CN105418616A - JAK kinase inhibitor containing 4-aminopyrazole structure, preparation method and application thereof - Google Patents
JAK kinase inhibitor containing 4-aminopyrazole structure, preparation method and application thereof Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to a JAK kinase inhibitor containing a 4-aminopyrazole structure, a preparation method and an application thereof. Compounds of the series have structures shown in a general formula (I) or a general formula (II). The invention also provides the preparation method of the kinase inhibitor, and the application of the kinase inhibitor in preparation of medicines for preventing or treating inflammation, tumor and blood-related diseases.
Description
Technical field
The present invention relates to a kind of jak kinase inhibitor containing 4-amino-pyrazol structure and its preparation method and application, belong to organic compound synthesis and medical applications technical field.
Background technology
Jak kinase is the Tyrosylprotein kinase of one group of intracellular non-acceptor, generates at inflammation adjustment, blood and serves very important physiological action in tumour generation.In JAK-Stat signal path, the bioinformation of the signal factor of upstream as Interferon, rabbit, cytokine, somatomedin, g protein coupled receptor etc. feed back to be delivered in the signal path in downstream as a kind of important medium and to go thus the expression of regulatory gene by jak kinase.Jak kinase contains 4 kinds of hypotypes, i.e. JAK1, JAK2, JAK3, TYK2. wherein, JAK1 with JAK3 can regulate the interleukin factor (ILs) relevant to immunologic function, JAK2 then can regulate the various cytokine relevant to medullary cell and erythropoiesis and somatomedin as macrophage colony stimulating factor (GM-CSF), erythropoietin (EPO) etc., and TYK2 then mainly regulates the cytokine profiles relevant to virus and bacteriological infection as Interferon, rabbit (INF) and various interleukins etc.In clinical disease; the abnormal expression of JAK2 can cause serious myelosis knurl; the overexpression of JAK3 then can cause various immune disease, and as Reconstruction in Sever Combined Immunodeciency (SCID), the unconventionality expression of TYK2 then partly can damage antiviral and immunizing power that is bacterium.
Therefore, jak kinase inhibitor in the diseases such as haematological disorders, myelosis and immune deficiency as a kind of very important methods for the treatment of.Up to now, the listing of jak kinase inhibitor is still few.Go on the market the earliest be Pfizer (Pfizer) company research and development holder method for Buddhist nun (Tofacitinib) in 2012 by FDA ratify listing be used for the treatment of rheumatic arthritis, then Incyte company research and development Luso for Buddhist nun (Ruxolitinib) in 2013 listing be used for the treatment of myelofibrosis.The Baricitinib that Li Lai company (Lilly) and Incyte company research and develop jointly is expected to listing in 2015.Although Luso replaces the successful listing of Buddhist nun for Buddhist nun and Tuo Fa, these two kinds of medicines all have the serious side effect relevant with blood to immunity.
We replace Buddhist nun as lead compound using Luso for this reason, have synthesized a series of jak kinase inhibitor containing 4-amino-pyrazol ring skeleton on this basis.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of jak kinase inhibitor containing 4-amino-pyrazol structure, present invention also offers preparation method and the purposes of above-claimed cpd.
Technical scheme of the present invention is:
One, the jak kinase inhibitor containing 4-amino-pyrazol structure
The present invention contains the jak kinase inhibitor of 4-amino-pyrazol structure, and its optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, and solvate or prodrug have the structure shown in following general formula I or II:
Wherein:
R
1hydrogen, cycloalkyl, alkyl or aryl;
R
2hydrogen, cycloalkyl, alkyl or aryl;
R
3hydrogen, naphthenic hydrocarbon, alkyl or aryl;
Virtue heterocycle mainly comprises pyrimidine ring, pyrrolopyrimidine ring, purine skeleton, pyrazolopyrimidine ring, Furanopyrimidines ring, Thienopyrimidine ring or quinazoline.
* be steric configuration be S or R optical purity or its raceme.
Preferably, R
1hydrogen, C1-C6 alkyl, cyclopropane, pentamethylene or hexanaphthene; R
2hydrogen, C1-C6 alkyl, cyclopropane, pentamethylene or hexanaphthene; R
3it is C1-C6 alkyl or aryl;
More preferred, above-claimed cpd is one of following:
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionitrile (16a),
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionitrile (16b),
2-(4-(1-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol))-cyclohexyl acetonitrile (16c),
2-(4-(1-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol))-pentamethylene base acetonitrile (16d),
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionic acid amide (17a),
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17b),
2-(4-(1-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol))-cyclohexyl ethanamide (17c),
2-(4-(1-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol))-pentamethylene yl acetamide (17d),
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl-N-n-propyl propionic acid amide (17e),
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl-N-isobutyl-propionic acid amide (17f),
3-(4-quinazoline-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17g),
3-(4-9H-purine-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17h),
3-(4-(7H-thieno-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17i),
3-(4-(1H-pyrazolo [3,4-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17j),
3-(2-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17k),
3-(2-(4-methylamino-5-chloropyrimide)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17l),
3-(2-(4-methylamino-5-trifluoromethyl pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17m),
3-(2-(4-p-Chlorobenzoic acid amide base-5-chloropyrimide)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17n),
3-(4-(7H-thieno-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl-N-isobutyl-propionic acid amide (17o),
3-(4-quinazoline-4-amino-pyrazol)-3-cyclohexyl-N-isobutyl-propionic acid amide (17p),
3-(2-(4-methylamino-5-chloropyrimide)-4-amino-pyrazol)-3-pentamethylene base propionic acid amide (17q) or
3-(2-(4-methylamino-5-chloropyrimide)-4-amino-pyrazol)-3-cyclohexyl-N-n-propyl propionic acid amide (17r).
The preparation method of the jak kinase inhibitor two, containing 4-amino-pyrazol structure
The present invention contains the preparation method of the jak kinase inhibitor of 4-amino-pyrazol ring skeleton, is one of following method:
(1) with the chloro-7H-pyrrolo-[2 of 4-, 3-d] pyrimidine is starting raw material, intermediate 2 is generated through trimethyl silicon based ethoxymethyl protecting group protection, intermediate 2 obtains intermediate 3 with the generation nucleophilic substitution of 4-amino-pyrazol, different aldehyde or ketone and cyanogen methyl acid phosphate diethyl ester are obtained by reacting intermediate 5 by Wittig reaction, and intermediate 5 and intermediate 3 obtain intermediate 6 by Michael addition; Intermediate 6 is leniently sloughed trimethyl silicon based ethoxymethyl protecting group and is obtained end product 16 in Lewis acid.
