CN104059063A - Preparation method of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine and derivatives of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine - Google Patents
Preparation method of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine and derivatives of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine Download PDFInfo
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- 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
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Abstract
The invention relates to a preparation method of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (3-R2-5-R1-7,7-difluoro-4,5,6,7-tetrahydro-1H(or2H)-pyrazolo[4,3-c]pyridine) and derivatives of 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine. 7,7-difluoro-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine is shown in the specification, wherein R1 is hydrogen, C1-C9 alkyl or benzyl; R2 is hydrogen or hydroxyl. The method comprises the steps shown in a reaction formula shown in the specification.
Description
Technical field
The present invention relates to a kind of 7,7-bis-fluoro-4,5,6,7-tetrahydro-pyrazole is the preparation method of [4,3-c] pyridine and its derivatives also.
Background technology
Due to the uniqueness of fluorine atom, introduce in organic molecule and can bring theatrical change to molecular activity and pharmacology character thereof, especially, in the security of exploitation tool, there is obvious advantage alternative medicine molecule aspect.Thereby attracted increasing medicine scholar and drugmaker add Drugs Containing Fluorine research and development ranks (Klaus M ü ller, Christoph Faeh,
diederich, Sceience, 2007,317,1881, O ' Hagan, D., Chem.Soc.Rev., 2008,37,308; Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V .Chem.Soc.Rev., 2008,37,320; Kirk, K.L., Org.Process Res.Dev., 2008,12,305; Isanbor, C.; O ' Hagan, D., J.Fluorine Chem., 2006,127,992; Krik, K.L, J.Fluorine Chem., 2006,127,992).
Piperidines structure is the very important intermediate of a class in new drug development.In many medicines, all contain this class formation.A new direction of new drug development by fluorine atom and fluoro-containing group introducing piperidines molecule.Structural formula (A) compounds is not compared with there is no the parent of fluoro, with 5-HT
1Dand 5-HT
1Dreceptor binding capacity is suitable, but its oral absorption degree improves a lot (Monique B.van Niel, etc., J.Med.Chem.1999,42,2087-2104) than parent.Structural formula (B) compounds is T-type calcium-ion channel antagonists, can be used for treatment or prevention nerve or mental disorder (Barrow J.C., LindsleyC.W., Shipe W.D., Yang Z.; WO2007002361).Structural formula (C) and (D) compounds are found to have very strong anti-senile dementia disease activity.Structural formula (E) compounds it is reported antitumous effect (Fatheree, P. etc., US2006135764; John, V. etc., WO2003043987; Stanton, M.G. etc., WO2008030391; Burger, M. etc., WO2008106692).
Pyrazolo-pyridines in the present invention, suc as formula compound shown in (I) or formula (II), contains fluoro substituents group in 7-position, and document does not also have been reported at present, and the present invention is the report of the synthetic above-claimed cpd of first case.
Summary of the invention
The object of this invention is to provide a kind of 7,7-bis-fluoro-4,5,6,7-tetrahydro-pyrazole is the preparation method of [4,3-c] pyridine and its derivatives also, the inventive method, and reaction conditions gentleness, convenient operation, cost is lower, and productive rate is good, and is suitable for suitability for industrialized production.
For realizing object of the present invention, technical scheme of the present invention is:
Shown in a kind of formula (I) or formula (II) 7,7-bis-is fluoro-4,5,6, and 7-tetrahydro-pyrazole is the preparation method of [4,3-c] pyridine derivate also,
Wherein R
1hydrogen, C1-C9 alkyl or benzyl; R
2hydrogen or hydroxyl; It is characterized in that, the method comprises the step shown in following reaction formula:
In a preferred embodiment of the present invention, work as R
1benzyl or hydrogen, R
2be hydrogen, the concrete reaction formula of the method is as follows:
The method comprises the following steps:
(1) compound shown in formula (VI) is under the first solvent and DMF dimethylacetal, at compound shown in-20 DEG C to 150 DEG C reaction productions (VII);
(2) compound shown in formula (VII) is under the second solvent and hydrazine hydrate existence, at compound shown in-10 DEG C to 100 DEG C reaction productions (VIII);
(3) compound shown in formula (VIII) is under palladium carbon or the existence of platinum carbon, under 0 to 20 atmospheric pressure hydrogen atmospheric pressure, at compound shown in 0 DEG C to 50 DEG C reaction production (IX);
(4) compound shown in formula (IX) is under hydrogenchloride exists, at compound shown in 0 DEG C to 40 DEG C reaction production (X).
In a more preferred embodiment, in described step (1), the first described solvent is selected from tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF, dimethyl sulfoxide (DMSO), benzene, toluene or glycol dimethyl ether.
In a more preferred embodiment, in described step (2), the second described solvent is selected from tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or the trimethyl carbinol.
