CN104610254A - Low-cost preparation method for palbociclib - Google Patents
Low-cost preparation method for palbociclib Download PDFInfo
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Abstract
The invention relates to a low-cost preparation method for palbociclib. The low-cost preparation method comprises the following steps: by taking 2,4-dichloro-5-cyanopyrimidine as an initial raw material, performing cyano Grignard and hydrolysis so as to obtain 5-acetyl-2,4-dichloropyrimidine, protecting carbonyl, performing amination, removing carbonyl, performing acylation reaction by using diketene and amino so as to obtain 5-acetyl-4-acetoacetamide-2-chloropyrimidine, performing intramolecular dehydration on the product so as to obtain 6-acetyl-8-cyclopentyl-5-methyl-2-chlorine-8H-pyridino-[2,3-d] pyrimidine-7-ketone, protecting 6 acetyl groups by using carbonyl, further realizing reaction with an aminopyridine derivative so as to obtain 4-{6-[(6-1,1 dialkoxyl) ethyl-8-cyclopentyl-5-methyl-7-keton-7,8 dihydropyridino-[2,3-d]pyrimidine-2-amino]-pyridine-3-yl}-piperazine-1-carboxylic acid tert-butyl ester, and finally performing acid hydrolysis and neutralization to obtain palbociclib free alkali. By adopting the low-cost preparation method, the raw materials are easy to obtain, the cost is low, and the environment can be protected.
Description
Technical field
The present invention relates to the preparation method of a kind of Pa Bosaibu, belong to medicine bioengineering chemical field.
Background technology
Pa Bosaibu (Palbociclib) is oral, the targeting preparation of one of Pfizer's exploitation, can Selective depression cell cycle protein dependent kinase 4 and 6 (CDK4/6), recovers the cell cycle to control, and blocks tumor cell proliferation.Treatment Palbociclib II phase clinical data for postmenopausal women's estrogen receptor in late period (ER) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer shows, compared with standard care medicine letrozole (Letrozole) treatment group, Pa Bosaibu and letrozole drug combination group progressive free lifetime (PFS) achieve significant prolongation (20.2 months vs 10.2 months of statistical significance, p=0.0004), the Primary Endpoint of research is reached.Overall survival (OS) preliminary data when final PFS analyzes shows, drug combination group median overall survival is 37.5 months, and Letrozole treatment group is 33.3 months, without statistically-significant difference.On October 13rd, 2014, FDA accepts Palbociclib new drug application (NDA), and has specified be on April 13rd, 2015 prescription drugs user fee method (PDUFA) target date.If granted, Pa Bosaibu and letrozole (Letrozole) conjoint therapy will provide an important new selection for metastatic breast cancer patient.
No. CAS of Pa Bosaibu is [571190-30-2], and chemical name is: 6-ethanoyl-8-cyclopentyl-5-methyl-2-[[5-(piperazine-1-base) pyridine-2-base] is amino]-8H-pyrido [2,3-D] pyrimidin-7-ones, and structural formula is as follows:
WO2003062236 reports the synthetic method of Pa Bosaibu, and WO2010039997WO2012068381 have employed identical synthetic route, and yield increases, and synthetic route is as follows:
This route 1 uses 2-methylthio group-4 chloro-5-carboxylic acid, ethyl ester pyrimidine as starting raw material, through ammonification, reduction, oxidation, grignard, the multisteps such as oxidation, just obtain 5-acetyl 4-cyclopentamine base-2-methanesulfonyl-pyrimidine by polystep reaction, reactions steps is long, and employs expensive lithium aluminum hydride as reductive agent.Bibliographical information yield is higher to the greatest extent, and actual being difficult to realizes.Utilize sulfoxide as leavings group, carry out the nucleophilic substitution reaction of pyrimidine with aminopyrazole derivatives (J), the very low 28-35% of yield, synthesis cost is improved greatly.Utilize stille coupling to introduce ethanoyl, yield reaches 80%, but needs to use expensive Pd as catalyzer, and the reagent that ethoxy vinyltributyltin, triphenylphosphine etc. are not cheap.Total recovery 9.49% (relative to 2-methylthio group-4 chloro-5-carboxylic acid, ethyl ester pyrimidine), yield is lower and step is tediously long, technique is loaded down with trivial details.
The synthetic method of WO2008032157 and WO2014128588A1 to this product is improved; use 2; the chloro-5-bromo pyrimi piperidine of 4-bis-is as starting raw material; cyclopentamine base is introduced by pyrimidine 4 cyclopentamine ammonifications; use for twice heck reaction to introduce double bond and ethanoyl respectively, make synthesis step very succinct.The precursor of ethanoyl is vinyl butyl ether, and can slough easily in acid condition with amino protecting group Boc, and the by product generated very easily is separated, deprotection and salify can complete in one pot simultaneously.The nucleophilic substitution reaction of aminopyridine and pyrimidine uses highly basic Lithamide or isopropylmagnesium chloride, and yield brings up to 92-93%.WO2014128588 reports that total recovery brings up to 43.55% (with 2,4-bis-chloro-5-bromo pyrimi piperidine meter).This route reaction formula is as follows
This synthetic route 2 weak point is that twice utilization Heck reacts, and needs to use precious metal Palladous chloride or palladium, and more expensive part, improves synthesis cost.
