CN101805279A - Preparation method of atorvastatin calcium - Google Patents
Preparation method of atorvastatin calcium Download PDFInfo
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- CN101805279A CN101805279A CN201010100932A CN201010100932A CN101805279A CN 101805279 A CN101805279 A CN 101805279A CN 201010100932 A CN201010100932 A CN 201010100932A CN 201010100932 A CN201010100932 A CN 201010100932A CN 101805279 A CN101805279 A CN 101805279A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses a preparation method of atorvastatin calcium, which comprises the steps of: firstly, synthesizing a primary ring segment compound of the atorvastatin calcium in the formula 5, and simultaneously synthesizing a side chain segment compound in the formula 16; carrying out pyrrole cyclization reaction on the primary ring segment compound in the formula 5and the side chain segment compound in the formula 16 to obtain a connecting intermediate compound in the formula 17; removing protective groups of the compound in the formula 17, carrying out saponification on ester groups of the compound in the formula 17 to obtain sodium salt compound in the formula 18 of the atorvastatin; and adding a calcium chloride water solution in a water solution of the compound in the formula 18 to be filtered to obtain the atorvastatin calcium. The invention has easy obtaining and low cost of the raw materials and higher synthesis yield, and can overcome the defects of the prior art.
Description
Technical field
The present invention relates to a kind of preparation method of atorvastatincalcuim.
Background technology
Statins (statins) is hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, this type of medicine is by synthetic rate-limiting enzyme (HMG-CoA) reductase enzyme of competitive inhibition endogenous cholesterol, hydroxyl first valeric acid pathways metabolism in the blocking-up cell, make the synthetic minimizing of cell inner cholesterol, (low density lipoprotein, thereby LDL) acceptor quantity and activity increase, make serum cholesterol to remove increases feedback irritation cell film surface (being mainly liver cell) low-density lipoprotein, level reduces.Statins also can suppress the synthetic Apolipoprotein B-100 of liver, thereby reduces the synthetic and secretion of being rich in triglyceride level AV, lipoprotein.Be described as " magical medicine " at the medical circle Statins.Medical experts are consistent to be thought, Statins is role in coronary heart disease control, at all not second to the penicillin medical science great revolution that treatment is caused to infectious diseases before 70 years; Can not rant out, the appearance of statins and application are milestones on the modern coronary heart disease treatment history, and it has started new era of coronary heart disease control.
Atorvastatincalcuim is as the outstanding person in the statins, have advantages such as the low side effect of high reactivity and low toxicity, just caused the concern of numerous drugmakers in the world from listing, its molecule is the pyrrole ring that is replaced by highly dense and has and be in 1, the side chain of two chiral hydroxyl groups of 3-position is formed, 2,3 of pyrrole ring, the 4-position is the substituting group that contains benzene ring structure, and structure is seen formula 19:
The synthetic route of U.S. Pat 5273995 disclosed atorvastatincalcuims is to introduce first chiral centre by raw material, second chiral centre obtains by substrate for induction again, referring to chemical equation 1, but it is not natural product that this patent is introduced the raw material of chirality, causes synthetic cost higher because of its cost of material is very expensive.
Chemical equation 1
The synthetic route of U.S. Pat 5298627 disclosed atorvastatincalcuims has been simplified the synthesis step of target product side chain.This route steps is compared step with last route and is obviously reduced, and referring to chemical equation 2, but it need obtain optically pure compound by splitting.
Chemical equation 2
Summary of the invention
The object of the present invention is to provide a kind of preparation method of atorvastatincalcuim, raw material of the present invention is cheap and easy to get, and synthetic yield is higher, can overcome the deficiencies in the prior art.
In order to achieve the above object, technical scheme of the present invention is:
The preparation method of a kind of atorvastatincalcuim (formula 19 compounds), main ring section type 5 compounds of earlier synthetic its spit of fland calcium of atropic method, synthetic simultaneously side chain section type 16 compounds react main ring section type 5 compounds and side chain section type 16 compounds in flakes, finally obtain atorvastatincalcuim.