In another preferred embodiment of the present invention, work as R
1benzyl or hydrogen, R
2be hydroxyl, the concrete reaction formula of the method is as follows:
The method comprises the following steps:
(1) compound shown in formula (XI) is under the second solvent and hydrazine hydrate existence, at compound shown in-10 DEG C to 100 DEG C reaction productions (XII);
(2) compound shown in formula (XII) is under palladium carbon or the existence of platinum carbon, under 0 to 20 atmospheric pressure hydrogen atmospheric pressure, at compound shown in 0 DEG C to 50 DEG C reaction production (XIII);
(3) compound shown in formula (XIII) is under hydrogenchloride exists, at compound shown in 0 DEG C to 40 DEG C reaction production (XIV).
In a more preferred embodiment, in described step (1), the second described solvent is selected from tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or the trimethyl carbinol.
Reported first of the present invention 7,7-bis-is fluoro-4,5,6,7-tetrahydro-pyrazole is [4,3-c] pyridine and its derivatives also, this 7,7-bis-is fluoro-4,5,6,7-tetrahydro-pyrazole also [4,3-c] pyridine and its derivatives can be used in the aspects such as new drug development.In addition reported first of the present invention with N-benzyl-3, the fluoro-4-piperidone of 3-bis-or N-benzyl-3, the fluoro-5-ethoxycarbonyl-4-of 3-bis-piperidone prepares 7 as starting raw material, 7-bis-fluoro-4,5,6,7-tetrahydro-pyrazole also [4,3-c] pyridine and its derivatives, reaction does not generally need low temperature, and reaction is simple, easy to operate, yield is high, is suitable for industrial amplification production.
Embodiment
The invention provides compound shown in preparation formula (I) or formula (II).At this, preparation process of compound of the present invention is described.
Run through in the following description of this process and be to be understood that when appropriate, will be on various reactants and intermediate, can hold intelligible mode with the technician in organic synthesis field increases suitable protecting group, removes subsequently.For example " blocking group in organic synthesis ", T.W.Green, P.G.M.Wuts, Wiley-Interscience, New York, has described in (1999) and has used the conventional steps of this protecting group and the example of suitable protecting group.Also be appreciated that, manipulate from a kind of group or substituting group is converted to another kind of group or substituting group can any intermediate or end product the synthesis path to end product carry out by chemistry, wherein possible the type of conversion only by lead to the molecule in the process of state or change in the inherent uncompatibility of the reagent the used function of carrying limit.The technician in organic synthesis field can easily understand this inherent uncompatibility, and carries out suitable conversion and synthesis step and overcome their method by suitable order.Below provide the example of conversion, be appreciated that described conversion is not only confined to illustrate general group or the substituting group in conversion." Comprehensive Organic Transformations – A Guide to Functional Group Preparations " R.C.Larock, VHC Publishers, Inc. (1989) has provided reference and the explanation of other suitable conversion.Organic chemistry textbook, for example " Advanced Organic Chemistry ", March, 4th ed.McGraw Hill (1992) or " Organic Synthesis ", Smith, McGraw Hill, (1994) have described reference and the explanation of other suitable reactions.The purification process of intermediate and end product comprises for example positive on post or flap or reverse-phase chromatography, recrystallization, distillation and liquid-liquid or leaching, and it is intelligible that these methods are all that those skilled in the art hold.
Unless there is different explanations, the definition of substituting group and group is with the same in formula (I).
Except as otherwise noted, term " room temperature " and " envrionment temperature " are illustrated in the temperature between 16 DEG C to 25 DEG C.
Below in conjunction with specific embodiment, further illustrate the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer.Ratio and per-cent are based on weight, unless stated otherwise.
Embodiment 1: preparation N-benzyl-5-dimethylaminomethylene-3, the fluoro-4-piperidone of 3-bis-(VII)
N-benzyl-3, the fluoro-4-piperidone of 3-bis-(VI) (93.0g, 413.0mmol, 1.0eq) be dissolved in 1.5 liters of toluene, add subsequently DMF dimethylacetal (138.0g, 1.16mol, 2.8eq), gained mixture is heated to back flow reaction 1.5 hours.Reaction solution is cooled to room temperature, add respectively the ethyl acetate of 1.0 premium on currency and 1.5 liters, separatory, 500 milliliters of washings of saturated aqueous common salt for organic layer, dried over sodium sulfate, filters, concentrated, gained resistates column chromatography purification (petrol ether/ethyl acetate=5/1) obtains colorless oil N-benzyl-5-dimethylaminomethylene-3,32.0 grams of the fluoro-4-piperidone of 3-bis-(VII), yield 27.6%.
Compound shown in formula (VII): 1H NMR (300MHz, CDCl3): δ (ppm): 7.67 (s, 1H); 7.35～7.26 (m, 5H), 3.72 (s, 2H); 3.64 (s, 2H); 3.09 (s, 6H); 3.06～2.97 (m, 2H).