Summary of the invention
For the deficiencies in the prior art, the invention provides the low cost preparation method of a kind of Pa Bosaibu, do not use precious metals palladium catalyst and more expensive part.
Technical solution of the present invention is specific as follows:
A low cost preparation method of Pa Bosaibu, comprises step as follows:
(1) 2,4-bis-chloro-5-cyanopyrimidine is in suitable solvent, and react with methyl Grignard, temperature of reaction is 20 ~ 100 DEG C, is then hydrolyzed in acid condition, obtained 5-ethanoyl-2,4-dichloro pyrimidine (II);
(2) 2 are made, formula III after 4-bis-chloro-5-ethanoyl pyrimidine (II) and carbonyl protective agent are obtained by reacting carbonyl-protection under acid catalyst effect or formula III-1 compound, described carbonyl protective agent is the dibasic alcohol of C1-C6, the monohydroxy-alcohol of C1-C6 or the binary mercaptan of C1-C6;
Formula III, in formula III-1, X is Sauerstoffatom or sulphur atom;
In formula III, R
1, R
2be selected from the alkyl of C1-C6 independently of one another, can be identical, also can be different;
In formula III-1, n=1 ~ 5, with R in formula III
1, R
2the substituting group of correspondence position is C2-C6-CH
2-cyclic substituents;
Described acid catalyst is selected from mineral acid, the organic acid of C1-C6, methylsulfonic acid, tosic acid or amidosulfonic acid;
(3) formula III or formula III-1 compound and cyclopentamine add the aminating reaction that alkali carries out 4 in a solvent, and aminating reaction temperature is 10 ~ 150 DEG C, and sloughs blocking group, obtains 5-ethanoyl-4-amido-2-chloropyrimide (IV);
Described alkali is trimethylamine or mineral alkali; The mol ratio of described cyclopentamine and formula III or formula III-1 compound be (0.95 ~ 5): 1;
(4) the chloro-4-amido of 2--5-ethanoyl pyrimidine (IV) reacts with acetoacetylating agent in a solvent, temperature of reaction 5 ~ 100 DEG C, obtains 5-ethanoyl-4-acetoacetyl amido-2-chlorine compound (V);
Described acetoacetylating agent is ketene dimer, methyl acetoacetate, methyl aceto acetate, ISOPROPYL ACETOACETATE or ketene dimer contracting acetone; Described acetoacetylating agent mole dosage is 0.95 ~ 1.5 times of formula IV compound molar weight;
(5) by 5-ethanoyl-4-acetoacetyl amido-2-chlorine compound (V) in the presence of a catalyst, in solvent, cyclization temperature is under 20 DEG C of-120 DEG C of conditions, 6-ethanoyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido [2,3-d] pyrimidin-7-ones (VI) is generated through intramolecular condensation dehydration;
Described catalyzer is selected from pyridine, piperidines, quinoline, N-picoline, N-methyl piperidine, DBU (1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene), tetrabutyl ammonium fluoride, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium methylate, sodium ethylate, potassium ethylate, triethylamine, diisopropylethylamine, Tributylamine or N, one of N-Diethyl Aniline, or the combination of piperidines and pyridine;
(6) 6-ethanoyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido [2,3-d] pyrimidin-7-ones (VI) is reacted with carbonyl protective agent under catalyst action, obtain formula VIIa or the formula VIIb compound of carbonyl-protection;
When carbonyl protective agent used is the binary mercaptan of the dibasic alcohol of C1-C6, the monohydroxy-alcohol of C1-C6 or C1-C6, obtain formula VIIa compound;
In formula VIIa, X is Sauerstoffatom or sulphur atom; R
3, R
4be selected from the alkyl of C1-C6 independently of one another, or (R
3+ R
4) be-CH of the C2-C6 be connected with carbon-carbon bond jointly
2-cyclic substituents;
When selected carbonyl protective agent is trimethylchlorosilane, the silyl enol ether compound of production VIIb structure;
(7) pyridine in the presence of a catalyst for formula VIIa or formula VIIb compound and 2-amino-5-(4-N-tert-butoxycarbonyl-1-N-piperazinyl), substitution reaction is carried out in toluene or tetrahydrofuran (THF), under 0-40 DEG C temperature of reaction, obtain following formula VIII a or VIII b respectively, be referred to as formula VIII compound:
X is Sauerstoffatom or sulphur atom;
R
5, R
6be selected from the alkyl of 1-6 carbon atom independently of one another, or (R
5+ R
6) common-CH representing the C2-C6 be connected with carbon-carbon bond
2-cyclic substituents;
