CN102690254B - Simvastatin ammonium salt intermediates and preparation methods thereof - Google Patents
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Abstract
The invention discloses simvastatin ammonium salt intermediates which are represented in the formula IV and the formula I and preparation methods of the intermediates represented by the formulas I and IV. The intermediate represented by the formula IV is prepared by reacting the intermediate represented by the formula I with 2,2-dimethyl butyryl chloride. The intermediate represented by the formula I is prepared by performing transesterification on glycol lactone represented by the formula II and ortho-formate represented by the formula III. R represents methyl or ethyl. According to the methods for preparing the simvastatin ammonium salt intermediates, the operation is easy, the conditions are mild, and the yield is relatively high.
Description
The application is application number: CN200810037175.4, the applying date: on May 9th, 2008, the divisional application of application " a kind of synthetic method of simvastatin ammonium salt and intermediate therefor and preparation method thereof " patent application by name.
Technical field
The present invention relates to simvastatin ammonium salt intermediate and preparation method thereof.
Background technology
Simvastatin ammonium salt (VI) is to prepare the key intermediate of blood lipid-lowering medicine Simvastatin (VII).Utilize simvastatin ammonium salt and the simvastatin acid different solubilities in water and organic phase, make effective constituent fully extract organic phase, become again the process of ammonium salt crystallization, impurity is effectively separated, obtain the simvastatin ammonium salt of higher degree, then Simvastatin is prepared in cyclization, makes finished product Simvastatin quality controllable, and purity is high.
Report (US5159104) the 4-position hydroxyl selective protection to diol lactone with ethanoyl of Merck company, then prepares simvastatin ammonium salt through acidylate and deprotection, and by its synthetic Simvastatin.Acetyl derivatives in this synthetic route is unstable under alkaline condition, easily produces and eliminates by product, and be difficult to remove from product when reaction.The Simvastatin making by this operational path is of poor quality, is not suitable for the suitability for industrialized production of Simvastatin.
Summary of the invention
Technical problem to be solved by this invention is that the method in order to overcome existing synthetic Simvastatin easily generates the by product that is difficult to removal, make total product of poor quality, be unsuitable for the defect of suitability for industrialized production, and provide one can avoid the problems referred to above, and simple to operate, there is the novel method of higher industrial application value, and the method intermediate used and preparation method thereof.
Method of the present invention comprises the steps: under protection of inert gas, at C
1-C
4lower aliphatic alcoholic solvent in, under the effect of acid catalyst, to carry out alcoholysis reaction suc as formula the intermediate shown in IV, then under the effect of alkali, reaction is hydrolyzed, add afterwards acid to carry out acidifying, then react through ammonium with ammonia or ammoniacal liquor, can make suc as formula the simvastatin ammonium salt shown in VI.
Wherein, R is methyl or ethyl.
In alcoholysis reaction, acid catalyst and consumption thereof, temperature of reaction and time conditions are the normal condition of the alcoholysis reaction of ketal in organic synthesis field, optimum condition is as follows: the preferred tosic acid of described acid catalyst and/or hydrogenchloride, and the consumption of an acidic catalyst is preferably suc as formula 5 ~ 10% of the intermediate molar weight shown in IV; The temperature of alcoholysis reaction is preferably 0 ~ 30 DEG C, generally under natural room temperature; Till the time of reaction preferably runs out of with TLC detecting reactant.
In hydrolysis reaction, alkali and consumption thereof, temperature of reaction and time conditions are the normal condition of the hydrolysis reaction of ester compound in organic synthesis field, optimum condition is as follows: the preferred sodium hydroxide of alkali and/or potassium hydroxide, and the consumption of alkali is preferably 4 ~ 5 times suc as formula the intermediate molar weight shown in IV; The temperature of hydrolysis reaction is preferably 0 ~ 30 DEG C, generally under natural room temperature; Till the time of reaction preferably runs out of with TLC detecting reactant.
Acidifying acid used is the conventional acid of organic synthesis field acidifying, is preferably hydrochloric acid.The amount that acidifying sour consumption used is preferably 3 ~ 4 for adjusting pH.The temperature of acidifying is preferably 0 ~ 5 DEG C.Can adopt ordinary method, as ethyl acetate extraction, isolate acidizing product and carry out next step ammoniumization reaction.