Wherein the segmental synthetic method of main ring is as follows:
With isopropyl methyl keto-acid 1 compound is starting raw material, in the presence of sodium hydride, carry out condensation and generate 3-carbonyl-4-methylvaleric acid methyl esters formula 2 compounds with methylcarbonate, the aminolysis reaction that formula 2 compounds are taken place ester again generates acid amides formula 3 compounds, formula 3 compounds generate acid amides formula 4 compounds with the phenyl aldehyde condensation in the presence of Beta-alanine and acetate, formula 4 compounds are in the presence of catalyst n-ethyl-4-methyl-5-hydroxyethyl thiazole bromide, with p-Fluorobenzenecarboxaldehyde the Stetter reaction takes place and generated main ring section type 5 compounds, referring to chemical equation 3;
Chemical equation 3
The synthetic method of described side chain section type 16 compounds is: with (S)-apple acid 6 compounds is starting raw material; obtain oxysuccinic acid dimethyl ester formula 7 compounds through double esterification reaction; the 1-position ester group of selective reduction oxysuccinic acid dimethyl ester formula 7 compounds obtains 1; 2-glycol formula 8 compounds; the one-level hydroxyl of formula 8 compounds is obtained 2-hydroxyl silicon ether formula 9 compounds by the protection of selectivity again; the Claisen ester condensation reaction takes place and generates 1 in formula 9 compounds and tert.-butyl acetate; 3-dicarbapentaborane formula 10 compounds; utilize the chiral hydroxyl group of 5-position in formula 10 compound molecules to carry out Stereoselective reduction under the substrate for induction; with 3-position carbonyl reduction is that the hydroxyl of chirality obtains formula 11 compounds; to 1 of formula 11 compounds; chiral hydroxyl group contract acetone protection in 3-position obtains formula 12 compounds; slough the protecting group on the one-level hydroxyl in formula 12 compounds; obtain primary alconol formula 13 compounds; hydroxyl to formula 13 compounds carries out obtaining formula 14 compounds behind sulfonic acid esterification or the halo, and SN takes place for formula 14 compounds and cyanogen salt
2Reaction obtains itrile group formula 15 compounds, and last, the itrile group of formula 15 compounds is reduced to amino and obtains side chain section type 16 compounds.Referring to chemical equation 4;
Chemical equation 4
In the building-up process of described side chain section type 16 compounds, the R in formula 7,8,9 compounds is non-hydrogen alkyl group; X in formula 14 compounds is halogen or sulphonate; R in formula 12,13,14,15,16 compounds
1And R
2Be silica-based class protecting group, benzyl class protecting group or R
1And R
2A kind of in the common alkyl class protecting group that forms ketal; R in formula 9,10,11,12 compounds
3A kind of in silica-based class protecting group, alkyls protecting group, benzyl class protecting group or the alcoxyl base class protecting group, and R
3Must and R
1, R
2Different.
Preferred R is methyl (Me) in described formula 7,8,9 compounds, preferred R in formula 9,10,11,12 compounds
3Be tert-butyl diphenyl silica-based (TBDPS) preferred R in formula 12,13,14,15,16 compounds
1And R
2Common is 1-methyl ethylidene base (C (CH
3)
2), forming ketal compound, the X in formula 14 compounds is the p-chlorobenzenesulfonic acid ester group.
In the building-up process of described side chain section type 16 compounds, formula 7 compounds are reduced in the process of formula 8 cyclocomplex, adopt the negative hydrogen metal reagent of boron and borane compound to make up as reductive agent.
Described reductive agent preferably adopts NaBH
4/ BH
3
In the building-up process of described side chain section type 16 compounds, when the Claison condensation takes place for formula 9 compounds and tert.-butyl acetate, adopt a kind of metal reagent in lithium diisopropyl amido or the hmds lithium as reaction.
In the building-up process of described side chain section type 16 compounds, formula 10 compounds are reduced in the process of formula 11 compounds, adopt the negative hydrogen metal reagent of boron and the alkoxy compound of boron to make up as reductive agent.
Described reductive agent preferably adopts NaBH
4/ B (OMe) Et
2
Step in flakes
Then main ring section type 5 compounds and hand hay cutter chain section type 16 compounds are carried out pyrroles's cyclization; obtain key intermediate formula 17 compounds in flakes; slough protecting group in formula 17 compounds then, the ester group in formula 17 compounds is carried out sodium salt formula 18 compounds that saponification reaction obtains atorvastatin; add calcium chloride water in the aqueous solution of right backward type 18 compounds; make the target molecule atorvastatincalcuim separate out; obtain atorvastatincalcuim (formula 19 compounds), referring to chemical equation 5.
Chemical equation 5
Beneficial effect of the present invention is: it is side chain fragment synthetic raw material that the present invention adopts natural oxysuccinic acid, is main ring fragment synthetic raw material with isopropyl methyl ketone, and its raw material is cheap and easy to get, and synthetic yield is higher, can overcome the deficiencies in the prior art.