Or, directly with the chloro-8H-pyrido [2 of compound 6-ethanoyl-8-cyclopentyl-5-methyl-2-that step (5) is obtained, 3-d] pyrimidin-7-ones (VI) and 2-amino-5-(4-N-tert-butoxycarbonyl-1-N-piperazinyl) pyridine in the presence of a catalyst, in toluene or tetrahydrofuran (THF), under 0-40 DEG C temperature of reaction, carry out substitution reaction prepare following formula VIII-2 compound;
The above catalyzer is amido lithium derivative, alkali metal hydroxide, alkaline carbonate, alkalimetal hydride, basic metal C2-C4 alkoxide, DBU, aluminum isopropylate, isopropylmagnesium chloride or tertiary butyl magnesium chloride;
Formula VIII compound is referred to as with above formula VIII a, VIII b, VIII-2 compound;
(8) formula VIII compound in a solvent, carry out acidic hydrolysis deprotection, the free alkali of obtained Pa Bosaibu (I) or salt at temperature 10-100 DEG C;
Described acidic hydrolysis deprotection used catalyst hydrochloric acid, sulfuric acid, formic acid, acetic acid, butyric acid, propionic acid, tartrate, toxilic acid, succinic acid, trifluoroacetic acid, methylsulfonic acid, hydroxyethylsulfonic acid or tosic acid.
Terminological interpretation:
" (R in above step (6)
3+ R
4) common-CH representing the C2-C6 be connected with carbon-carbon bond
2-cyclic substituents " refer in formula VIIa, with R
3, R
4the substituting group of correspondence position is the C2-C6 cycloalkyl be connected with carbon-carbon bond, be analogous in formula III-1 with R
1, R
2the cyclic substituents of correspondence position.(R in step (7)
5+ R
6) also do same explanation.
The preparation method of Pa Bosaibu of the present invention, carbonyl protective agent is for ethylene glycol, and reaction scheme is as follows:
Preferred according to the present invention, the grignard reaction temperature described in step (1) is 20 ~ 80 DEG C, especially preferably 65 DEG C; Described suitable solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether or cyclopentyl methyl ether; Preferred tetrahydrofuran (THF); Described methyl Grignard reacts by monobromethane, methyl iodide or methyl chloride and MAGNESIUM METAL to be prepared; Also can buy in market.
Preferred according to the present invention, in carbonyl protective agent described in step (2), the dibasic alcohol of C1-C6 is selected from ethylene glycol, 1,2-PD, 1,3-PD, BDO or 1,3 butylene glycol; The monohydroxy-alcohol of C1-C6 is methyl alcohol, ethanol, Virahol or butanols; The binary mercaptan of C1-C6 is selected from dithioglycol, 1,2-dimercaptopropane, 1,3-dimercaptopropane, Isosorbide-5-Nitrae-succinimide mercaptans or 1,3-succinimide mercaptans; Particularly preferably described carbonyl protective agent is ethylene glycol.
Preferred according to the present invention, in the acid catalyst described in step (2), mineral acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid; Organic acid is selected from formic acid, acetic acid or propionic acid; Most preferred acid catalyzer is tosic acid.The consumption of catalyzer is the 0.01-2% of 2,4-bis-chloro-5-ethanoyl pyrimidine molar weight, especially preferably 0.5%.
Preferred according to the present invention, the solvent described in step (3) is protonic solvent, aprotic solvent or trimethylamine solvent; Protonic solvent is methyl alcohol, ethanol, Virahol or propyl carbinol etc., aprotic solvent is as N-Methyl pyrrolidone (NMP), N, dinethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran (THF) (THF); Trimethylamine solvent is triethylamine, tripropyl amine, Tributylamine or diisopropylethylamine, and particularly preferably use NMP or ethanol as solvent, preferably this polar solvent is conducive to nucleophilic substitution reaction.
Preferred according to the present invention, in alkali described in step (3), trimethylamine is selected from triethylamine, tripropyl amine, Tributylamine or diisopropylethylamine, and mineral alkali is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, Quilonum Retard or lithium bicarbonate etc., wherein, described alkali preferably uses triethylamine;
Preferred according to the present invention, described in step (3), the temperature of aminating reaction is 15 ~ 80 DEG C, especially preferably 20 DEG C;
Preferred according to the present invention, described in step (3), the mol ratio of cyclopentamine and formula III compound is (1 ~ 5): 1, especially preferably 3:1.The nucleophilic substitution reaction using excessive nucleophilic reagent cyclopentamine to be conducive to halogenated aryl hydrocarbon carries out.