In ammoniumization reaction, reactant and consumption thereof, temperature of reaction and time conditions are the normal condition of carboxylic acid ammoniumization reaction in organic synthesis field, and optimum condition is as follows: the consumption of ammoniacal liquor or ammonia is preferably for regulating the amount that pH is 7 ~ 8; Preferably adopt ammoniacal liquor to react, while adopting ammoniacal liquor, generally need adopt the diluting solvent of methyl alcohol as ammoniacal liquor by this area routine operation; The temperature of ammoniumization reaction is preferably 0 ~ 5 DEG C.
Described inertia organic gas is preferably nitrogen.The lower aliphatic alcoholic solvent of described C1-C4 is preferably selected from methyl alcohol and/or ethanol, and the consumption of solvent can be 5 ~ 10 times of reactant solubilized amount.
The invention still further relates in aforesaid method used suc as formula the new intermediate shown in IV, with and preparation method thereof: under protection of inert gas, in inert organic solvents or pyridine, under the catalysis of alkali, by suc as formula the intermediate shown in I with suc as formula 2 shown in V, 2-dimethyl-butyrylchlorine reacts;
Wherein, R is methyl or ethyl.
Wherein, reactant consumption, alkali and consumption thereof, temperature of reaction and time conditions are the normal condition that in organic synthesis field, the reaction of ester is prepared in the reaction of carboxylic acid halides and alcohol, optimum condition is as follows: suc as formula 2 shown in V, the consumption of 2-dimethyl-butyrylchlorine is preferably 4 ~ 8 times suc as formula the intermediate molar weight shown in I; Described alkali is preferably tertiary amine (as pyridine, DMAP (DMAP), triethylamine and xylidene(s)), and that better is DMAP (DMAP); While using inert organic solvents, the consumption of described alkali is preferably 1.2 ~ 1.5 times suc as formula the intermediate molar weight shown in I; While using pyridine solvent, the consumption of alkali is preferably suc as formula 10 ~ 20% of the intermediate molar weight shown in I; Described inert organic solvents is preferably one or more in hexanaphthene, benzene, toluene and methylene dichloride, and preferably using pyridine as solvent, it has the effect of acid binding agent and catalyzer simultaneously, and the consumption of solvent can be 2 ~ 5 times of reactant solubilized amount; The temperature of reaction is preferably 40 ~ 50 DEG C; Till the time of reaction preferably runs out of with TLC detecting reactant.Described rare gas element is preferably nitrogen.
The invention still further relates in aforesaid method used suc as formula the new intermediate shown in I, with and preparation method thereof: under protection of inert gas, in inert organic solvents, under the effect of acid catalyst, to react suc as formula the diol lactone shown in II with suc as formula the ortho-formiate derivative shown in III;
Wherein, R is methyl or ethyl.
Wherein, consumption, acid catalyst and consumption thereof, temperature of reaction and the time conditions of reactant are the normal condition of transesterification reaction in organic synthesis field, and optimum condition is as follows: suc as formula the diol lactone shown in II be preferably mol ratio 1: 3 ~ 1: 5 suc as formula the consumption of the ortho-formiate derivative shown in III; The described mode that adds suc as formula the ortho-formiate derivative shown in III is preferably dropping; One or more in the preferred hydrogenchloride of acid catalyst, tosic acid and methylsulfonic acid, the consumption of acid catalyst is preferably suc as formula 10 ~ 20% of the diol lactone molar weight shown in II; The temperature of reaction is preferably 0 ~ 5 DEG C; Till the time of reaction preferably runs out of with TLC detecting reactant.Described inert organic solvents is preferably one or more in hexanaphthene, benzene, toluene and methylene dichloride, and the consumption of inert organic solvents can be 2 ~ 5 times of reactant solubilized amount.Described rare gas element is preferably nitrogen.