Embodiment
Present embodiment adopts natural product cheap and easy to get as the synthetic atorvastatincalcuim of raw material for overcoming the deficiencies in the prior art.The atorvastatincalcuim preparation method is: synthetic respectively main ring fragment and side chain fragment, again it is formed the purpose product in flakes, the segmental new method that synthesizes of side chain wherein, the main ring fragment adopts the method for document synthetic, because the segmental difference of side chain, make side chain and main ring in flakes so that the process of synthetic atorvastatincalcuim also different with existing method.Its concrete way is:
The A main ring is segmental synthetic
1) synthetic (referring to the chemical equation 6) of isobutyryl methyl acetate (formula 2 compounds),
Chemical equation 6
In exsiccant 250mL round-bottomed flask, add the 0.20mol sodium hydride, add 150mL benzene, 16.6mL (0.12mol) methylcarbonate is heated to reaction solution and refluxes.In constant pressure funnel, add the benzole soln 50mL that contains 5.727g (75mmol) isopropyl methyl keto-acid 1 compound, slowly dripping the back keeps backflow to continue about 7 hours of reaction, reduce to room temperature, slowly drip 15mL Glacial acetic acid and the cancellation of 50mL frozen water reaction, stir, layering, water layer merges organic layer with the benzene extraction of 100mL * 3, uses distilled water successively, the saturated sodium-chloride water solution washing, the organic layer anhydrous sodium sulfate drying.Normal pressure boils off benzene, the resistates underpressure distillation, pale yellow oily liquid body formula 2 compound 9.942g (88 ℃/37mmHg).(productive rate: 92%).It is as follows that product detects data:
1H NMR (CDCl
3, 300MHz, δ ppm) 1.13 (d, 6H, J=6.6Hz), 2.72 (dt, 1H, J=6.6Hz), 3.52 (s, 2H), 3.74 (s, 3H);
13C NMR (CDCl
3, 75MHz, δ ppm) and 19.6,41.1,46.6,52.1,167.8,206.4; EIMS, m/z (%): 84 (100), 101 (85), 144 (M-14,67)
2) synthetic (referring to the chemical equation 7) of isobutyryl Acetanilide (formula 3 compounds)
Chemical equation 7
With 7.532g (52.3mmol) isobutyryl methyl acetate formula 2 compounds; 150mL toluene is put into the 250mL three-necked bottle; splash into the quadrol of 0.325g (5.41mmol); under the magnetic agitation; heating; slowly splash into the toluene solution 50mL that contains 5.200g (55.0mmol) aniline with constant pressure funnel; after dripping off; keep back flow reaction after about 18 hours; normal pressure boils off solvent, and decompression steams unreacted aniline, resistates 150mL acetic acid ethyl dissolution; use the saturated common salt water washing, the organic layer anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, resistates separates (sherwood oil: ethyl acetate=4: 1), get yellow oil formula 3 compound 9.203g with silica gel column chromatography.(productive rate: 85%).It is as follows that product detects data:
1H NMR (CDCl
3, 300MHz, δ ppm) 1.11 (d, 6H, J=6.6Hz), 2.67 (dt, 1H, J=6.6Hz), 3.55 (s, 2H), 7.10 (dd, 1H), 7.28 (dd, 2H), 7.55 (d, 2H), 9.16 (br, 1H);
13C NMR (CDCl
3, 75MHz, δ ppm) and 17.5,41.7,47.2,119.9,124.3,128.7,137.2,164.2,210.6; EIMS, m/z (%): 43 (45), 93 (100), 205 (M-1,40)
3) synthetic (referring to the chemical equation 8) of formula 4 compounds
Chemical equation 8
In the 500ml round-bottomed flask, add 7.643g (37.3mmol) isobutyryl Acetanilide formula 3 compounds, stir down; add the 200mL normal hexane with 50mL toluene dissolving back; add 300mg β-alanine then successively, 4.20g phenyl aldehyde and 1mL (1.05g, Glacial acetic acid 17.5mmol).System is heated to backflow, uses fraction water device water-dividing.React and the product crystal occurs after 3 hours, after 40 hours, boil off solvent and unreacted phenyl aldehyde.Resistates is used the 500mL acetic acid ethyl dissolution after reducing to room temperature, uses saturated sodium bicarbonate solution successively, and the anhydrous sodium sulfate drying organic layer is used in the saturated common salt water washing.Behind the pressure reducing and steaming solvent, resistates gets formula 4 compound 7.785g, productive rate: 76% with recrystallization from ethyl acetate/petroleum ether.It is as follows that product detects data:
1H NMR (CDCl
3, 300MHz, δ ppm) 1.21 (d, 6H, J=6.6Hz), 3.34 (dt, 1H, J=6.6Hz), 7.12-7.62 (m, 10H), 7.71 (br, 1H);
13CNMR (CDCl