Preferred according to the present invention, solvent described in step (4) is aliphatic ether, fatty cyclic ethers, polar aprotic solvent, toluene or one of dimethylbenzene, aliphatic hydrocarbon; Wherein, aliphatic ether is selected from ether, isopropyl ether or methyl tertiary butyl ether, fat cyclic ethers is selected from tetrahydrofuran (THF), methyltetrahydrofuran or 1,4-dioxane, polar aprotic solvent is selected from N-Methyl pyrrolidone (NMP), DMF (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran (THF) (THF); Aliphatic hydrocarbon is selected from normal hexane, normal heptane, octane-iso, hexanaphthene, suberane etc.;
The temperature of described acetoacetylate reaction is 10 ~ 60 DEG C, especially preferably 15 ~ 35 DEG C; Described acetoacetylating agent mole dosage is 1 ~ 1.2 times of formula IV compound molar weight, especially preferably 1.05 times.
After the above-mentioned reactions steps of the present invention (4) terminates, without aftertreatment, can directly add the catalyzer described in step (5), react according to step (5); Also after aftertreatment, then the catalyzer described in step (5) can be added, react according to step (5).
Preferred according to the present invention, in step (5), described catalyzer is the combination of piperidines or piperidines-pyridine mol ratio 1:1; Described catalyzer dosage is catalytic amount.Different sorts catalyst levels is different, and the mol ratio of catalyzer and 5-ethanoyl-4-acetoacetyl amido-2-chlorine compound (V) at 0.5-110%, can be preferably 10-15%.
Preferred according to the present invention, in step (5), described solvent is aliphatic ether, as ether, and isopropyl ether, methyl tertiary butyl ether; May also be fatty cyclic ethers, as tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane etc.; Can be protonic solvent as methyl alcohol, ethanol, Virahol, propyl carbinol, water etc.; Also can be polar aprotic solvent, as DMF, DMA, DMSO, NMP etc.; Also aromatic hydrocarbons can be used, as toluene, dimethylbenzene; Also aliphatic hydrocarbon can be used as normal hexane, normal heptane, octane-iso, hexanaphthene, suberane etc.; May also be the mixed solvent of above-mentioned solvent;
Preferred according to the present invention, in step (5), the preferred 60-100 DEG C of described cyclization temperature; Especially preferably 80-85 DEG C; Reaction times 5-24h;
Preferred according to the present invention, in carbonyl protective agent described in step (6), the dibasic alcohol of C1-C6 is selected from ethylene glycol, 1,2-PD, 1,3-PD, BDO or 1,3 butylene glycol; The monohydroxy-alcohol of C1-C6 is methyl alcohol, ethanol, Virahol or butanols; The binary mercaptan of C1-C6 is selected from dithioglycol, 1,2-dimercaptopropane, 1,3-dimercaptopropane, Isosorbide-5-Nitrae-succinimide mercaptans or 1,3-succinimide mercaptans; Particularly preferably described carbonyl protective agent is ethylene glycol.
Preferred according to the present invention, in the catalyzer described in step (7), amido lithium derivative is selected from amido lithium, two (trimethyl silicon based) amido lithium, lithium diisopropyl amido; Alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and alkaline carbonate is selected from salt of wormwood, Quilonum Retard or sodium carbonate; Alkalimetal hydride is selected from sodium hydride or potassium hydride KH; Basic metal C2-C4 alkoxide is selected from sodium ethylate, potassium tert.-butoxide or sodium tert-butoxide.
Preferred according to the present invention, described in step (7), solvent is selected from ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), methyltetrahydrofuran, 1,4-dioxane, N-Methyl pyrrolidone (NMP), N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran (THF) (THF), toluene or dimethylbenzene etc.Preferred use toluene, tetrahydrofuran (THF) or methyltetrahydrofuran;
Preferred according to the present invention, in step (8), institute uses sour amount to be 2-10 times of raw materials used formula VIII compound molar weight, preferred 3.5-5 times molar weight, especially preferably 5 times of molar weights.The temperature 40-80 DEG C of described hydrolysis deprotection, especially preferably 50-55 DEG C.Described solvent is selected from: methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF), butanone.
Technical characterstic of the present invention and excellent results:
The method utilizes 2, the chloro-5-cyanopyrimidine of 4-bis-is as starting raw material, by the grignard of cyano group, hydrolysis obtains 5-ethanoyl-2, 4-dichloro pyrimidine (II), the carbonyl of compound (II) is protected to obtain compound (III) with carbonyl protective agent, cyclopentamine is utilized to carry out ammonification to pyrimidine 4, and slough carboxy protecting group, then ketene dimer and amido is adopted to carry out acylation reaction, obtain compound 5-ethanoyl-4-acetoacetyl amido-2-chloropyrimide (V), product in the presence of a catalyst, the chloro-8H-pyrido [2 of 6-ethanoyl-8-cyclopentyl-5-methyl-2-is obtained by intramolecular dehydration, 3-d] pyrimidin-7-ones (VI), 6 ethanoyl are protected to obtain compound (VII) by carbonyl protective agent, compound (VII) and amido pyridine derivate react, obtain 4-{6-[6-(1, 1 dioxane (sulphur) oxygen base) ethyl-8-cyclopentyl-5-methyl-7-ketone-7, 8 dihydro pyridos [2, 3-d] pyrimidine-2-amido]-pyridin-3-yl }-piperazine-1-carboxylic acid tert-butyl ester (VIII), finally in the mixing solutions of organic solvent and water, pass through acid hydrolysis, sodium hydroxide neutralizes, obtain Pa Bosaibu (I) free alkali.