Reaction formula is as follows:
Wherein, R
1, R
2as described in above-mentioned general formula I;
Reagent in above-mentioned reaction formula and condition: (a), 2-chloromethoxyethyl trimethyl silane, N,N-dimethylacetamide, 0 DEG C, 4h; (b), 4-amino-pyrazol, DIPEA, propyl carbinol, 150 DEG C, 2-3h, microwave; (c), potassium tert.-butoxide, tetrahydrofuran (THF), room temperature, reaction is spent the night; (d), 1,8-diazabicylo 11 carbon-7-alkene, acetonitrile, 65 DEG C, 5-6 days; (e), tetrafluoro boryl lithium, acetonitrile/water, 90 DEG C, 5-6 days.
For compound 16a, concrete preparation process is as follows:
The preparation method of 3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionitrile (16a), step is as follows:
(1) preparation of the chloro-7-of 4-((2-trimethyl silicane base oxethyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine (2)
Under condition of ice bath, by chloro-for 4-7H-pyrrolo-[2,3-d] pyrimidine 2.0g is dissolved in N, in N-N,N-DIMETHYLACETAMIDE 50mL, NaH0.58g is repeatedly joined in solution in batches and stir 15 minutes, and then in reaction solution, add 2-chloromethoxyethyl trimethyl silane 2.2g, and maintain the temperature at less than 5 DEG C continuation reaction 4h; By the saturated solution termination reaction of ammonium chloride, aqueous phase is extracted with ethyl acetate, organic phase washed with water, and each 100mL of common salt aqueous solution washs three times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure, obtains crude product; With sherwood oil: the purification by silica gel column chromatography of ethyl acetate=50:1 volume ratio can obtain intermediate 2. for colourless liquid 2.6g, yield: 70%;
(2) preparation of 4-(1H-pyrazoles-4-amido)-7-((2-trimethyl silicane base oxethyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine (3)
Intermediate 20.2g and 4-amidopyrazole 0.11g is dissolved in propyl carbinol, adds the DIPEA of 0.27g in the solution, at 150 DEG C, microwave, react 2h, after reaction terminates, namely solvent decompression Rotary Evaporators evaporate to dryness is obtained crude product; By the crude product obtained by column purification methylene dichloride: methyl alcohol=20:1 volume ratio obtains compound 3, be yellow solid 0.15g, productive rate: 65%;
(3) preparation of 3-hexanaphthene vinyl cyanide (5a)
Under condition of ice bath, cyanogen methyl acid phosphate diethyl ester 5.9g is dissolved in anhydrous tetrahydro furan 100mL, more repeatedly adds potassium tert.-butoxide 5.6g in the solution in batches, stir three hours at ambient temperature; Reduce the temperature to 0 DEG C again, to above-mentioned reaction solution drip ring pentane formaldehyde, room temperature reaction spends the night; After TLC detection reaction is complete, adds the saturated solution 100ml cancellation reaction of ammonium chloride, steam after desolventizing, residue with ethyl acetate is extracted, wash organic phase 3 times with water, each 100mL of saturated nacl aqueous solution; The anhydrous anhydrous magnesium sulfate drying of organic phase spends the night, and suction filtration removes solvent under reduced pressure and namely obtains crude product; Crude product sherwood oil: the purification by silica gel column chromatography of ethyl acetate=80:1 volume ratio can obtain intermediate 5a is colourless liquid 2.5g, yield: 67%;
(4) preparation of 3-(4-(7-((2-trimethyl silicane base oxethyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionitrile (6a)
Compound 30.15g and compound 5a0.14g is dissolved in acetonitrile 30mL, and add 1,8-diazabicylo 11 carbon-7-alkene 0.10g in above-mentioned solution after, 65 DEG C are reacted 5-6 days, steaming desolventizes rear acetic acid ethyl dissolution, with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound 6a after column purification methylene chloride/methanol 80:1, is yellow solid 0.10g, productive rate: 37%;
(5) preparation of 3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionitrile (16a)
Be dissolved in the acetonitrile/water of 20mL/5mL by compound 6a0.10g, add tetrafluoro boryl lithium 0.6g, 85 DEG C of back flow reaction are after 5 days; Steaming desolventizes rear acetic acid ethyl dissolution, and with water, each 100mL of the saturated common salt aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound 16a after column purification methylene chloride/methanol 20:1, is pale solid 20mg, productive rate: 28%.
(2) with 4-nitropyrazole for starting raw material, 4-amino-pyrazol intermediate 8 is obtained by the reduction of palladium carburetted hydrogen gas, intermediate 8 Boc protects amino to obtain intermediate 9, intermediate 9 obtains intermediate 10 with intermediate 5 by Michael addition again, intermediate 10 obtains intermediate 11 and intermediate 14 respectively in highly basic NaOH Water Under solution, intermediate 11 and different amine are by O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid condensation obtains various intermediate 12, intermediate 13 and 15 is obtained after intermediate 12 and intermediate 14 slough Boc protecting group in HCl/EA, intermediate 13 and 15 obtains end product 17a-r from different chlorinated aromatic heterocycles by nucleophilic attack.
Reaction formula is as follows:
Wherein, R
1, R
2, R
3as described in above-mentioned general formula II;
Reagent in above-mentioned reaction formula and condition: (a), Pd/C, H
2, ethanol, room temperature, reaction is spent the night; (b), tert-Butyl dicarbonate, NaHCO
3/ H
2o, tetrahydrofuran (THF), room temperature, reaction is spent the night; (c), 1,8-diazabicylo 11 carbon-7-alkene, acetonitrile, 65 DEG C, 2 days; (d), NaOH, H
2o/ methyl alcohol/dioxane, 90 DEG C, 5-6h; (e), O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, triethylamine, R
3nH
2, CH
2cl
2, room temperature, reaction is spent the night.(f), HCl/ ethyl acetate, room temperature, reaction is spent the night; (g), DIPEA, propyl carbinol, 150 DEG C, 1-2h, microwave or trifluoroacetic acid, propyl carbinol, 100 DEG C, 1-2h, microwave; (h) NaOH, water/dioxane, 60 DEG C, 30min.