MS-ESI: theoretical value (M): 380; Actual value: 381(M+H).
Embodiment 2: preparation 5-benzyl-7,7-bis-is fluoro-4,5,6, and 7-tetrahydro-pyrazole is [4,3-c] pyridine (VIII) also
N-benzyl-5-dimethylaminomethylene-3, the fluoro-4-piperidone of 3-bis-(VII) (12g, 42.8mmol, 1.0eq) is dissolved in 50 milliliters of ethanol, adds subsequently hydrazine hydrate (4.3g, 85.6mmol, 2.0eq), stirs 5 hours under reaction mixture room temperature.200 ml waters join in reaction solution, cancellation reaction, and 200 milliliters of ethyl acetate add reaction solution, and separatory separates organic layer.Organic layer is water and saturated common salt water washing respectively, and anhydrous sodium sulfate drying filters, and concentrating under reduced pressure obtains white solid 5-benzyl-7, and 7-bis-is fluoro-4,5,6, also 9.8 grams of [4,3-c] pyridines (VIII) of 7-tetrahydro-pyrazole, yield 92%.
Compound shown in formula (VIII): 1H NMR (300MHz, CDCl3): δ (ppm)=7.37～7.27 (m, 5H); 6.88～6.87 (dd, 1H), 6.08 (s; 1H), 3.62～3.60 (dd, 2H); 3.10～3.04 (m; 2H), 2.65～2.51 (m, 1H); 1.79～1.70 (m, 1H);
MS-ESI: theoretical value (M): 249; Actual value: 268(M+H+H
2o).
Embodiment 3: 7,7-bis-is fluoro-4,5,6 in preparation, and 7-tetrahydro-pyrazole is [4,3-c] pyridine hydrochloride (X) also
5-benzyl-7,7-bis-fluoro-4,5,6,7-tetrahydro-pyrazole also [4,3-c] pyridine (VIII) (1.0 grams, 4.0mmol, 1.0eq) is dissolved in 10 ml methanol, add subsequently Pd/C(0.1 gram, 10%), reaction mixture is stirred overnight at room temperature under 1 normal atmosphere hydrogen.Reaction mixture filtering and concentrating, gained resistates is dissolved in the saturated hydrogen chloride solution of Isosorbide-5-Nitrae dioxane of 10 milliliters, stirs 3 hours under room temperature.The solid filtering of separating out, the dry white solid 7 that to obtain, 7-bis-is fluoro-4,5,6, also 0.5 gram of [4,3-c] pyridine hydrochloride (X) of 7-tetrahydro-pyrazole, yield 53.9%.
Compound shown in formula (X): 1H NMR (300MHz, CDCl3): δ (ppm)=10.29～10.27 (b, 2H); 7.80 (s, 1H), 4.19 (s; 2H), 3.97～3.89 (m, 2H);
MS-ESI: theoretical value (M): 231; Theoretical value (M): 160(M+H-2HCl).
Embodiment 4: preparation 3-hydroxyl-5-benzyl-7,7-bis-is fluoro-4,5,6, and 7-tetrahydro-pyrazole is [4,3-c] pyridine (XII) also
N-benzyl-3,3-bis-fluoro-5-ethoxycarbonyl-4-piperidone (XI) (120g, 0.41moL, 1.0eq) and hydrazine hydrate (20g, 0.41moL, 1.0eq) are dissolved in the dehydrated alcohol of 150 milliliters, and reaction mixture is heated to 50 DEG C of reactions 2 hours.Revolve desolventizing, gained resistates column chromatography (petrol ether/ethyl acetate=3/1) 3-hydroxyl-5-benzyl-7 of purifying to obtain, 7-bis-is fluoro-4,5,6, also 82 grams of [4,3-c] pyridines (XII) of 7-tetrahydro-pyrazole, yield 75%.
Compound shown in formula (XII): 1H NMR (300MHz, DMSO): δ (ppm)=9.28 (s, 1H); 7.35～7.27 (m; 5H), 6.48 (s, 1H); 5.73 (s; 1H), 3.62 (s, 2H); 2.67～2.62 (m, 2H);
MS-ESI: theoretical value (M): 265; Theoretical value (M): 266(M+H).