The raw material that the present invention uses is easy to get, simple flow, process safety environmental protection, easy handling, avoids using noble metal catalyst, reduces costs, is conducive to suitability for industrialized production.
Embodiment
Below in conjunction with embodiment and reaction scheme 3, preparation process of the present invention is described in detail.But the present invention is not only confined to this.Embodiment is raw materials used is commercially available prod with reagent.Described in embodiment, " % " is mass percent, except special instruction.The massfraction of concentrated hydrochloric acid is 37.5%
The preparation of embodiment 1:2,4-dichloro pyrimidine-5-(ethylenedioxy) ethyl-pyrimidine (III-1)
The chloro-5-cyanopyrimidine 34.8g of initial feed 2,4-bis-, is dissolved in 100ml tetrahydrofuran solution; be warmed up to 55-60 DEG C, start to drip equimolar methyl-magnesium-bromide tetrahydrofuran (THF) grignard solution, dropwise latter 65 DEG C; insulation 3h, then cools to 15-20 DEG C, adds dilute hydrochloric acid 50mL; stir, layering, after oil reservoir anhydrous sodium sulfate drying; reclaim tetrahydrofuran (THF); residuum is 2,4-bis-chloro-5-ethanoyl pyrimidine (II) 34.4g, yield 90%.
By chloro-for 2,4-bis-5-ethanoyl pyrimidine (II) 34.4g, be dissolved in 120mL toluene; add ethylene glycol 11.5g, add 0.17g tosic acid, backflow band water; until the water of generative theory amount, stopped reaction, is down to room temperature; add sodium methylate 0.5g; add 20mL washing, layering, toluene is reclaimed in underpressure distillation; residuum is 2,4-dichloro pyrimidine-5-(ethylenedioxy) ethyl-pyrimidine (III-1).
Reaction formula is as follows:
The preparation of the chloro-4-cyclopentamine yl pyrimidines (IV) of embodiment 2:5-ethanoyl-2-two
The compound (III-1) of embodiment 1 is dissolved in the NMP of 100ml, add triethylamine 30mL, add cyclopentamine 65g, be warmed up to 20-25 DEG C of reaction 8h, then the remaining cyclopentamine of reclaim under reduced pressure, triethylamine and NMP, residuum adds 50mL water, add concentrated hydrochloric acid 6mL again, be warmed up to 60-70 DEG C, reaction 2h, pH is regulated to be 9 ~ 10 with sodium carbonate solution, add 100mL extraction into ethyl acetate, extract three times, merge oil reservoir, Distillation recovery portion of ethyl acetate, cooling, suction filtration, dry, obtain 5-ethanoyl-2-two chloro-4-cyclopentamine yl pyrimidines (IV) 34.5g, two step yields 80%.
The preparation of embodiment 3:5-ethanoyl-4-acetoacetyl amido-2-chloropyrimide (V)
5-ethanoyl-2-two chloro-4-cyclopentamine yl pyrimidines (IV) 34.5g, is dissolved in 200mL tetrahydrofuran (THF), 5-10 DEG C; drip the mixing solutions of 12.7g ketene dimer and 50mL tetrahydrofuran (THF) wherein; after dropwising, room temperature reaction 4h, is then warmed up to 60 degree of reaction 2h.Concentrating under reduced pressure partial solvent, cooling suction filtration, obtains compound 5-ethanoyl-4-acetoacetyl amido-2-chloropyrimide (V) 43.3g, yield 93%.
The preparation of embodiment 4:6-ethanoyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido [2,3-d] pyrimidin-7-ones (VI)
5-ethanoyl-4-acetoacetyl amido-2-chloropyrimide (V) 32.3g is dissolved in 50m tetrahydrofuran (THF), and 5-15 DEG C, adds 3gN-methyl piperidine; the mixture of 3g pyridine; stirring reaction 4h, is then warmed up to 35-40 DEG C of reaction 2h, then backflow insulation 2h; cool to 20 DEG C; add 100mL water, suction filtration, washing, tetrahydrofuran (THF) are washed, and dry and obtain the chloro-8H-pyrido [2 of 6-ethanoyl-8-cyclopentyl-5-methyl-2-; 3-d] pyrimidin-7-ones (VI) 25.3g, yield 83%.