3, 75MHz, δ ppm) and 19.1,36.6,120.2,124.9,128.9,129.1,129.9,130.7,132.8,136.0,137.3,140.7,164.7,165.5,202.6; EIMS, m/z (%): 43 (100), 71 (69), 131 (65), 201 (50), 292 (M-1,55)
4) synthetic (referring to the chemical equation 9) of formula 5 compounds
Chemical equation 9
3-ethyl-5-(2-hydroxyethyl)-4-methylthiazol bromine salt of 300mg (1.2mmol) is dissolved in the dehydrated alcohol of 10ml.Under the Ar atmosphere, add 5.932g (20mmol) formula 4 compounds, 2.020g (20mmol) triethylamine, the p-Fluorobenzenecarboxaldehyde of 3.720g (30mmol).Stir down, system is heated to 75 ℃, keeps after 48 hours pressure reducing and steaming solvent and unreacted p-Fluorobenzenecarboxaldehyde, the resistates acetic acid ethyl dissolution, use distilled water wash, with the water layer ethyl acetate extraction, the organic layer anhydrous sodium sulfate drying, boil off solvent, resistates is drained, and gets white crystal formula 5 compound 4.48g, productive rate 80% with Virahol/sherwood oil crystallization.It is as follows that product detects data:
1H NMR (CDCl
3, 300MHz, δ ppm) 1.12 (d, 3H, J=6.6), 1.20 (d, 3H, J=6.6), 2.69 (dt, 1H, J=6.6), 4.63 (d, 1H), 5.42 (d, 1H), 6.97-7.37 (m, 12H), 7.61 (br, 1H), 7.69-8.01 (m, 2H);
13C NMR (CDCl
3, 75MHz, δ ppm) and 18.0,18.6,40.9,54.1,64.1,115.5,115.8,120.1,124.9,128.0,128.5,128.8,129.4,131.6,131.7,135.2,136.7,165.5,196.3,209.5; EIMS, m/z (%): 43 (25), 123 (100), 131 (42), 201 (76), 292 (50), 346 (90), 417 (M
+, 13)
The B side chain is synthetic
In the side chain synthetic real reaction of the present invention, the R in the compound 7,8 or 9 can be non-hydrogen alkyl group, can be according to the selected corresponding group of the situation of reaction cost, operation in the reaction of reality.Preferably adopt methyl (Me) in an embodiment of the present invention, preferred R in formula 9,10,11,12 compounds
3Adopt tert-butyl diphenyl silica-based (TBDPS), preferred R in formula 12,13,14,15,16 compounds
1And R
2Common is 1-methyl ethylidene base (C (CH
3)
2), forming ketal compound, X can be halogen or sulphonate in the compound 14; Present embodiment X adopts the p-chlorobenzenesulfonic acid ester group.When compound 9 with tert.-butyl acetate the Claison condensation takes place, adopt a kind of metal reagent in lithium diisopropyl amido or the hmds lithium as reaction; Compound 10 is reduced in the process of compound 11, can adopt the negative hydrogen metal reagent of boron and the alkoxy compound of boron to make up as reductive agent.Below be a preferred embodiment of the present invention:
1) (S)-synthetic (referring to the chemical equation 10) of oxysuccinic acid dimethyl ester (formula 7 chemical combination)
Chemical equation 10
13.4g (100mmol) apple acid 6 compounds are dissolved in the methyl alcohol of 20～500mL, splash into boron trifluoride diethyl etherate, after reacting by heating is complete, in the impouring water, use ethyl acetate extraction, merge organic layer, use saturated nacl aqueous solution successively, saturated sodium bicarbonate solution and saturated nacl aqueous solution washing, the organic layer anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, resistates use silica gel column chromatography to separate (sherwood oil: ethyl acetate=4: 1).Get colourless oil liquid formula 7 compounds.As methanol usage 100mL, when the consumption of boron trifluoride diethyl etherate is the 15%mol of oxysuccinic acid, reaction yield 90%.
2) (S)-3, synthetic (referring to the chemical equation 11) of 4-dihydroxyl methyl-butyrate (formula 8 compounds)
Chemical equation 11
Oxysuccinic acid dimethyl ester formula 7 compounds of 2.259g (13.9mmol) are dissolved among the anhydrous THF (tetrahydrofuran (THF)), and stirring splashes into the borine dimethyl thioether down, adds sodium borohydride then, continues to be stirred to react completely.In system, add absolute anhydrous methanol, stirred 30 minutes.With the solvent evaporated under reduced pressure in the reaction system, get water white oil dress liquid, use silica gel column chromatography to separate (sherwood oil: ethyl acetate=1: 1), get colourless oil liquid formula 8 compounds.When the borine dimethyl thioether is 1.3 times of molar weights of oxysuccinic acid dimethyl ester, when sodium borohydride was 0.7 times of molar weight of oxysuccinic acid dimethyl ester, yield was 88%.It is as follows that product detects data: [α]
D 20=-22 (c=1.6, CHCl
3);
1H NMR (CDCl
3, 300MHz, δ ppm) 2.53 (dd, 2H), 3.53 (dd, 2H), 3.76 (s, 3H), 4.13 (m, 1H);
13C NMR (CDCl