For the purity of product is further provided, preferably first will react with methyl alcohol or ethanol suc as formula the diol lactone shown in II, add again afterwards suc as formula the ortho-formiate derivative shown in III and react.While adding methyl alcohol, subsequent reactions adds ortho-formiate trimethyl; While adding ethanol, subsequent reactions adds ortho-formiate triethyl.Each conditions such as consumption, acid catalyst and consumption thereof, temperature of reaction and the time of reactant are with aforementioned, for the normal condition of transesterification reaction in organic synthesis field, optimum condition is as follows: the consumption of methyl alcohol or ethanol is preferably 1 ~ 2 times suc as formula the diol lactone molar weight shown in II; The time of reacting with methyl alcohol or ethanol, preferably till the amount substantially constant with HPLC detecting reactant and product, temperature was preferably 0 ~ 30 DEG C, generally under natural room temperature.Add each condition of reacting suc as formula the ortho-formiate derivative shown in III each condition with aforementioned direct reaction.
In the present invention, method that can reference [US4444784] suc as formula the preparation method of the diol lactone shown in II be hydrolyzed also cyclization with lovastatin under alkaline condition.Other agents useful for same and raw material be commercially available obtaining all.
The present invention prepares total synthetic route of simvastatin ammonium salt for adopting ring-type ortho-formiate form protection 1,3-dihydroxyl structure, and the product after hydroxyl protection is prepared simvastatin ammonium salt by a few step reactions such as acidylate and deprotection again.Synthetic route is as follows:
Wherein, R is methyl or ethyl.
Positive progressive effect of the present invention is: the method that adopts the synthetic simvastatin ammonium salt of intermediate of the present invention, and the synthetic method of midbody compound of the present invention is all simple to operate, mild condition, reaction yield is higher, purity is high, has higher industrial application value.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.
The preparation of embodiment 1 triol acid original acid A ester derivative (I, R is methyl)
Under nitrogen protection; by diol lactone 2.0g(6.25mmol) be suspended in toluene 20.0ml; add methyl alcohol 0.2g(6.25mmol) and tosic acid monohydrate 0.12g(0.63mmol); room temperature (25 DEG C) stirring reaction, till the amount of HPLC detecting reactant and product is constant (2.0h).After 0 ~ 5 DEG C of ice bath temperature control, slowly drip the toluene solution 10.0ml of trimethyl orthoformate, containing trimethyl orthoformate 2.7g(25.47mmol), 1.0h dropwises, and continues insulated and stirred.TLC detecting reactant runs out of reaction and finishes (2.0h).Add afterwards triethylamine 0.13g(1.29mmol) neutralizing acid catalyzer, the saturated NaCl solution washing of 2 × 10.0ml for reaction solution, the anhydrous MgSO of organic layer
4after dry, remove solvent under reduced pressure and obtain light yellow oil (2.2g, 89.3%), purity is that 95.4%(HPLC measures).
TLC shows that product is two components, is a pair of diastereomer, measures structured data as follows after chromatography column separates:
A component (R
f=0.33, ethyl acetate: sherwood oil=1: 3):
1H-NMR(400MHz,CDCl
3)δ5.97(d,J=10.0Hz,1H),5.78(dd,J=6.0,9.6Hz,1H),5.52(m,1H),5.39(s,1H),4.52(m,1H),4.23(m,1H),4.16(m,1H),3.69(s,3H),3.33(s,3H),2.57-2.35(AB?of?an?ABX,J=15.6Hz,2H),2.39(m,2H),2.13(dd,J=2.4,12.4Hz,1H),1.18(d,J=7.2Hz,3H),0.88(d,J=6.8Hz,3H)。
13C-NMR?and?DEPT(100MHz,CDCl