Embodiment 5: preparation 3-hydroxyl-7,7-bis-is fluoro-4,5,6, and 7-tetrahydro-pyrazole is [4,3-c] pyridine hydrochloride (XIV) also
3-hydroxyl-5-benzyl-7,7-bis-fluoro-4,5,6,7-tetrahydro-pyrazole also [4,3-c] pyridine (XII) (60g, 0.23mol, 1.0eq) is dissolved in 70 milliliters of ethanol and 19 milliliters of concentrated hydrochloric acids (12mol/L), in reaction solution, add Pd/C (3.0g, 5%),, under 1 atmospheric pressure hydrogen atmospheric pressure, under room temperature, stir and spend the night.Reaction mixture filters, and resistates is washed three times with the methyl alcohol of 100 milliliters, and filtrate merges, anhydrous sodium sulfate drying, filtering and concentrating, obtains white solid 3-hydroxyl-7,7-bis-fluoro-4,5, also 48.5 grams of [4,3-c] pyridine hydrochlorides (XIV) of 6,7-tetrahydro-pyrazole, yield 84%.
Compound: 1HNMR (300MHz, DMSO): δ (ppm) shown in formula (XIV)=3.85(s, 2H), 3.20～3.30 (m, 2H);
MS-ESI: theoretical value (M): 248; Theoretical value (M): 176(M+H-2HCl).
Claims (6)
1. shown in a formula (I) or formula (II) 7,7-bis-is fluoro-4,5,6, and 7-tetrahydro-pyrazole is the preparation method of [4,3-c] pyridine derivate also,
Wherein R
1hydrogen, C1-C9 alkyl, benzyl; R
2hydrogen or hydroxyl; The method comprises the step shown in following reaction formula:
2. as claimed in claim 17,7-bis-is fluoro-4,5,6, and 7-tetrahydro-pyrazole is the preparation method of [4,3-c] pyridine derivate also, it is characterized in that, works as R
1benzyl or hydrogen, R
2be hydrogen, the concrete reaction formula of the method is as follows:
The method comprises the following steps:
(1) compound shown in formula (VI) is under the first solvent and the existence of DMF dimethylacetal ,-20
ocompound shown in C to 150 DEG C of reaction production (VII);
(2) compound shown in formula (VII) is under the second solvent and hydrazine hydrate existence, at compound shown in-10 DEG C to 100 DEG C reaction productions (VIII);
(3) compound shown in formula (VIII) is under palladium carbon or the existence of platinum carbon, and under 0 to 20 atmospheric pressure hydrogen atmospheric pressure, 0 DEG C to 50 DEG C is reacted compound shown in production (IX);
(4) compound shown in formula (IX) is under hydrogenchloride exists, at compound shown in 0 DEG C to 40 DEG C reaction production (X).
3. as claimed in claim 27,7-bis-fluoro-4,5,6,7-tetrahydro-pyrazole is the preparation method of [4,3-c] pyridine derivate also, it is characterized in that, the first solvent used in step (1) is selected from tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF, dimethyl sulfoxide (DMSO), benzene, toluene or glycol dimethyl ether.
4. as claimed in claim 27,7-bis-fluoro-4,5,6,7-tetrahydro-pyrazole is the preparation method of [4,3-c] pyridine derivate also, it is characterized in that, the second solvent used in step (2) is selected from tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or the trimethyl carbinol.
5. as claimed in claim 17,7-bis-is fluoro-4,5,6, and 7-tetrahydro-pyrazole is the preparation method of [4,3-c] pyridine derivate also, it is characterized in that, works as R
1benzyl or hydrogen, R
2be hydroxyl, the concrete reaction formula of the method is as follows:
The method comprises the following steps:
(1) compound shown in formula (XI) is under the second solvent and hydrazine hydrate existence, at compound shown in-10 DEG C to 100 DEG C reaction productions (XII);
(2) compound shown in formula (XII) is under palladium carbon or the existence of platinum carbon, under 0 to 20 atmospheric pressure hydrogen atmospheric pressure, at compound shown in 0 DEG C to 50 DEG C reaction production (XIII);
(3) compound shown in formula (XIII) is under hydrogenchloride exists, at compound shown in 0 DEG C to 40 DEG C reaction production (XIV).
6. as claimed in claim 57,7-bis-fluoro-4,5,6,7-tetrahydro-pyrazole is the preparation method of [4,3-c] pyridine derivate also, it is characterized in that, the second solvent used in step (1) is selected from tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF, glycol dimethyl ether, methyl alcohol, ethanol, Virahol or the trimethyl carbinol.
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| CN110551123A (en) * | 2019-07-23 | 2019-12-10 | 常州合全药业有限公司 | Preparation method of 5- (tert-butyloxycarbonyl) -2-methyl-4, 5,6, 7-tetrahydro-2H-pyrazolo [4,3-C ] pyridine-7-carboxylic acid |
| CN111978321A (en) * | 2020-09-22 | 2020-11-24 | 海南梵圣生物科技有限公司 | Preparation method of 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof |
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| CN111978321A (en) * | 2020-09-22 | 2020-11-24 | 海南梵圣生物科技有限公司 | Preparation method of 4-Boc-2,5,6, 7-tetrahydropyrazolo [4,3-b ] pyridine and derivatives thereof |
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Application publication date: 20140924 |