For compound 17a, concrete preparation process is as follows:
The preparation method of 3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionic acid amide (17a), step is as follows:
(1) preparation of 4-amino-pyrazol (8)
4-nitropyrazole 5.0g is dissolved in 160mL ethanol, then adds 10%Pd/C0.8g in above-mentioned solution; In reaction solution, pass into hydrogen and react at ambient temperature and spend the night; After TLC detection reaction, fall Pd/C with diatomite filtration; Evaporate to dryness alcohol solvent, namely obtains pure intermediate 8, is red solid 3.6g, quantitative reaction;
(2) preparation of the tertiary butyl-4-(1H-pyrazoles) carbamate (9)
Compound 83.0g is dissolved in NaHCO3/ tetrahydrofuran (THF) 7.5g/160mL mixing solutions, adds tert-Butyl dicarbonate 8.6g, room temperature reaction 2 days.Steaming desolventizes rear acetic acid ethyl dissolution, and with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Can obtain pure intermediate 9 after crude product n-hexane, be pink solid, 5.0g, productive rate: 75%;
(3) preparation of the tertiary butyl-4-(1-(2-itrile group-1-pentamethylene ethyl)-1H-pyrazoles) carbamate (10a)
Compound 93.0g and compound 5a2.9g is dissolved in 150mL acetonitrile solution, and drip 1,8-diazabicylo 11 carbon-7-alkene 3.2g, reaction solution stirs 2 days at 65 DEG C, after TLC detection reaction, steam and desolventize rear acetic acid ethyl dissolution, with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound 10a after column purification methylene chloride/methanol 80:1, is white solid 2.4g, productive rate 48%.The synthesis of compound 10b is identical with this step;
(4) preparation of 3-(4-tertiary fourth oxygen formamido group-1H-pyrazoles)-3-hexanaphthene propionic acid (11)
Be dissolved in by compound 10b4.5g in water/methyl alcohol/dioxane 16mL/16mL/100mL mixing solutions, add 5.4gNaOH solid to above-mentioned solution, reaction solution stirs 6h at 65 DEG C.After TLC detection reaction, after regulating acid-basicity to neutrality with the aqueous hydrochloric acid of 1Mol, steam after desolventizing, crude product obtains compound 11 after column purification methylene chloride/methanol 50:1, is white foam solid 2.0g, productive rate 45%;
(5) preparation of the tertiary butyl-(1-(1-cyclohexyl-3-oxo-(3-Propylamino) propyl group-1H-pyrazoles))-4-carbamate (12a)
By compound 112.4g and O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid 2.6g is dissolved in 160mL tetrahydrofuran (THF), drip triethylamine 2.7g. reaction solution to above-mentioned solution and react half hour at ambient temperature, then Tri N-Propyl Amine 0.8g is added drop-wise in above-mentioned reaction solution gradually, and reaction is spent the night at ambient temperature; After TLC detection reaction, steam and desolventize rear acetic acid ethyl dissolution, with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound 12a after column purification methylene chloride/methanol volume ratio 80:1, white solid 2.0g. productive rate 77%;
(6) preparation of 3-(4-amino-1H-pyrazoles-1-alkane)-3-hexanaphthene-N-n-propyl propionic acid amide (13a)
Compound 12a2.0g is dissolved in HCl/EtOAc50mL, room temperature reaction 8h; After reacting completely, filter out white solid and be compound 13a, white solid 1.2g, productive rate 81%;
(7) preparation of the tertiary butyl-(1-(3-amido-1-pentamethylene-3-oxopropan)-1H-pyrazoles-4-alkane) carbamate (14a)
Be dissolved in by compound 10a0.7g in water/methyl alcohol/dioxane 16mL/16mL/100mL mixing solutions, add 5.4gNaOH solid to above-mentioned solution, reaction solution stirs 6h at 65 DEG C; After TLC detection reaction, after regulating acid-basicity to neutrality with the aqueous hydrochloric acid of 1Mol, steam after desolventizing, crude product obtains compound 14a after column purification methylene chloride/methanol 60:1, is white solid 0.5g, productive rate 67%;
(8) preparation of 3-(4-amino-1H-pyrazoles-1-alkane)-3-pentamethylene propionic acid amide (15a)
Compound 14a0.5g is dissolved in HCl/EtOAc50mL, room temperature reaction 8h, waits after reacting completely, filter out white solid and be compound 15a, white solid 0.2g, productive rate 61%;
(9) preparation of 3-pentamethylene-3-(4-((7-is to Methyl benzenesulfonyl base-7H-pyrrolo-[2,3-d] pyrimidine-4-alkane) is amino)-1H-pyrazoles-1-alkane) propionic acid amide (18a)
Be dissolved in 20mL propyl carbinol by chloro-for 4-7-to benzenesulfonyl 7H-pyrrolo-[2,3-d] pyrimidine 0.4g and compound 15a0.15g, drip diisopropylethylamine 0.32g to above-mentioned solution, reaction solution reacts 2h under microwave 150 DEG C of conditions; After reaction terminates, namely solvent decompression Rotary Evaporators evaporate to dryness is obtained crude product; By the crude product obtained by column purification methylene dichloride: methyl alcohol=40:1 obtains compound 18a, pale solid 0.3g, productive rate 91%;
(10) preparation of 3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionic acid amide (17a)
Compound 18a0.3g is dissolved in water/methyl alcohol/dioxane 3mL/3mL/10mL and adds 0.4gNaOH solid to above-mentioned solution, reaction solution stirs 0.5h at 55 DEG C, after TLC detection reaction, after regulating acid-basicity to neutrality with the aqueous hydrochloric acid of 1Mol, after steaming desolventizes, crude product obtains compound 17a after column purification methylene chloride/methanol 20:1, white solid 80mg, productive rate 48%.
The structural formula of target compound is as follows:
The concrete preparation process of described compound will be described in detail in an embodiment.
Those skilled in the art can change to improve yield to above-mentioned steps; they can determine the route of synthesis according to the ABC of this area; as selective reaction thing, solvent and temperature, can by using various GPF (General Protection False base to avoid the generation of side reaction thus to improve yield.The guard method of these routines can see such as T.Greene, ProtectingGroupsinOrganicSynthesis.
Detailed Description Of The Invention
Term and definition implication used herein is as follows:
" alkane " refers to the aliphatic chain referring to C1-C6, cyclopropane, tetramethylene, pentamethylene, hexanaphthene, suberane etc.
" aryl " refers to that preferred aromatic ring contains 6-10 carbon atom with substituent substituted aryl on group containing aromatic carbon ring and ring.
" fragrant heterocycle " mainly comprises pyrimidine ring, pyrrolopyrimidine ring, purine skeleton, pyrazolopyrimidine ring, Furanopyrimidines ring, Thienopyrimidine ring, quinazoline etc.
Hela cell is a kind of cell used in biology and medical research, is derived from the clone of the cervical cancer cell of an American Women Hai Liyeta lachs (HenriettaLacks).Be widely used in tumor research, Bioexperiment or cell cultures at medical circle HeLa cell, become very important instrument in medical research.
The application of the jak kinase inhibitor three, containing 4-amino-pyrazol structure
Screening active ingredients experiment display the compounds of this invention has the inhibit activities of good external JAK1, JAK2, JAK3, and therefore, the present invention also provides the application of compound in the medicine of preparation prevention or treatment and inflammation, tumour, blood-related diseases; Described comprises with inflammation, tumour, blood-related diseases: rheumatic arthritis, rheumatoid arthritis, myelofibrosis, severe combined immune Defect etc.
A kind of prevention or treatment and inflammation, tumour, blood-related diseases pharmaceutical composition, comprise of the present invention contain 4-amino-pyrazol ring skeleton jak kinase inhibitor or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or vehicle.
Accompanying drawing explanation
Fig. 1 is that 5 μMs of compound 17n and 17m suppress result figure to JAK2 phosphorylation in Hela cell.