3, 75MHz, δ ppm) and 37.5,51.7,65.6,68.5,172.8; EIMS, m/z (%): 43 (100), 71 (55), 103 (97), 116 (78), 135 (M+1,46)
3) synthetic (referring to the chemical equation 12) of 3-hydroxyl-4-tert-butyl diphenyl siloxy methyl-butyrate (formula 9 compounds)
Chemical equation 12
In an exsiccant 100mL round-bottomed flask, add 3 of 5.963g (44.5mmol), 4-dihydroxyl methyl-butyrate, stir and add methylene dichloride and triethylamine down, slowly splash into tert-butyl diphenyl chlorine, continue reaction under the room temperature after 4 hours, the cancellation reaction, with the ethyl acetate extraction inorganic layer of 150mL * 3, merge organic layer, with saturated common salt water washing 3 times, anhydrous sodium sulfate drying, pressure reducing and steaming solvent, resistates use silica gel column chromatography to separate (sherwood oil: ethyl acetate=4: 1), get pale yellow oily liquid body formula 9 compounds.When triethylamine is 3,1.5 times of molar weights of 4-dihydroxyl methyl-butyrate, tert-butyl diphenyl chlorine is 3, during 1 times of molar weight of 4-dihydroxyl methyl-butyrate, productive rate 85%.It is as follows that product detects data: [α]
D 20=-10 (c=0.6, CHCl
3);
1H NMR (CDCl
3, 300MHz, δ ppm) 1.13 (s, 9H), 2.61 (dd, 2H), 3.13 (dd, 2H), 3.71 (s, 3H), 4.23 (m, 1H), 7.36-7.49 (m, 6H), 7.71-7.79 (m, 4H);
13C NMR (CDCl
3, 75MHz, δ ppm) and 19.1,26.7,37.8,51.5,66.8,68.4,127.6,129.7,132.8,135.4,172.3; EIMS, m/z (%): 195 (61), 237 (100), 283 (76), 315 (46), 341 (m-31,32)
4) synthetic (referring to the chemical equation 13) of 3-carbonyl-5-hydroxyl-6-tert-butyl diphenyl siloxy hecanoic acid t-butyl ester (formula 10 compounds)
Chemical equation 13
In an exsiccant 25mL round-bottomed flask, add a kind of in lithium diisopropyl amido or the hmds lithium, liquid nitrogen-acetone is cooled to-60 ℃, slowly splashes into tert.-butyl acetate, is warming up to-30 ℃ and kept this thermotonus 30 minutes after dripping off.Be cooled to-78 ℃, in system, slowly splash into the THF solution that contains formula 9 compounds, dropwise the back and disappear in reacting below-30 ℃ to formula 9 compounds.The cancellation reaction, water layer merges organic layer with the ethyl acetate extraction of 30mL * 3, with saturated common salt water washing 1 time, anhydrous sodium sulfate drying, pressure reducing and steaming solvent, resistates use silica gel column chromatography to separate (sherwood oil: yellow oily formula 10 compounds ethyl acetate=8: 1).When the ratio of the molar weight of lithium diisopropyl amido, tert.-butyl acetate and formula 9 compounds is 2: 1.6: 1, productive rate 90%.It is as follows that product detects data: [α]
D 20=-13.8 (c=3.1, CHCl
3);
1H NMR (CDCl
3, 300MHz, δ ppm) 1.07 (s, 9H), 1.48 (s, 9H), 2.72 (d, 2H), 2.87 (br, 1H), 3.39 (s, 3H), 3.66 (dd, 2H), 4.21 (m, 1H), 7.35-7.46 (m, 6H), 7.63-7.67 (m, 4H);
13C NMR (CDCl
3, 75MHz, δ ppm) and 19.2,26.8,27.9,45.9,51.2,66.9,68.0,82.0,127.8,129.8,132.9,135.5,166.2,202.8; EIMS, m/z (%): 57 (76), 265 (85), 309 (56), 325 (57)
5) 3, synthetic (referring to the chemical equation 14) of 5-dihydroxyl-6-tert-butyl diphenyl hecanoic acid t-butyl ester (formula 11 compounds)
Chemical equation 14
Get an exsiccant 50mL round-bottomed flask, 1.183g (2.6mmol) formula 10 compounds are dissolved in THF and methyl alcohol.System is cooled to below-60 ℃, slowly splashes into the THF solution of diethyl methoxyl group borine.System is cooled to below-80 ℃ after drip finishing, in 20 minutes, adds sodium borohydride in batches, keep that reaction slowly rose to room temperature with system after 10 hours below-80 ℃, continue reaction under the argon gas atmosphere to fully.Carefully splash into 1mL Glacial acetic acid cancellation reaction, pressure reducing and steaming solvent, remaining oily matter use silica gel column chromatography to separate (sherwood oil: ethyl acetate=4: 1) pale yellow oily liquid body formula 11 compounds.When the ratio of the molar weight of formula 10 compounds, diethyl methoxyl group borine and sodium borohydride is 1: 1.0: 1.3, productive rate 91%.It is as follows that product detects data: [α]
D 20=-8 (c=2.62, CHCl
3);
1H?NMR(CDCl
3，300MHz，δppm)1.06(s，9H)，1.45(s，9H)，1.62(dd，2H)，2.40(dd，2H)，3.29(br，1H)，3.59(d，2H)，3.84(br，1H)，3.97(m，1H)，4.22(m，1H)，7.35-7.45(m，6H)，7.64-7.67(m，4H)；
13C?NMR(CDCl
3，75MHz，δppm)19.2，26.8，28.0，38.6，42.6，67.6，68.1，71.8，81.1，127.7，129.8，133.0，135.5，171.8；EIMS，m/z(％)：57(33)，84(100)，199(81)，207(76)，345(23)
