liquor Jing described in step c point
Layer, extraction, concentration and crystallize, specific operation process is：
Add saturated ammonium chloride that reaction, layering is quenched in gained reactant liquor, take organic faciess, water is mutually extracted with ethyl acetate twice；
Merge gained organic faciess, remove organic faciess under reduced pressure solvent under 60～70 DEG C, 0.08～0.095MPa of vacuum, gained is remaining
Add water to be stirred in thing, separate out solid and filtered, gained filter cake is under 60～80 DEG C, 0.08～0.095MPa of vacuum
It is dried 12～20h.
6. the preparation method of the western croak of Leo according to claim 1, it is characterised in that：The concrete behaviour of recrystallization in step d
As：
Leo western croak crude product is added in reactor, dehydrated alcohol is subsequently adding and is heated to 75～80 DEG C, be subsequently added into dimethyl
Sulfoxide DMSO is to solid dissolving, and adds activated carbon back flow reaction 30min, and heat filtering is carried out after reaction, and gained filtrate is cooled to
20 DEG C, stirring and crystallizing 5h；After crystallize filter, gained filter cake under 60～80 DEG C, 0.08～0.095MPa of vacuum be dried 12～
20h, obtains the western croak finished product of Leo；
Between the western croak crude product of the Leo and dehydrated alcohol, DMSO, the ratio of addition is 1g：20mL：10mL；The Leo west
The mass ratio added between croak crude product and activated carbon is 20：0.8～1.2.
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