Embodiment
Below in conjunction with embodiment, the present invention is described further, but be not limited thereto.
Embodiment 1: the synthesis of compound 16a-16d, for 16a.
(1) preparation of the chloro-7-of 4-((2-trimethyl silicane base oxethyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine (2)
Under condition of ice bath, by chloro-for 4-7H-pyrrolo-[2,3-d] pyrimidine 2.0g is dissolved in N, in N-N,N-DIMETHYLACETAMIDE 50mL, NaH0.58g is repeatedly joined in solution in batches and stir 15 minutes, and then in reaction solution, add 2-chloromethoxyethyl trimethyl silane 2.2g, and maintain the temperature at less than 5 DEG C continuation reaction 4h; By the saturated solution termination reaction of ammonium chloride, aqueous phase is extracted with ethyl acetate, organic phase washed with water, and each 100mL of common salt aqueous solution washs three times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure, obtains crude product; With sherwood oil: ethyl acetate=50:1 purification by silica gel column chromatography can obtain intermediate 2, is colourless liquid 2.6g, yield: 70%.
1HNMR(DMSO-d
6,400MHz)δ8.67(s,1H),7.87(d,J＝3.8Hz,1H),6.71(d,J＝3.6Hz,1H),5.63(s,2H),3.50(t,J＝7.9Hz,2H),0.80(t,J＝8.1Hz,2H),0.24(s,9H).ESI-MS,m/z＝284[M+H]
+
(2) preparation of 4-(1H-pyrazoles-4-amido)-7-((2-trimethyl silicane base oxethyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine (3)
Compound 20.2g and 4-amidopyrazole 0.11g is dissolved in propyl carbinol, adds the DIPEA of 0.27g in the solution, at 150 DEG C, microwave, react 2h, after reaction terminates, namely solvent decompression Rotary Evaporators evaporate to dryness is obtained crude product.By the crude product obtained by column purification methylene dichloride: methyl alcohol=20:1 obtains compound 3, be yellow solid 0.15g, productive rate: 65%.
1HNMR(400MHz,DMSO-d
6)δ10.90(s,1H),8.41(s,1H),7.99(s,2H),7.66(s,1H),7.16(s,1H),5.66(s,2H),3.59(t,J＝8.0Hz,2H),0.94(dt,J＝16.0,7.7Hz,2H),0.00(s,9H).ESI-MS,m/z＝331[M+H]
+
(3) preparation of 3-hexanaphthene vinyl cyanide (5a)
Under condition of ice bath, cyanogen methyl acid phosphate diethyl ester 5.9g is dissolved in anhydrous tetrahydro furan 100mL, more repeatedly adds potassium tert.-butoxide 5.6g in the solution in batches, stir three hours at ambient temperature; Reduce the temperature to 0 DEG C again, to above-mentioned reaction solution slow drip ring pentane formaldehyde, room temperature reaction spends the night; After TLC detection reaction is complete, adds the saturated solution 100ml cancellation reaction of ammonium chloride, steam after desolventizing, extracted by residue with ethyl acetate, with water, each 100mL of saturated nacl aqueous solution washs organic phase 3 times; The anhydrous anhydrous magnesium sulfate drying of organic phase spends the night, and suction filtration removes solvent under reduced pressure and namely obtains crude product.Crude product silica gel column chromatography (sherwood oil: ethyl acetate=80:1) purifying can obtain intermediate 5a, is colourless liquid 2.5g, yield: 67%ESI-MS, m/z=122 [M+H]
+(weak)
(4) preparation of 3-(4-(7-((2-trimethyl silicane base oxethyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionitrile (6a)
Compound 30.15g and compound 50.14g is dissolved in acetonitrile 30mL, and add 1,8-diazabicylo 11 carbon-7-alkene 0.10g in above-mentioned solution after, 65 DEG C are reacted 5-6 days, steaming desolventizes rear acetic acid ethyl dissolution, with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound 6a after column purification methylene chloride/methanol 80:1, is yellow solid 0.10g, productive rate: 37%; ESI-MSm/z=452 [M+H]
+
(5) preparation of 3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionitrile (16a)
Compound 6a0.10g is dissolved in acetonitrile/water (20mL/5mL), add tetrafluoro boryl lithium 0.6g, 85 DEG C of back flow reaction are after 5 days; Steaming desolventizes rear acetic acid ethyl dissolution, and with water, each 100mL of the saturated common salt aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound after column purification methylene chloride/methanol 20:1, is pale solid 20mg, productive rate: 28%;
1hNMR (400MHz, DMSO-d
6) δ 11.63 (s, 1H), 9.41 (s, 1H), 8.22 (m, 2H), (7.61 s, 1H), 7.25 – 6.99 (m, 1H), 6.53 (s, 1H), 4.30 (td, J=9.5,3.8Hz, 1H), 3.10 – 2.86 (m, 2H), 2.24 (m, 1H), 1.72 – 1.59 (m, 1H), 1.57 – 1.25 (m, 5H), 1.18 (m, 2H) .HRMS (AP-ESI) m/zcalcdforC
17h
19n
7[M+H]
+322.1775, found322.1779.m.p.110-112 DEG C.
The same 16a of synthesis of 16b-16d, the aldehyde or the ketone that are starting raw material are different.
Embodiment 2: the synthesis of compound 17a-f and 17k, for 17a.
(1) preparation of 4-amino-pyrazol (8).
4-nitropyrazole 5.0g is dissolved in 160mL ethanol, then adds 10%Pd/C0.8g in above-mentioned solution.In reaction solution, pass into hydrogen and react at ambient temperature and spend the night.After TLC detection reaction, fall Pd/C with diatomite filtration.Evaporate to dryness alcohol solvent, namely obtains pure intermediate 8, is red solid 3.6g, quantitative reaction.
1H-NMR(400MHz,DMSO-d
6)δ11.92(brs,1H).6.99(s,2H),3.72(brs,2H).ESI-MS,m/z＝84[M+H]
+
(2) preparation of the tertiary butyl-4-(1H-pyrazoles) carbamate (9).
Compound 83.0g is dissolved in NaHCO3/ tetrahydrofuran (THF) (7.5g/160mL) mixing solutions, adds Boc
2o8.6g, room temperature reaction 2 days.Steaming desolventizes rear acetic acid ethyl dissolution, and with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Can obtain pure intermediate 9 after crude product n-hexane, be pink solid, 5.0g, productive rate: 75%.
1HNMR(400MHz,DMSO-d
6)δ12.44(s,1H),9.07(s,1H),7.58(s,1H),7.34(s,1H),1.44(s,9H).ESI-MS,m/z＝184[M+H]
+
(3) preparation of the tertiary butyl-4-(1-(2-itrile group-1-pentamethylene ethyl)-1H-pyrazoles) carbamate (10a)
Compound 93.0g and compound 5a2.9g is dissolved in 150mL acetonitrile solution, and drip 1,8-diazabicylo 11 carbon-7-alkene 3.2g, reaction solution stirs 2 days at 65 DEG C, after TLC detection reaction, steam and desolventize rear acetic acid ethyl dissolution, with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound 10a after column purification methylene chloride/methanol 80:1, is white solid 2.4g, productive rate 48%.