3)δ170.92(C),133.67(CH),131.45(C),129.96(CH),128.45(CH),109.05(CH),67.84(CH),65.20(CH),64.37(CH),52.66(CH
3),51.57(CH
3),40.50(CH
2),38.88(CH),36.33(CH
2),36.22(CH),35.82(CH
2),32.78(CH
2),30.80(CH),27.47(CH),23.66(CH
3),23.63(CH
2),13.90(CH
3)。
ES-MS(m/z)811(2M+Na),433(M+K),418(M+1+Na),417(M+Na,100)。
B component (R
f=0.23, ethyl acetate: sherwood oil=1: 3):
1H-NMR(400MHz,CDCl
3)δ5.97(d,J=10.0Hz,1H),5.79(dd,J=6.0,9.6Hz,1H),5.53(m,1H),5.18(s,1H),4.22(m,1H),4.18(m,1H),3.77(m,1H),3.69(s,3H),3.46(s,3H),2.71-2.35(AB?of?an?ABX,J=15.6Hz,2H),2.39(m,2H),2.14(dd,J=2.8,11.6Hz,1H),1.18(d,J=7.2Hz,3H),0.89(d,J=6.8Hz,3H)。
13C-NMR?and?DEPT(100MHz,CDCl
3)δ170.75(C),133.67(CH),131.43(C),129.91(CH),128.42(CH),111.75(CH),74.71(CH),71.06(CH),65.20(CH),52.72(CH
3),51.56(CH
3),40.17(CH
2),38.82(CH),36.24(CH),35.81(CH
2),35.73(CH
2),32.41(CH
2),30.76(CH),27.41(CH),23.75(CH
3),23.65(CH
2),13.84(CH
3)。
ES-MS(m/z)433(M+K),418(M+1+Na),417(M+Na,100)。
The preparation of embodiment 2 triol acid original acid A ester derivatives (I, R is methyl)
Under nitrogen protection; by diol lactone 2.0g(6.25mmol) be suspended in benzene 20.0ml, add methyl alcohol 0.4g(12.5mmol) and methylsulfonic acid (0.12g, 1.25mmol); room temperature (30 DEG C) stirring reaction, till the amount of HPLC detecting reactant and product is constant (2.0h).After 4 ~ 5 DEG C of ice bath temperature controls, slowly drip the toluene solution 10.0ml of trimethyl orthoformate, containing trimethyl orthoformate 2.0g(18.75mmol), 1.0h dropwises, and continues insulated and stirred.TLC detecting reactant runs out of reaction and finishes (1.0h).Add afterwards triethylamine 0.13g(1.29mmol) neutralizing acid catalyzer, the saturated NaCl solution washing of 2 × 10.0ml for reaction solution, the anhydrous MgSO of organic layer
4after dry, remove solvent under reduced pressure and obtain light yellow oil (2.3g, 93.4%), purity is that 93.6%(HPLC measures).
The preparation of embodiment 3 triol acid original acid A ester derivatives (I, R is methyl)
Under nitrogen protection; by diol lactone 2.0g(6.25mmol) be suspended in toluene 20.0ml; add methyl alcohol 0.2g(6.25mmol) and 25wt% methanol hydrochloride solution 0.14g(0.96mmol), 0 DEG C of stirring reaction, till the amount of HPLC detecting reactant and product is constant (2.0h).After 0 ~ 1 DEG C of ice bath temperature control, slowly drip the toluene solution 10.0ml of trimethyl orthoformate, containing trimethyl orthoformate 3.3g(31.25mmol), 1.0h dropwises, and continues insulated and stirred, and TLC detecting reactant runs out of reaction and finishes (1.0h).Add afterwards triethylamine 0.13g(1.29mmol) neutralizing acid catalyzer, the saturated NaCl solution washing of 2 × 10.0ml for reaction solution, the anhydrous MgSO of organic layer
4after dry, remove solvent under reduced pressure and obtain light yellow oil (2.3g, 93.4%), purity is that 93.2%(HPLC measures).
The preparation of embodiment 4 Simvastatin original acid A ester derivatives (IV, R is methyl)
Under nitrogen protection; by triol acid original acid A ester derivative (I; R is methyl) 2.2g(5.58mmol) be dissolved in dry pyridine 7.0ml; add DMAP 0.14g(1.15mmol) and 2; 2-dimethyl-butyrylchlorine 6.0g(44.61mmol); be heated to 45 DEG C of left and right, insulation reaction, TLC detecting reactant runs out of reaction and finishes (48h).Remove solvent and excessive acyl chlorides under reduced pressure, residuum 15.0ml acetic acid ethyl dissolution, with the saturated NaHCO of 3 × 5.0ml
3the saturated NaCl solution washing of solution and 5.0ml, the anhydrous MgSO of organic layer
4after dry, remove solvent under reduced pressure and obtain light yellow oil (2.3g, 83.8%), purity is that 91.5%(HPLC measures).