The preparation of embodiment 5: Pa Bosaibu (I)
The compound (VI) obtained by embodiment 4, undertaken by following reaction formula:
By the chloro-8H-pyrido [2 of 6-ethanoyl-8-cyclopentyl-5-methyl-2-, 3-d] pyrimidin-7-ones (VI) 45g, ethylene glycol 10g, add 0.14g tosic acid, toluene 150mL, backflow band water, until the water of generative theory amount, stopped reaction, be down to room temperature, add sodium methylate 0.5g to neutralize, add 20ml washing, layering, toluene is reclaimed in underpressure distillation, residuum toluene, after tetrahydrofuran (THF) recrystallization, obtain as 6-(1, 1-dioxoethyl) the chloro-8H-pyrido [2 of-8-cyclopentyl-5-methyl-2-, 3-d] pyrimidin-7-ones (VII-1) 46g, yield 88%
Under room temperature condition, by 2-amino-5-(4-N-tert-butoxycarbonyl-1-N-piperazinyl) pyridine 27.8g, be dissolved in 100mL toluene, nitrogen protection, then two (trimethyl silicon based) amido lithium tetrahydrofuran solution (0.1mol) is added, stir 0.5h, by the 6-(1 of preparation, 1-ethylenedioxy) the chloro-8H-pyrido [2 of-8-cyclopentyl-5-methyl-2-, 3-d] pyrimidin-7-ones (VII-1) 34.9g is dissolved in 100mL toluene, then joined in solution above, stirring at room temperature 60 minutes, add 100mL saturated solution of sodium bicarbonate, stir 0.5h, suction filtration, solid washed with water, washing with acetone, 65 degree of oven dry, obtain 4-{6-[6-(1, 1-ethylenedioxy) ethyl-8-cyclopentyl-5-methyl-7-ketone-7, 8 dihydro pyridos [2, 3-d] pyrimidine-2-amido]-pyridin-3-yl }-piperazine-1-carboxylic acid tert-butyl ester (VIII-1) 54.4g, yield 92%
Get the 4-{6-[6-(1 of preparation, 1 ethylenedioxy) ethyl-8-cyclopentyl-5-methyl-7-ketone-7, 8 dihydro pyridos [2, 3-d] pyrimidine-2-amido]-pyridin-3-yl }-piperazine-1-carboxylic acid tert-butyl ester (VIII-1) 29.6g, add 296g water, then methyl alcohol 148mL is added, be warmed up to 50-55 DEG C, then concentrated hydrochloric acid 25.5g is dripped, insulation 4h, cool to 35-40 DEG C, drip 10% sodium hydroxide solution, regulate pH=9 ~ 10, be slow cooling to 10 ~ 15 DEG C, insulation 0.5h, suction filtration, washing, cold methanol washs, decompression drying obtains Pa Bosaibu free alkali 24g, 6-ethanoyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-base-pyridine-2-base amido)-8-H-pyrido [2, 3-d] pyrimidin-7-ones (I).
Characterization of The Products data are as follows:
LC-MS:448.5 (ESI, M+H), purity: ~ 99%;
1H NMR(300MHz，D2O)：9.00(s,1H),8.12(dd,J＝9.3Hz,2.1Hz,1H),7.81(d,J＝2.4Hz,1H),7.46(d,J＝9.6Hz,1H),5.80-5.74(m,1H),3.57-3.48(m,8H),2.48(s,3H),2.37(s,3H),2.13-1.94(m,6H),1.73-1.71(m,2H).