1HNMR(400MHz,DMSO)δ9.6(s,1H),7.78(s,1H),7.44(s,1H),4.30(td,J＝9.6,4.0Hz,1H),3.06(m,2H),2.27(m,1H),1.73(m,1H),1.65–1.54(m,2H),1.54–1.48(m,1H),1.46(s,9H),1.38(m,1H),1.31–1.01(m,3H).ESI-MSm/z＝305[M+H]
+
The synthesis of compound 10b is identical with this step.
(4) preparation of 3-(4-tertiary fourth oxygen formamido group-1H-pyrazoles)-3-hexanaphthene propionic acid (11)
Be dissolved in by compound 10b4.5g in water/methyl alcohol/dioxane (16mL/16mL/100mL) mixing solutions, add 5.4gNaOH solid to above-mentioned solution, reaction solution stirs 6h at 65 DEG C.After TLC detection reaction, after regulating PH to neutrality with the aqueous hydrochloric acid of 1Mol, steam after desolventizing, crude product obtains compound 11 after column purification methylene chloride/methanol 50:1, is white foam solid 2.0g, productive rate 45%.
1HNMR(400MHz,DMSO-d
6)δ12.18(s,1H),9.10(d,J＝17.3Hz,1H),7.58(s,1H),7.26(s,1H),4.22(dd,J＝14.0,7.7Hz,1H),2.81(dd,J＝17.2,6.2Hz,2H),1.78–1.52(m,5H),1.44(s,9H),1.29–0.97(m,4H),0.95–0.76(m,2H).ESI-MSm/z＝338[M+H]
+
(5) preparation of the tertiary butyl-(1-(1-cyclohexyl-3-oxo-(3-Propylamino) propyl group-1H-pyrazoles))-4-carbamate (12a)
By compound 112.4g and O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid 2.6g is dissolved in 160mL tetrahydrofuran (THF), drip triethylamine 2.7g. reaction solution to above-mentioned solution and react half hour at ambient temperature, then Tri N-Propyl Amine 0.8g is added drop-wise in above-mentioned reaction solution gradually, and reaction is spent the night at ambient temperature.After TLC detection reaction, steam and desolventize rear acetic acid ethyl dissolution, with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound 12a after column purification methylene chloride/methanol 80:1, white solid 2.0g. productive rate 77%.ESI-MSm/z＝379[M+H]
+
(6) preparation of 3-(4-amino-1H-pyrazoles-1-alkane)-3-hexanaphthene-N-n-propyl propionic acid amide (13a)
Compound 12a2.0g is dissolved in HCl/EtOAc (50mL), room temperature reaction 8h.After reacting completely, filter out white solid and be compound 13a, white solid 1.2g.Productive rate 81%.
1HNMR(400MHz,DMSO-d
6)δ7.74(s,1H),6.95(s,1H),6.90(s,1H),4.18(d,J＝5.0Hz,2H),3.06(q,J＝7.1Hz,1H),2.89(dt,J＝17.3,6.3Hz,2H),2.60(dt,J＝14.7,17.3Hz,2H),1.63(m,5H),1.27(dt,J＝14.3,7.2Hz,2H),1.6–1.05(m,4H),0.85(m,2H),0.74(t,J＝7.3Hz,3H).ESI-MSm/z＝279[M+H]
+
(7) preparation of the tertiary butyl-(1-(3-amido-1-pentamethylene-3-oxopropan)-1H-pyrazoles-4-alkane) carbamate (14a)
Be dissolved in by compound 10a0.7g in water/methyl alcohol/dioxane (16mL/16mL/100mL) mixing solutions, add 5.4gNaOH solid to above-mentioned solution, reaction solution stirs 6h at 65 DEG C.After TLC detection reaction, after regulating PH to neutrality with the aqueous hydrochloric acid of 1Mol, steam after desolventizing, crude product obtains compound 14a after column purification methylene chloride/methanol 60:1, is white solid 0.5g, productive rate 67%.
1HNMR(400MHz,DMSO-d
6)δ9.08(s,1H),7.56(s,1H),7.26(s,2H),6.71(s,1H),4.28(td,J＝9.6,3.9Hz,1H),2.71(dd,J＝15.1,9.9Hz,1H),2.53(d,J＝4.0Hz,1H),2.28–2.09(m,1H),1.78–1.68(m,1H),1.61–1.46(m,3H),1.44(s,9H),1.39(d,J＝7.6Hz,1H),1.25–1.06(m,3H).ESI-MSm/z＝323[M+H]
+
(8) preparation of 3-(4-amino-1H-pyrazoles-1-alkane)-3-pentamethylene propionic acid amide (15a)
Compound 14a0.5g is dissolved in HCl/EtOAc (50mL), room temperature reaction 8h.After reacting completely, filter out white solid and be compound 15a, white solid 0.2g, productive rate 61%.ESI-MSm/z=223 [M+H]
+
(9) preparation of 3-pentamethylene-3-(4-((7-is to Methyl benzenesulfonyl base-7H-pyrrolo-[2,3-d] pyrimidine-4-alkane) is amino)-1H-pyrazoles-1-alkane) propionic acid amide (18a)
Be dissolved in 20mL propyl carbinol by chloro-for 4-7-to benzenesulfonyl 7H-pyrrolo-[2,3-d] pyrimidine 0.4g and compound 15a0.15g, drip DIPEA0.32g to above-mentioned solution, reaction solution reacts 2h under microwave 150 DEG C of conditions.After reaction terminates, namely solvent decompression Rotary Evaporators evaporate to dryness is obtained crude product.By the crude product obtained by column purification methylene dichloride: methyl alcohol=40:1 obtains compound 18a, pale solid 0.3g, productive rate 91%.
1HNMR(400MHz,DMSO-d
6)δ9.78(s,1H),8.37(s,1H),7.97(d,J＝8.3Hz,3H),7.62(d,J＝5.0Hz,2H),7.45(t,J＝10.7Hz,2H),7.28(s,1H),6.99(s,1H),6.74(s,1H),4.37(dd,J＝9.3,5.4Hz,1H),2.79–2.55(m,2H),2.35(s,3H),1.49(m,4H),1.18(m,5H).ESI-MSm/z＝494[M+H]
+
(10) preparation of 3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionic acid amide (17a)
Compound 18a0.3g is dissolved in water/methyl alcohol/dioxane (3mL/3mL/10mL) and adds 0.4gNaOH solid to above-mentioned solution, reaction solution stirs 0.5h at 55 DEG C, after TLC detection reaction, after regulating PH to neutrality with the aqueous hydrochloric acid of 1Mol, after steaming desolventizes, crude product obtains compound 17a after column purification methylene chloride/methanol 20:1, white solid 80mg, productive rate 48%.