TLC shows that product is two components, is a pair of diastereomer, measures structured data as follows after chromatography column separates:
A component (R
f=0.65, ethyl acetate: sherwood oil=1: 3):
1H-NMR(400MHz,CDCl
3)δ5.96(d,J=9.6Hz,1H),5.76(dd,J=6.0,9.6Hz,1H),5.48(m,1H),5.36(s,1H),5.31(m,1H),4.51(m,1H),4.05(m,1H),3.69(s,3H),3.32(s,3H),2.55-2.33(AB?of?an?ABX,J=15.6Hz,2H),2.38(m,2H),2.22(dd,J=2.8,12.0Hz,1H),1.12(s,3H),1.11(s,3H),1.07(d,J=7.2Hz,3H),0.86(d,J=6.8Hz,3H),0.83(t,J=7.6Hz,3H)。
ES-MS(m/z)1007(2M+Na),516(M+H+Na,100),515(M+Na,100)。
B component (R
f=0.54, ethyl acetate: sherwood oil=1: 3):
1H-NMR(400MHz,CDCl
3)δ5.98(d,J=9.6Hz,1H),5.77(dd,J=6.0,9.6Hz,1H),5.49(m,1H),5.34(m,1H),5.16(s,1H),4.18(m,1H),3.70(s,3H),3.65(m,1H),3.46(s,3H),2.70-2.36(AB?of?an?ABX,J=15.6Hz,2H),2.39(m,2H),2.24(dd,J=2.8,12.0Hz,1H),1.12(s,3H),1.11(s,3H),1.08(d,J=7.6Hz,3H),0.86(d,J=7.2Hz,3H),0.83(t,J=7.2Hz,3H)。
ES-MS(m/z)1007(2M+Na),532(M+H+K,100),531(M+K,100),516(M+H+Na,100),515(M+Na,100)。
The preparation of embodiment 5 Simvastatin original acid A ester derivatives (IV, R is methyl)
Under nitrogen protection; by triol acid original acid A ester derivative (I; R is methyl) 2.2g(5.58mmol) be dissolved in hexanaphthene 7.0ml; add triethylamine 0.84g(8.32mmol) and 2; 2-dimethyl-butyrylchlorine 3.0g(22.3mmol); be heated to 40 DEG C of left and right, insulation reaction, TLC detecting reactant runs out of reaction and finishes (72h).Remove solvent and excessive acyl chlorides under reduced pressure, residuum 15.0ml acetic acid ethyl dissolution, with the saturated NaHCO of 3 × 5.0ml
3the saturated NaCl solution washing of solution and 5.0ml, the anhydrous MgSO of organic layer
4after dry, remove solvent under reduced pressure and obtain light yellow oil (2.1g, 76.5%), purity is that 89.4%(HPLC measures).
The preparation of embodiment 6 Simvastatin original acid A ester derivatives (IV, R is methyl)
Under nitrogen protection; by triol acid original acid A ester derivative (I; R is methyl) 2.2g(5.58mmol) be dissolved in toluene 7.0ml; add pyridine (0.53g; 6.71mmol) with 2,2-dimethyl-butyrylchlorine 4.5g(33.45mmol), be heated to 50 DEG C of left and right; insulation reaction, TLC detecting reactant runs out of reaction and finishes (72h).Remove solvent and excessive acyl chlorides under reduced pressure, residuum 15.0ml acetic acid ethyl dissolution, with the saturated NaHCO of 3 × 5.0ml
3the saturated NaCl solution washing of solution and 5.0ml, the anhydrous MgSO of organic layer
4after dry, remove solvent under reduced pressure and obtain light yellow oil (2.2g, 80.1%), purity is that 88.7%(HPLC measures).