13C NMR(75MHz,D2O):203.6,159.0,153.5,153.3,152.2,139.9,139.4,139.2,133.1,129.0,118.7,113.8,107.4,51.8,42.2,40.0,28.0,25.2,22.6,10.8.。
Claims (10)
1. the low cost preparation method of Yi Zhong Pa Bosaibu, comprises step as follows:
(1) 2,4-bis-chloro-5-cyanopyrimidine is in suitable solvent, and react with methyl Grignard, temperature of reaction is 20 ~ 100 DEG C, is then hydrolyzed in acid condition, obtained 5-ethanoyl-2,4-dichloro pyrimidine (II);
(2) 2 are made, formula III after 4-bis-chloro-5-ethanoyl pyrimidine (II) and carbonyl protective agent are obtained by reacting carbonyl-protection under acid catalyst effect or formula III-1 compound, described carbonyl protective agent is the dibasic alcohol of C1-C6, the monohydroxy-alcohol of C1-C6 or the binary mercaptan of C1-C6;
In formula III, formula III-1, X is Sauerstoffatom or sulphur atom;
In formula III, R
1, R
2be selected from the alkyl of C1-C6 independently of one another, can be identical, also can be different;
In formula III-1, n=1 ~ 5, with R in formula III
1, R
2the substituting group of correspondence position is the cyclic substituents be connected with carbon-carbon bond of C2-C6;
Described acid catalyst is selected from mineral acid, the organic acid of C1-C6, methylsulfonic acid, tosic acid or amidosulfonic acid;
(3) formula III or formula III-1 compound and cyclopentamine add the aminating reaction that alkali carries out 4 in a solvent, and aminating reaction temperature is 10 ~ 150 DEG C, and sloughs blocking group, obtains 5-ethanoyl-4-amido-2-chloropyrimide (IV);
Described alkali is trimethylamine or mineral alkali; The mol ratio of described cyclopentamine and formula III or formula III-1 compound be (0.95 ~ 5): 1;
(4) the chloro-4-amido of 2--5-ethanoyl pyrimidine (IV) reacts with acetoacetylating agent in a solvent, temperature of reaction 5 ~ 100 DEG C, obtains 5-ethanoyl-4-acetoacetyl amido-2-chlorine compound (V);
Described acetoacetylating agent is ketene dimer, methyl acetoacetate, methyl aceto acetate, ISOPROPYL ACETOACETATE or ketene dimer contracting acetone; Described acetoacetylating agent mole dosage is 0.95 ~ 1.5 times of formula IV compound molar weight;
(5) by 5-ethanoyl-4-acetoacetyl amido-2-chlorine compound (V) in the presence of a catalyst, in solvent, cyclization temperature is under 20 DEG C of-120 DEG C of conditions, 6-ethanoyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido [2,3-d] pyrimidin-7-ones (VI) is generated through intramolecular condensation dehydration;
Described catalyzer is selected from pyridine, piperidines, quinoline, N-picoline, N-methyl piperidine, DBU (1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene), tetrabutyl ammonium fluoride, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium methylate, sodium ethylate, potassium ethylate, triethylamine, diisopropylethylamine, Tributylamine or N, one of N-Diethyl Aniline, or the combination of piperidines and pyridine;
(6) 6-ethanoyl-8-cyclopentyl-5-methyl-2-chloro-8H-pyrido [2,3-d] pyrimidin-7-ones (VI) is reacted with carbonyl protective agent under catalyst action, obtain formula VIIa or the formula VIIb compound of carbonyl-protection;
When carbonyl protective agent used is the binary mercaptan of the dibasic alcohol of C1-C6, the monohydroxy-alcohol of C1-C6 or C1-C6, obtain formula VIIa compound;
In formula VIIa, X is Sauerstoffatom or sulphur atom; R
3, R
4be selected from the alkyl of C1-C6 independently of one another, or (R
3+ R
4) common-CH representing the C3-C6 be connected with carbon-carbon bond
2-cyclic substituents;
When selected carbonyl protective agent is trimethylchlorosilane, the silyl enol ether compound of production VIIb structure;
(7) pyridine in the presence of a catalyst for formula VIIa or formula VIIb compound and 2-amino-5-(4-N-tert-butoxycarbonyl-1-N-piperazinyl), substitution reaction is carried out in toluene or tetrahydrofuran (THF), under 0-40 DEG C temperature of reaction, obtain following formula VIII a or VIII b respectively, be referred to as formula VIII compound:
X is Sauerstoffatom or sulphur atom;
R
5, R
6be selected from the alkyl of 1-6 carbon atom independently of one another, or (R
5+ R
6) common-CH be connected with carbon-carbon bond representing 2-6 carbon atom
2-cyclic substituents;
Or, directly with the chloro-8H-pyrido [2 of compound 6-ethanoyl-8-cyclopentyl-5-methyl-2-that step (5) is obtained, 3-d] pyrimidin-7-ones (VI) and 2-amino-5-(4-N-tert-butoxycarbonyl-1-N-piperazinyl) pyridine in the presence of a catalyst, in toluene or tetrahydrofuran (THF), under 0-40 DEG C temperature of reaction, carry out substitution reaction prepare following formula VIII-2 compound;
The above catalyzer is amido lithium derivative, alkali metal hydroxide, alkaline carbonate, alkalimetal hydride, basic metal C2-C4 alkoxide, DBU, aluminum isopropylate, isopropylmagnesium chloride or tertiary butyl magnesium chloride;
Formula VIII compound is referred to as with above formula VIII a, VIII b, VIII-2 compound;
(8) formula VIII compound in a solvent, carry out acidic hydrolysis deprotection, the free alkali of obtained Pa Bosaibu (I) or salt at temperature 10-100 DEG C;
Described acidic hydrolysis deprotection used catalyst hydrochloric acid, sulfuric acid, formic acid, acetic acid, butyric acid, propionic acid, tartrate, toxilic acid, succinic acid, trifluoroacetic acid, methylsulfonic acid, hydroxyethylsulfonic acid or tosic acid.