1HNMR(400MHz,DMSO-d
6)δ12.03(s,1H),9.84(s,1H),8.29(s,1H),8.05(s,1H),7.68(s,1H),7.48(d,J＝7.8Hz,1H),7.29(s,1H),7.11(d,J＝7.7Hz,1H),6.77(s,1H),4.51–4.15(m,1H),2.80–2.55(m,2H),1.77(s,1H),1.69–1.38(m,4H),1.38–0.98(m,4H).HRMS(AP-ESI)m/zcalcdforC
17H
21N
7O[M+H]
+340.1880,found340.1884.m.p.155-157℃
Wherein the synthesis of 17b-f with 17k is identical with 17a, but the aldehyde of starting raw material or ketone or aromatic heterocycle different.
Embodiment 3: the synthesis of compound 17g-j and 17l-r, for 17g.
(1) preparation of 3-(4-amino-1H-pyrazoles-1-alkane)-3-hexanaphthene propionic acid amide (15b)
Synthetic method is with compound 15a.
(2) preparation of 3-(4-quinazoline-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17g)
Be dissolved in 8mL propyl carbinol by 4-chloro-quinazoline 0.16g and compound 15b0.15g, after adding 2 TFA, reaction solution reacts after 1h. reaction terminates under microwave 120 DEG C of conditions, and namely the Rotary Evaporators evaporate to dryness of being reduced pressure by solvent obtains crude product.By the crude product obtained by column purification methylene dichloride: methyl alcohol=20:1 obtains compound 17g, 0.17g white solid, productive rate 55%.
1HNMR(400MHz,DMSO-d
6)δ10.05(s,1H),8.62(s,1H),8.44(d,J＝8.2Hz,1H),8.17(s,1H),7.87–7.78(m,2H),7.75(d,J＝8.0Hz,1H),7.60(t,J＝7.5Hz,1H),7.32(s,1H),6.75(s,1H),4.40(m,1H),2.72(m,2H),1.84–1.49(m,5H),1.35–0.74(m,6H).HRMS(AP-ESI)m/zcalcdforC
20H
24N
6O[M+H]
+365.2084,found365.2082.m.p.216-222℃
Embodiment 4: the test experiments of the external Inhibiting enzyme activity of compound
By measuring compound, then JAK substrate phosphorylation level is used
detection method detects.
Table 1 compound and positive drug staurosporine are to the external Inhibiting enzyme activity of JAK1, JAK2, JAK3
Experiment conclusion: compound all has certain restraining effect to JAK1, JAK2, JAK3, IC
50be worth at micro-molar range, it is preferred that compound 17l, 17m, 17n.
Embodiment 5: part of compounds suppresses situation Western blotting (western blot test) to JAK2 phosphorylation
Be 3 × 10 by concentration
6the cell in individual/hole is inoculated in 6 orifice plates, establishes corresponding Vehicle controls, at 37 DEG C with the liquid that concentration is 5 μ Μ, after cultivating 2h under 5%CO2 condition, with the stimulating factor INF-γ process 10min that concentration is 150ng/mL, collecting cell, discards liquid, wash with PBS and once add protein lysate 60 μ L, cracking 15min, add 2 × SDS sample-loading buffer 60 μ L, 100 DEG C are boiled 5min and cause protein denaturation, then the centrifugal 15min of 12000r/min, collects supernatant and get final product.
Experiment conclusion: under the concentration of 5 μMs, compound 17n partly can suppress the phosphorylation of JAK2, and compound 17m can suppress the phosphorylation of JAK2 completely, sees accompanying drawing 1.Accompanying drawing Chinese and English annotation: INF-γ is interferon-γ, and PBS is phosphate buffered saline buffer, and SDS is sodium laurylsulfonate, and Ctrl is control group, and INF is Interferon, rabbit.Bar is the size of the JAK that positive drug baricitinib, P-JAK (126KD) are phosphorylation, JAK is 126KD.ACTIN is blank group.
Claims (9)
1. there is the compound of structure shown in following general formula I or II, and its optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug:
Wherein:
R
1hydrogen, cycloalkyl, alkyl or aryl;
R
2hydrogen, cycloalkyl, alkyl or aryl;
R
3hydrogen, naphthenic hydrocarbon, alkyl or aryl;
Virtue heterocycle mainly comprises pyrimidine ring, pyrrolopyrimidine ring, purine skeleton, pyrazolopyrimidine ring, Furanopyrimidines ring, Thienopyrimidine ring or quinazoline;
* be steric configuration be S or R optical purity or its raceme.
2. compound as claimed in claim 1, is characterized in that: R
1hydrogen, C1-C6 alkyl, cyclopropane, pentamethylene or hexanaphthene; R
2hydrogen, C1-C6 alkyl, cyclopropane, pentamethylene or hexanaphthene; R
3it is C1-C6 alkyl or aryl.
3. compound as claimed in claim 1, is characterized in that for one of following compounds:
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionitrile (16a),
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionitrile (16b),
2-(4-(1-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol))-cyclohexyl acetonitrile (16c),
2-(4-(1-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol))-pentamethylene base acetonitrile (16d),
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionic acid amide (17a),
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17b),
2-(4-(1-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol))-cyclohexyl ethanamide (17c),
2-(4-(1-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol))-pentamethylene yl acetamide (17d),
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl-N-n-propyl propionic acid amide (17e),
3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl-N-isobutyl-propionic acid amide (17f),
3-(4-quinazoline-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17g),
3-(4-9H-purine-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17h),
3-(4-(7H-thieno-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17i),
3-(4-(1H-pyrazolo [3,4-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17j),
3-(2-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17k),
3-(2-(4-methylamino-5-chloropyrimide)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17l),
3-(2-(4-methylamino-5-trifluoromethyl pyrimidine)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17m),
3-(2-(4-p-Chlorobenzoic acid amide base-5-chloropyrimide)-4-amino-pyrazol)-3-cyclohexyl propionic acid amide (17n),
3-(4-(7H-thieno-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-cyclohexyl-N-isobutyl-propionic acid amide (17o),
3-(4-quinazoline-4-amino-pyrazol)-3-cyclohexyl-N-isobutyl-propionic acid amide (17p),
3-(2-(4-methylamino-5-chloropyrimide)-4-amino-pyrazol)-3-pentamethylene base propionic acid amide (17q) or
3-(2-(4-methylamino-5-chloropyrimide)-4-amino-pyrazol)-3-cyclohexyl-N-n-propyl propionic acid amide (17r).