Embodiment 7 prepares simvastatin ammonium salt (VI) by Simvastatin trimethyl orthoformate derivative
Under nitrogen protection; by Simvastatin trimethyl orthoformate derivative (IV, R is methyl) 2.3g(4.67mmol) be dissolved in methyl alcohol 50ml, add tosic acid monohydrate 0.09g(0.47mmol); room temperature (25 DEG C) stirs, and TLC detecting reactant runs out of reaction and finishes (1.0h).Add 2N NaOH solution 10.0ml, room temperature (25 DEG C) stirs, and TLC detecting reactant runs out of reaction and finishes (2.0h).Remove first alcohol and water under reduced pressure, when being concentrated into solid and separating out, add 5.0ml distilled water diluting, 0 ~ 5 DEG C of ice bath temperature control, with 3N HCl adjust pH to 6 ~ 7.Then add ethyl acetate 10.0ml, continue to regulate pH to 3 ~ 4, separate organic layer.After being cooled to 0 ~ 5 DEG C, organic layer adjusts pH to 7 ~ 8, insulated and stirred 2.0h crystallization with methyl alcohol and ammoniacal liquor (1: 1, V/V) mixing solutions, filter ethyl acetate and methyl alcohol (3: 1, V/V) washing for filter cake, be dried to obtain white solid (1.4g, 66.2%), mp 158.0-159.8 DEG C.
1H-NMR(400MHz,DMSO-d
6)δ5.94(d,J=9.2Hz,1H),5.77(dd,J=6.4,9.6Hz,1H),5.48(m,1H),5.18(m,1H),3.86(m,2H),3.49(m,1H),1.06(s,3H),1.05(s,3H),1.02(d,J=7.2Hz,3H),0.83(d,J=6.8Hz,3H),0.77(t,J=7.6Hz,3H)。
ES-MS(m/z)891(M+436+2H),890(M+436+H),438(436+2H),437(436+H,100),419,321,303,285,256,177,149,74。
Ultimate analysis C
25h
38o
5: calculated value (%) C, 66.28; H, 9.71; N, 3.19.
Measured value (%) C, 66.20; H, 9.55; N, 3.09.
Embodiment 8 prepares simvastatin ammonium salt (VI) by Simvastatin trimethyl orthoformate derivative
Under nitrogen protection; by Simvastatin trimethyl orthoformate derivative (IV; R is methyl) 2.3g(4.67mmol) be dissolved in ethanol 50ml; add tosic acid monohydrate 0.045g(0.234mmol); room temperature (30 DEG C) stirs, and TLC detecting reactant runs out of reaction and finishes (3.0h).Add 2N KOH solution 9.0ml, room temperature (30 DEG C) stirs, and TLC detecting reactant runs out of reaction and finishes (3.0h).Remove first alcohol and water under reduced pressure, when being concentrated into solid and separating out, add 5.0ml distilled water diluting, 4 ~ 5 DEG C of ice bath temperature controls, with 3N HCl adjust pH to 6 ~ 7.Then add ethyl acetate 10.0ml, continue to regulate pH to 4, separate organic layer.After being cooled to 4 ~ 5 DEG C, organic layer adjusts pH to 8, insulated and stirred 2.0h crystallization with methyl alcohol and ammoniacal liquor (1: 1, V/V) mixing solutions, filter ethyl acetate and methyl alcohol (3: 1, V/V) washing for filter cake, be dried to obtain white solid (1.3g, 61.5%), mp 158.0-159.8 DEG C.
Embodiment 9 prepares simvastatin ammonium salt (VI) by Simvastatin trimethyl orthoformate derivative
Under nitrogen protection; by Simvastatin trimethyl orthoformate derivative (IV, R is methyl) 2.3g(4.67mmol) be dissolved in propyl carbinol 50ml, add 25wt% methanol hydrochloride solution 0.07g(0.47mmol); 0 DEG C of stirring, TLC detecting reactant runs out of reaction and finishes (1h).Add 2N NaOH solution 11.7ml, 0 DEG C of stirring, TLC detecting reactant runs out of reaction and finishes (2h).Remove first alcohol and water under reduced pressure, when being concentrated into solid and separating out, add 5.0ml distilled water diluting, 0 ~ 1 DEG C of ice bath temperature control, with 3N HCl adjust pH to 6 ~ 7.Then add ethyl acetate 10.0ml, continue to regulate pH to 3, separate organic layer.After organic layer is cooled to 0 ~ 1 DEG C, lead to ammonia and adjust pH to 7, insulated and stirred 2h crystallization, filters, and ethyl acetate and methyl alcohol (3: 1, V/V) washing for filter cake, be dried to obtain white solid (1.2g, 56.7%), mp158.0-159.8 DEG C.