2. the low cost preparation method of Pa Bosaibu as claimed in claim 1, is characterized in that in carbonyl protective agent described in step (2), the dibasic alcohol of C1-C6 is selected from ethylene glycol, 1,2-propylene glycol, 1,3-PD, BDO or 1,3 butylene glycol; The monohydroxy-alcohol of C1-C6 is methyl alcohol, ethanol, Virahol or butanols; The binary mercaptan of C1-C6 is selected from dithioglycol, 1,2-dimercaptopropane, 1,3-dimercaptopropane, Isosorbide-5-Nitrae-succinimide mercaptans or 1,3-succinimide mercaptans.
3. the low cost preparation method of Pa Bosaibu as claimed in claim 1, is characterized in that in the acid catalyst described in step (2), mineral acid is selected from hydrochloric acid, sulfuric acid or phosphoric acid; Organic acid is selected from formic acid, acetic acid or propionic acid; The consumption of catalyzer is the 0.01-2% of 2,4-bis-chloro-5-ethanoyl pyrimidine molar weight.
4. the low cost preparation method of Pa Bosaibu as claimed in claim 1, is characterized in that the solvent described in step (3) is protonic solvent, aprotic solvent or trimethylamine solvent; Protonic solvent is methyl alcohol, ethanol, Virahol or propyl carbinol, and aprotic solvent is selected from N-Methyl pyrrolidone, DMF, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF); Trimethylamine solvent is triethylamine, tripropyl amine, Tributylamine or diisopropylethylamine;
In alkali described in step (3), trimethylamine is selected from triethylamine, tripropyl amine, Tributylamine or diisopropylethylamine, and mineral alkali is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus, Quilonum Retard or lithium bicarbonate.
5. the low cost preparation method of Pa Bosaibu as claimed in claim 1, is characterized in that the temperature of aminating reaction described in step (3) is 15 ~ 80 DEG C; The mol ratio of described cyclopentamine and formula III compound is (1 ~ 5): 1.
6. the low cost preparation method of Pa Bosaibu as claimed in claim 1, is characterized in that solvent described in step (4) is aliphatic ether, fatty cyclic ethers, polar aprotic solvent, toluene or one of dimethylbenzene, aliphatic hydrocarbon; Wherein, aliphatic ether is selected from ether, isopropyl ether or methyl tertiary butyl ether, fat cyclic ethers is selected from tetrahydrofuran (THF), methyltetrahydrofuran or 1,4-dioxane, polar aprotic solvent is selected from N-Methyl pyrrolidone, DMF, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF); Aliphatic hydrocarbon is selected from normal hexane, normal heptane, octane-iso, hexanaphthene or suberane.
7. the low cost preparation method of Pa Bosaibu as claimed in claim 1, is characterized in that, in step (5), described solvent is ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, methyl alcohol, ethanol, Virahol, propyl carbinol, DMF (DMF), N,N-dimethylacetamide (DMA), methyl sulfoxide (DMSO), N-Methyl pyrrolidone (NMP), toluene, dimethylbenzene; , one of normal hexane, normal heptane, octane-iso, hexanaphthene, suberane or combination; Preferred described cyclization temperature is 60-100 DEG C.
8. the low cost preparation method of Pa Bosaibu as claimed in claim 1, is characterized in that in carbonyl protective agent described in step (6), the dibasic alcohol of C1-C6 is selected from ethylene glycol, 1,2-propylene glycol, 1,3-PD, BDO or 1,3 butylene glycol; The monohydroxy-alcohol of C1-C6 is methyl alcohol, ethanol, Virahol or butanols; The binary mercaptan of C1-C6 is selected from dithioglycol, 1,2-dimercaptopropane, 1,3-dimercaptopropane, Isosorbide-5-Nitrae-succinimide mercaptans or 1,3-succinimide mercaptans.
9. the low cost preparation method of Pa Bosaibu as claimed in claim 1, is characterized in that, in the catalyzer described in step (7), amido lithium derivative is selected from amido lithium, two (trimethyl silicon based) amido lithium, lithium diisopropyl amido; Alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, and alkaline carbonate is selected from salt of wormwood, Quilonum Retard or sodium carbonate; Alkalimetal hydride is selected from sodium hydride or potassium hydride KH; Basic metal C2-C4 alkoxide is selected from sodium ethylate, potassium tert.-butoxide or sodium tert-butoxide; Solvent described in preferred step (7) is ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), methyltetrahydrofuran, 1,4-dioxane, N-Methyl pyrrolidone (NMP), N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran (THF) (THF), toluene or dimethylbenzene.
10. the low cost preparation method of Pa Bosaibu as claimed in claim 1, is characterized in that in step (8), and the amount of acid used is 2-10 times of raw materials used formula VIII compound molar weight; The temperature of selective hydrolysis deprotection is 40-80 DEG C; Preferred solvent is methyl alcohol, ethanol, Virahol, acetone, tetrahydrofuran (THF) or butanone.
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