4. the preparation method of compound as claimed in claim 1, it is characterized in that, step is as follows:
(1) with the chloro-7H-pyrrolo-[2 of 4-, 3-d] pyrimidine is starting raw material, intermediate 2 is generated through trimethyl silicon based ethoxymethyl protecting group protection, intermediate 2 obtains intermediate 3 with the generation nucleophilic substitution of 4-amino-pyrazol, different aldehyde or ketone and cyanogen methyl acid phosphate diethyl ester are obtained by reacting intermediate 5 by Wittig reaction, and intermediate 5 and intermediate 3 obtain intermediate 6 by Michael addition; Intermediate 6 is leniently sloughed trimethyl silicon based ethoxymethyl protecting group and is obtained end product 16 in Lewis acid;
Reaction formula is as follows:
Wherein, R
1, R
2as described in above-mentioned general formula I;
Reagent in above-mentioned reaction formula and condition: (a), 2-chloromethoxyethyl trimethyl silane, N,N-dimethylacetamide, 0 DEG C, 4h; (b), 4-amino-pyrazol, DIPEA, propyl carbinol, 150 DEG C, 2-3h, microwave; (c), potassium tert.-butoxide, tetrahydrofuran (THF), room temperature, reaction is spent the night; (d), 1,8-diazabicylo 11 carbon-7-alkene, acetonitrile, 65 DEG C, 5-6 days; (e), tetrafluoro boryl lithium, acetonitrile/water, 90 DEG C, 5-6 days.
The preparation method of 5.3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionitrile (16a), step is as follows:
(1) preparation of the chloro-7-of 4-((2-trimethyl silicane base oxethyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine (2)
Under condition of ice bath, by chloro-for 4-7H-pyrrolo-[2,3-d] pyrimidine 2.0g is dissolved in N, in N-N,N-DIMETHYLACETAMIDE 50mL, NaH0.58g is repeatedly joined in solution in batches and stir 15 minutes, and then in reaction solution, add 2-chloromethoxyethyl trimethyl silane 2.2g, and maintain the temperature at less than 5 DEG C continuation reaction 4h; By the saturated solution termination reaction of ammonium chloride, aqueous phase is extracted with ethyl acetate, organic phase washed with water, and each 100mL of common salt aqueous solution washs three times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure, obtains crude product; With sherwood oil: the purification by silica gel column chromatography of ethyl acetate=50:1 volume ratio can obtain intermediate 2. for colourless liquid 2.6g, yield: 70%;
(2) preparation of 4-(1H-pyrazoles-4-amido)-7-((2-trimethyl silicane base oxethyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine (3)
Intermediate 20.2g and 4-amidopyrazole 0.11g is dissolved in propyl carbinol, adds the DIPEA of 0.27g in the solution, at 150 DEG C, microwave, react 2h, after reaction terminates, namely solvent decompression Rotary Evaporators evaporate to dryness is obtained crude product; By the crude product obtained by column purification methylene dichloride: methyl alcohol=20:1 volume ratio obtains compound 3, be yellow solid 0.15g, productive rate: 65%;
(3) preparation of 3-hexanaphthene vinyl cyanide (5a)
Under condition of ice bath, cyanogen methyl acid phosphate diethyl ester 5.9g is dissolved in anhydrous tetrahydro furan 100mL, more repeatedly adds potassium tert.-butoxide 5.6g in the solution in batches, stir three hours at ambient temperature; Reduce the temperature to 0 DEG C again, to above-mentioned reaction solution drip ring pentane formaldehyde, room temperature reaction spends the night; After TLC detection reaction is complete, adds the saturated solution 100ml cancellation reaction of ammonium chloride, steam after desolventizing, residue with ethyl acetate is extracted, wash organic phase 3 times with water, each 100mL of saturated nacl aqueous solution; The anhydrous anhydrous magnesium sulfate drying of organic phase spends the night, and suction filtration removes solvent under reduced pressure and namely obtains crude product; Crude product sherwood oil: the purification by silica gel column chromatography of ethyl acetate=80:1 volume ratio can obtain intermediate 5a is colourless liquid 2.5g, yield: 67%;
(4) preparation of 3-(4-(7-((2-trimethyl silicane base oxethyl) methyl)-7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionitrile (6a)
Compound 30.15g and compound 5a0.14g is dissolved in acetonitrile 30mL, and add 1,8-diazabicylo 11 carbon-7-alkene 0.10g in above-mentioned solution after, 65 DEG C are reacted 5-6 days, steaming desolventizes rear acetic acid ethyl dissolution, with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound 6a after column purification methylene chloride/methanol 80:1, is yellow solid 0.10g, productive rate: 37%;
(5) preparation of 3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionitrile (16a)
Be dissolved in the acetonitrile/water of 20mL/5mL by compound 6a0.10g, add tetrafluoro boryl lithium 0.6g, 85 DEG C of back flow reaction are after 5 days; Steaming desolventizes rear acetic acid ethyl dissolution, and with water, each 100mL of the saturated common salt aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound 16a after column purification methylene chloride/methanol 20:1, is pale solid 20mg, productive rate: 28%.
6. the preparation method of compound as claimed in claim 1, is characterized in that step is as follows:
With 4-nitropyrazole for starting raw material, 4-amino-pyrazol intermediate 8 is obtained by the reduction of palladium carburetted hydrogen gas, intermediate 8 Boc protects amino to obtain intermediate 9, intermediate 9 obtains intermediate 10 with intermediate 5 by Michael addition again, intermediate 10 obtains intermediate 11 and intermediate 14 respectively in highly basic NaOH Water Under solution, intermediate 11 and different amine are by O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid condensation obtains various intermediate 12, obtains intermediate 13 and 15 after intermediate 12 and intermediate 14 slough Boc protecting group in HCl/EA; Intermediate 13 and 15 obtains end product 17a-r from different chlorinated aromatic heterocycles by nucleophilic attack;
Reaction formula is as follows:
Wherein, R
1, R
2, R
3as described in above-mentioned general formula II;
Reagent in above-mentioned reaction formula and condition: (a), Pd/C, H
2, ethanol, room temperature, reaction is spent the night; (b), tert-Butyl dicarbonate, NaHCO
3/ H
2o, tetrahydrofuran (THF), room temperature, reaction is spent the night; (c), 1,8-diazabicylo 11 carbon-7-alkene, acetonitrile, 65 DEG C, 2 days; (d), NaOH, H
2o/ methyl alcohol/dioxane, 90 DEG C, 5-6h; (e), O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, triethylamine, R
3nH
2, CH
2cl
2, room temperature, reaction is spent the night; (f), HCl/ ethyl acetate, room temperature, reaction is spent the night; (g), DIPEA, propyl carbinol, 150 DEG C, 1-2h, microwave or trifluoroacetic acid, propyl carbinol, 100 DEG C, 1-2h, microwave; (h) NaOH, water/dioxane, 60 DEG C, 30min.