6) synthetic (referring to the chemical equation 15) of formula 12 compounds
Chemical equation 15
Formula 11 compounds that take by weighing 580mg (1.27mmol) place the 25mL round-bottomed flask, stir down and add 2,2-Propanal dimethyl acetal, camphorsulfonic acid, after room temperature reaction is complete, the pressure reducing and steaming solvent, residue acetic acid ethyl dissolution, organic layer are used saturated sodium bicarbonate respectively, the saturated common salt water washing, anhydrous sodium sulfate drying boils off solvent, gets pale yellow oily liquid body formula 12 compounds.When formula 11 compounds, 2, the ratio of the molar weight of 2-Propanal dimethyl acetal and camphorsulfonic acid is 1: 1.5: 0.1 o'clock, and it is as follows that productive rate 98%. products detect data: [α]
D 20=-2.2 (c=4.25, CHCl
3);
1H NMR (CDCl
3, 300MHz, δ ppm) 1.05 (s, 9H), 1.37 (s, 3H), 1.43 (s, 3H), 1.45 (s, 9H), 2.43 (dd, 2H), 3.53 (dd, 1H), 3.72 (dd, 1H), 3.92-3.06 (m, 1H), 3.21-3.33 (m, 1H), 7.33-7.41 (m, 6H), 7.66-7.69 (m, 4H);
13C NMR (CDCl
3, 75MHz, δ ppm) and 19.3,19.6,26.8,28.1,29.9,33.3,42.9,66.1,67.3,69.6,80.5,98.6,127.6,129.6,133.6,135.6,170.2; EIMS, m/z (%): 57 (100), 309 (21), 327 (28), 385 (78), 483 (M-15,15)
7) synthetic (referring to the chemical equation 16) of formula 13 compounds
Chemical equation 16
Formula 12 compounds of 535mg (1.05mmol) are dissolved among the THF, stir and add tetrabutyl ammonium fluoride down, after room temperature reaction is complete, add saturated aqueous common salt cancellation reaction, water layer merges organic layer with the ethyl acetate extraction of 50mL * 3, with saturated common salt water washing 1 time, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent gets pale yellow oily liquid body formula 13 compounds.When THF is 20mL, when tetrabutyl ammonium fluoride is 1.0mmol, product 259mg, productive rate 95%.It is as follows that product detects data: [α]
D 20=+13 (c=2.51, CHCl
3);
1H NMR (CDCl
3, 300MHz, δ ppm) 1.39 (s, 3H), 1.45 (s, 9H), 1.48 (s, 3H), 2.41 (dd, 2H), 3.55 (m, 2H), 4.01 (m, 1H), 4.30 (m, 1H);
13C NMR (CDCl
3, 75MHz, δ ppm) and 19.7,27.9,29.8,31.8,42.6,65.7,65.8,69.5,80.6,98.8,170.1; EIMS, m/z (%): 43 (66), 57 (100), 129 (35), 245 (13)
8) synthetic (referring to the chemical equation 17) of formula 14 compounds
Chemical equation 17
Formula 13 compounds that take by weighing 923mg (3.55mmol) are in an exsiccant 25mL round-bottomed flask, add the methylene dichloride dissolving under the magnetic agitation, splash into triethylamine, the ice-water bath cooling adds parachloroben-zenesulfonyl chloride down in batches, keep thermotonus after 2.5 hours, rise to room temperature, continue to react completely, in system impouring frozen water, the water layer ethyl acetate extraction of 50mL * 3, merge organic layer, use saturated ammonia chloride successively, saturated sodium bicarbonate, the saturated common salt water washing, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent is drained, get faint yellow solid, recrystallization gets white needle-like crystals formula p-chlorobenzenesulfonic acid ester cpds 14.When methylene dichloride is 10mL, when parachloroben-zenesulfonyl chloride is 4.0mmol, product 1.478g, productive rate 96%.It is as follows that product detects data: [α]
D 20=+12 (c=3.23, CHCl
3);
1H NMR (CDCl
3, 300MHz, δ ppm) 1.27 (s, 3H), 1.38 (s, 3H), 1.44 (s, 9H), 2.39 (dd, 2H), 4.00 (d, 2H), 4.13 (m, 1H), 4.24 (m, 1H), 7.54 (d, 2H), 7.87 (d, 2H);
13C NMR (CDCl
3, 75MHz, δ ppm) and 19.4,28.0,29.6,31.9,42.3,65.4,66.7,72.6,80.7,98.9,129.3,134.4,140.3,169.8; EIMS, m/z (%): 43 (67), 57 (100), 111 (72), 303 (90), 419 (M-15,34)
9) synthetic (referring to the chemical equation 18) of formula 15 compounds
Chemical equation 18
1.070g (2.47mmol) formula 14 compounds are dissolved in the 7mL dimethyl sulfoxide (DMSO), add sodium cyanide under the magnetic agitation, room temperature reaction is the back cancellation fully, water layer merges organic layer with the ethyl acetate extraction of 50mL * 3, with saturated common salt water washing 3 times, anhydrous sodium sulfate drying, the pressure reducing and steaming solvent is drained, and gets yellow oily liquid-type 15 compounds.When sodium cyanide is 1.5 times of molar weights of compound 14, get product 611mg, productive rate 92%.It is as follows that product detects data: [α]
D 20=-3 (c=1.6, CHCl
3);
1H NMR (CDCl
3, 300MHz, δ ppm) 1.39 (s, 3H), 1.45 (s, 9H), 1.47 (s, 3H), 1.74 (d, 2H), 2.37 (dd, 2H), 2.51 (dd, 2H), 4.15 (m, 1H), 4.27 (m, 1H);
13C NMR (CDCl
3, 75MHz, δ ppm) and 19.5,24.9,28.0,29.7,35.3,42.2,65.0,65.6,80.8,99.4,116.7,169.8; EIMS, m/z (%): 43 (78), 57 (100), 198 (55), 254 (M-15,73)
10) synthetic (referring to the chemical equation 19) of formula 16 compounds
Chemical equation 19
Formula 15 compounds of 100mg (0.37mmol) are dissolved in the methanol solution of 20mL ammonia, add the Raney Ni that 2 spoons are newly produced, H under stirring
2Under the atmosphere, room temperature reaction is after 18 hours, the elimination catalyzer, the evaporated under reduced pressure solvent is drained, yellow oil formula 16 compound 102mg, productive rate 90%.It is as follows that product detects data: [α]
D 20=+15 (c=2.26, CHCl
3);
1H NMR (CDCl
3, 300MHz, δ ppm) 1.38 (s, 3H), 1.44 (s, 9H), 1.47 (s, 3H), 1.59 (m, 2H), 1.92 (m, 2H), 2.38 (dd, 2H), 3.16 (t, 2H), 3.44 (br, 1H), 4.08 (m, 1H), 4.26 (m, 1H);
13C NMR (CDCl
3, 75MHz, δ ppm) and 19.6,27.9,29.8,33.0,35.8,37.2,42.3,65.7,67.6,80.5,98.9,169.9; EIMS, m/z (%): 43 (72), 57 (100), 173 (76), 258 (18), 273 (M
+, 5)
C reacts in flakes
1) preparation of formula 17 compounds (referring to chemical equation 20)
Chemical equation 20
Take by weighing 100mg (0.24mmol) formula 5 compounds, formula 16 compounds of 68mg (0.25mmol) are in an exsiccant 25mL round-bottomed flask, add 15mL mixed solvent (toluene: normal heptane: tetrahydrofuran (THF)=1: 3: 1), stir and add 10mg (0.1mmol) trimethylacetic acid down, system is heated to is back to the back pressure reducing and steaming solvent that reacts completely, resistates uses silica gel column chromatography to separate (sherwood oil: ethyl acetate=16: 1), get white solid formula 17 compound 122mg, productive rate 78%.It is as follows that product detects data: [α]
D 20=+7 (c=1.3, CHCl
3).
1H?NMR(CDCl
3，300MHz，δppm)1.30(s，3H)，1.36(s，3H)，1.43(s，9H)，1,52(d，6H)，1.70(m，2H)，2.37(dd，2H)，2.58(dt，1H)，3.69(m，1H)，3.85(m，1H)，4.40-4.17(m，2H)，6.84-7.21(m，15H)；
13C?NMR(CDCl
3，75MHz，δppm)19.6，21.5，21.7，26.0，28.0，29.9，35.9，38.0，40.8，42.4，65.9，66.4，80.6，98.6，115.2，115.3，115.4，119.5，121.7，123.4，126.5，128.3，128.6，128.7，130.5，133.1，133.2，134.6，138.4，141.5，160.6，163.9，164.8，170.2。MS(FAB)：654.2
2) preparation (referring to chemical equation 21) of sodium atorvastatin (formula 18 compounds)
Chemical equation 21
Formula 17 compounds that take by weighing 100mg (0.15mmol) stir adding 15mL methyl alcohol down in the 25mL round-bottomed flask, the hydrochloric acid soln of 2mL 1mol/L, room temperature reaction are after 12 hours, and decompress filter goes out precipitation, filter cake distilled water wash 3 times.Filter cake is transferred in the round-bottomed flask of another 25mL, stir and add 6mL 2mol/L sodium hydroxide solution down, 5mL methyl alcohol, with the system reacting by heating after 4 hours decompress filter go out precipitation, leaching thing washs with methyl tertiary butyl ether, water layer is transferred to PH=2 with the hydrochloric acid soln of 2mol/L and extract with methyl tertiary butyl ether, organic layer is told, add 5mL distilled water and 1mL methyl alcohol after boiling off most of solvent, sodium hydroxide solution with 2mol/L transfers to 12 with system PH, and solvent evaporated gets faint yellow solid sodium salt formula 18 compound 76mg, productive rate 83%
3) preparation (referring to chemical equation 22) of atorvastatincalcuim (formula 19 compounds)
Chemical equation 22
(o.15mmol) 78mg is dissolved in 3mL distilled water, and solution is heated to 60 ℃ with formula 18 compounds that make, the Calcium Chloride Powder Anhydrous that takes by weighing 1.1 molar equivalents is dissolved in the 1mL distilled water, after the heating, splashes in the aqueous solution of sodium salt, yellowish precipitation appears, continue reaction 5 minutes, ageing is filtered, filter cake 1mL distilled water wash, oven dry gets faint yellow solid calcium salt formula 19 compound 65mg, productive rate: 81%.It is as follows that product detects data: ([α]
D 20=-7.5, (c=1.00, DMSO);
1H NMR (DMSO, 300MHz, δ ppm) 1,54 (d, 6H), 1.71 (m, 2H), 2.38 (dd, 2H), 2.59 (dt, 1H), 3.72 (m, 1H), 3.87 (m, 1H), 4.41-4.18 (m, 2H), 6.84-7.21 (m, 15H);
13C NMR (DMSO, 75MHz, δ ppm) 19.5,21.4,21.7,28.2,35.7,38.1,40.9,42.5,65.8,66.5,115.2,115.3,115.4,119.5,121.7,123.4,126.5,128.3,128.6,128.7,130.5,133.1,133.2,134.6,138.4,141.5,160.7,163.8,164.9,169.2HRMS (ESI) calcd.for C
37H
70O
10(C
37H
70O
10+ H) 558.6324, found558.6320.