The preparation method of 7.3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionic acid amide (17a), step is as follows:
(1) preparation of 4-amino-pyrazol (8)
4-nitropyrazole 5.0g is dissolved in 160mL ethanol, then adds 10%Pd/C0.8g in above-mentioned solution; In reaction solution, pass into hydrogen and react at ambient temperature and spend the night; After TLC detection reaction, fall Pd/C with diatomite filtration; Evaporate to dryness alcohol solvent, namely obtains pure intermediate 8, is red solid 3.6g, quantitative reaction;
(2) preparation of the tertiary butyl-4-(1H-pyrazoles) carbamate (9)
Compound 83.0g is dissolved in NaHCO3/ tetrahydrofuran (THF) 7.5g/160mL mixing solutions, adds tert-Butyl dicarbonate 8.6g, room temperature reaction 2 days; Steaming desolventizes rear acetic acid ethyl dissolution, and with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Can obtain pure intermediate 9 after crude product n-hexane, be pink solid, 5.0g, productive rate: 75%;
(3) preparation of the tertiary butyl-4-(1-(2-itrile group-1-pentamethylene ethyl)-1H-pyrazoles) carbamate (10a)
Compound 93.0g and compound 5a2.9g is dissolved in 150mL acetonitrile solution, and drip 1,8-diazabicylo 11 carbon-7-alkene 3.2g, reaction solution stirs 2 days at 65 DEG C, after TLC detection reaction, steam and desolventize rear acetic acid ethyl dissolution, with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound 10a after column purification methylene chloride/methanol 80:1, is white solid 2.4g, productive rate 48%; The synthesis of compound 10b is identical with this step;
(4) preparation of 3-(4-tertiary fourth oxygen formamido group-1H-pyrazoles)-3-hexanaphthene propionic acid (11)
Be dissolved in by compound 10b4.5g in water/methyl alcohol/dioxane 16mL/16mL/100mL mixing solutions, add 5.4gNaOH solid to above-mentioned solution, reaction solution stirs 6h at 65 DEG C; After TLC detection reaction, after regulating acid-basicity to neutrality with the aqueous hydrochloric acid of 1Mol, steam after desolventizing, crude product obtains compound 11 after column purification methylene chloride/methanol 50:1, is white foam solid 2.0g, productive rate 45%;
(5) preparation of the tertiary butyl-(1-(1-cyclohexyl-3-oxo-(3-Propylamino) propyl group-1H-pyrazoles))-4-carbamate (12a)
By compound 112.4g and O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid 2.6g is dissolved in 160mL tetrahydrofuran (THF), drip triethylamine 2.7g. reaction solution to above-mentioned solution and react half hour at ambient temperature, then Tri N-Propyl Amine 0.8g is added drop-wise in above-mentioned reaction solution gradually, and reaction is spent the night at ambient temperature; After TLC detection reaction, steam and desolventize rear acetic acid ethyl dissolution, with water, aqueous citric acid solution, each 100mL of saturated nacl aqueous solution washs 3 times; Organic phase anhydrous magnesium sulfate drying spends the night, and suction filtration removes solvent under reduced pressure; Crude product obtains compound 12a after column purification methylene chloride/methanol volume ratio 80:1, white solid 2.0g. productive rate 77%;
(6) preparation of 3-(4-amino-1H-pyrazoles-1-alkane)-3-hexanaphthene-N-n-propyl propionic acid amide (13a)
Compound 12a2.0g is dissolved in HCl/EtOAc50mL, room temperature reaction 8h; After reacting completely, filter out white solid and be compound 13a, white solid 1.2g, productive rate 81%;
(7) preparation of the tertiary butyl-(1-(3-amido-1-pentamethylene-3-oxopropan)-1H-pyrazoles-4-alkane) carbamate (14a)
Be dissolved in by compound 10a0.7g in water/methyl alcohol/dioxane 16mL/16mL/100mL mixing solutions, add 5.4gNaOH solid to above-mentioned solution, reaction solution stirs 6h at 65 DEG C; After TLC detection reaction, after regulating acid-basicity to neutrality with the aqueous hydrochloric acid of 1Mol, steam after desolventizing, crude product obtains compound 14a after column purification methylene chloride/methanol 60:1, is white solid 0.5g, productive rate 67%;
(8) preparation of 3-(4-amino-1H-pyrazoles-1-alkane)-3-pentamethylene propionic acid amide (15a)
Compound 14a0.5g is dissolved in HCl/EtOAc50mL, room temperature reaction 8h, waits after reacting completely, filter out white solid and be compound 15a, white solid 0.2g, productive rate 61%;
(9) preparation of 3-pentamethylene-3-(4-((7-is to Methyl benzenesulfonyl base-7H-pyrrolo-[2,3-d] pyrimidine-4-alkane) is amino)-1H-pyrazoles-1-alkane) propionic acid amide (18a)
Be dissolved in 20mL propyl carbinol by chloro-for 4-7-to benzenesulfonyl 7H-pyrrolo-[2,3-d] pyrimidine 0.4g and compound 15a0.15g, drip diisopropylethylamine 0.32g to above-mentioned solution, reaction solution reacts 2h under microwave 150 DEG C of conditions; After reaction terminates, namely solvent decompression Rotary Evaporators evaporate to dryness is obtained crude product; By the crude product obtained by column purification methylene dichloride: methyl alcohol=40:1 obtains compound 18a, pale solid 0.3g, productive rate 91%;
(10) preparation of 3-(4-(7H-pyrrolo-[2,3-d] pyrimidine)-4-amino-pyrazol)-3-pentamethylene base propionic acid amide (17a)
Compound 18a0.3g is dissolved in water/methyl alcohol/dioxane 3mL/3mL/10mL and adds 0.4gNaOH solid to above-mentioned solution, reaction solution stirs 0.5h at 55 DEG C, after TLC detection reaction, after regulating acid-basicity to neutrality with the aqueous hydrochloric acid of 1Mol, after steaming desolventizes, crude product obtains compound 17a after column purification methylene chloride/methanol 20:1, white solid 80mg, productive rate 48%.
8. the compound described in claim 1,2 or 3 preparation prevention or treatment and inflammation, tumour, blood-related diseases medicine in application; Described comprises with inflammation, tumour, blood-related diseases: rheumatic arthritis, rheumatoid arthritis, myelofibrosis or severe combined immune Defect.
9. be suitable for a pharmaceutical composition that is oral or parenteral admin, comprise compound described in claim 1,2 or 3 and one or more pharmaceutically acceptable carriers or vehicle.
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| CN109535132A (en) * | 2017-09-21 | 2019-03-29 | 北京赛特明强医药科技有限公司 | 2- substituted pyrazolecarboxylic amino -4- substituted-amino -5- pyrimidinecarboxamides compound, composition and its application |
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| CN110028509A (en) * | 2019-05-27 | 2019-07-19 | 上海勋和医药科技有限公司 | The alternatively azolopyrimidines of property JAK2 inhibitor, its synthetic method and purposes |
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