Claims (10)
1. the preparation method of an atorvastatincalcuim (formula 19 compounds), main ring section type 5 compounds of earlier synthetic its spit of fland calcium of atropic method, it is characterized in that: synthetic simultaneously side chain section type 16 compounds, main ring section type 5 compounds and side chain section type 16 compounds are reacted in flakes, finally obtain atorvastatincalcuim.
2. the preparation method of atorvastatincalcuim according to claim 1; it is characterized in that: described reaction in flakes is meant carries out pyrroles's cyclization with main ring section type 5 compounds and hand hay cutter chain section type 16 compounds; obtain intermediate formula 17 compounds in flakes; slough protecting group in formula 17 compounds then, the ester group in formula 17 compounds is carried out sodium salt formula 18 compounds that saponification reaction obtains atorvastatin, add calcium chloride water in the aqueous solution of right backward type 18 compounds and filter and obtain atorvastatincalcuim.
3. the preparation method of atorvastatincalcuim according to claim 1; the synthetic method that it is characterized in that described side chain section type 16 compounds is: with (S)-apple acid 6 compounds is starting raw material; obtain oxysuccinic acid dimethyl ester formula 7 compounds through double esterification reaction; the 1-position ester group of selective reduction oxysuccinic acid dimethyl ester formula 7 compounds obtains 1; 2-glycol formula 8 compounds; the one-level hydroxyl of formula 8 compounds is obtained 2-hydroxyl silicon ether formula 9 compounds by the protection of selectivity again; the Claisen ester condensation reaction takes place and generates 1 in formula 9 compounds and tert.-butyl acetate; 3-dicarbapentaborane formula 10 compounds; utilize the chiral hydroxyl group of 5-position in formula 10 compound molecules to carry out Stereoselective reduction under the substrate for induction; with 3-position carbonyl reduction is that the hydroxyl of chirality obtains formula 11 compounds; to 1 of formula 11 compounds; chiral hydroxyl group contract acetone protection in 3-position obtains formula 12 compounds; slough the protecting group on the one-level hydroxyl in formula 12 compounds; obtain primary alconol formula 13 compounds; hydroxyl to formula 13 compounds carries out obtaining formula 14 compounds behind sulfonic acid esterification or the halo, and SN takes place for formula 14 compounds and cyanogen salt
2Reaction obtains itrile group formula 15 compounds, and last, the itrile group of formula 15 compounds is reduced to amino and obtains side chain section type 16 compounds.
4. the preparation method of atorvastatincalcuim according to claim 3 is characterized in that in the building-up process of described side chain section type 16 compounds, and the R in formula 7,8,9 compounds is non-hydrogen any basic groups; X in formula 14 compounds is halogen or sulphonate; R in formula 12,13,14,15,16 compounds
1And R
2Be silica-based class protecting group, benzyl class protecting group or R
1And R
2A kind of in the common alkyl class protecting group that forms ketal; R in formula 9,10,11,12 compounds
3A kind of in silica-based class protecting group, alkyls protecting group, benzyl class protecting group or the alcoxyl base class protecting group, and R
3Must and R
1, R
2Different.
5. the preparation method of atorvastatincalcuim according to claim 4 is characterized in that preferred R is a methyl in described formula 7,8,9 compounds, preferred R in formula 9,10,11,12 compounds
3For tert-butyl diphenyl silica-based, preferred R in formula 12,13,14,15,16 compounds
1And R
2Be 1-methyl ethylidene base, the X in formula 14 compounds is uncle's p-chlorobenzenesulfonic acid ester group.
6. the preparation method of atorvastatincalcuim according to claim 3, it is characterized in that: in the building-up process of described side chain section type 16 compounds, formula 7 compounds are reduced in the process of formula 8 cyclocomplex, adopt the negative hydrogen metal reagent of boron and borane compound to make up as reductive agent.
7. the preparation method of atorvastatincalcuim according to claim 6 is characterized in that: described reductive agent employing NaBH
4/ BH
3
8. the preparation method of atorvastatincalcuim according to claim 3, it is characterized in that: in the building-up process of described side chain section type 16 compounds, when the Claison condensation takes place for formula 9 compounds and tert.-butyl acetate, adopt a kind of metal reagent in lithium diisopropyl amido or the hmds lithium as reaction.
9. the preparation method of atorvastatincalcuim according to claim 3, it is characterized in that: in the building-up process of described side chain section type 16 compounds, formula 10 compounds are reduced in the process of formula 11 compounds, adopt the negative hydrogen metal reagent of boron and the alkoxy compound of boron to make up as reductive agent.
10. the preparation method of atorvastatincalcuim according to claim 9 is characterized in that: described reductive agent employing NaBH
4/ B (OMe) Et
2
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| CN102070504A (en) * | 2010-12-23 | 2011-05-25 | 蚌埠丰原医药科技发展有限公司 | Method for preparing atorvastatin sodium |
| CN102373250A (en) * | 2011-11-08 | 2012-03-14 | 张家港市信谊化工有限公司 | Preparation method of Alorvastin calcium side chain intermediate |
| CN102796036A (en) * | 2012-09-12 | 2012-11-28 | 江苏阿尔法药业有限公司 | Preparation method of atorvastatin calcium |
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