The preparation of embodiment 10 triol acid ethyl orthoformate derivatives (I, R is ethyl)
Under nitrogen protection; by diol lactone 2.0g(6.25mmol) be suspended in toluene 20.0ml; add ethanol 0.3g(6.52mmol) and tosic acid monohydrate 0.24g(1.26mmol), stirring at room temperature reaction, till the amount of HPLC detecting reactant and product is constant (2.0h).After 0 ~ 5 DEG C of ice bath temperature control, slowly drip the toluene solution 10.0ml of triethyl orthoformate, containing triethyl orthoformate 3.7g(25.00mmol), 1.0h dropwises, and continues insulated and stirred, and TLC detecting reactant runs out of reaction and finishes (2.0h).Add afterwards triethylamine 0.13g(1.29mmol) neutralizing acid catalyzer, the saturated NaCl solution washing of 2 × 10.0ml for reaction solution, the anhydrous MgSO of organic layer
4after dry, remove solvent under reduced pressure and obtain light yellow oil (2.3g, 87.2%), purity is that 95.8%(HPLC measures).
TLC shows that product is two components, is a pair of diastereomer, measures structured data as follows after chromatography column separates:
A component (R
f=0.47, ethyl acetate: sherwood oil=1: 3):
1H-NMR(400MHz,CDCl
3)δ5.96(d,J=10Hz,1H),5.77(m,1H),5.52(m,1H),5.17(m,1H),4.18(m,4H),3.95(m,1H),3.78(m,1H),3.75(t,J=7.2Hz,1H),3.54(m,1H),3.15(s,1H),2.69(d,J=6.4Hz,1H),2.55-2.34(m,4H),1.24(t,J=7.2Hz,3H),1.23(t,J=7.2Hz,3H),1.18(d,J=7.2Hz,3H),0.88(d,J=6.8Hz,3H)。
ES-MS(m/z)461(M+K),445(M+Na,100)。
B component (R
f=0.35, ethyl acetate: sherwood oil=1: 3):
1H-NMR(400MHz,CDCl
3)δ5.97(d,J=10Hz,1H),5.77(m,1H),5.53(m,1H),5.18(m,1H),4.18(m,4H),3.96(m,1H),3.78(m,1H),3.71(t,J=7.2Hz,1H),2.70(d,J=6.4Hz,1H),2.56-2.36(m,4H),1.27(t,J=7.2Hz,3H),1.25(t,J=7.2Hz,3H),1.19(d,J=7.2Hz,3H),0.88(d,J=6.8Hz,3H)。
ES-MS(m/z)461(M+K),445(M+Na,100)。
The preparation of embodiment 11 Simvastatin ethyl orthoformate derivatives (IV, R is ethyl)
Under nitrogen protection; by triol acid ethyl orthoformate derivative 2.3g(5.45mmol) be dissolved in dry pyridine 7.0ml; add DMAP 0.065g(0.54mmol) and 2; 2-dimethyl-butyrylchlorine 5.9g(43.87mmol); be heated to 45 DEG C of left and right; insulation reaction, TLC detecting reactant runs out of reaction and finishes (48 hours).Remove solvent and excessive acyl chlorides under reduced pressure, residuum 15.0ml acetic acid ethyl dissolution, with the saturated NaHCO of 3 × 5.0ml
3the saturated NaCl solution washing of solution and 5.0ml, the anhydrous MgSO of organic layer
4after dry, remove solvent under reduced pressure and obtain light yellow oil (2.3g, 81.2%), purity is that 92.5%(HPLC measures).
TLC shows that product is two components, is a pair of diastereomer, measures structured data as follows after chromatography column separates:
A component (R
f=0.71, ethyl acetate: sherwood oil=1: 3):
1H-NMR(400MHz,CDCl
3)δ5.97(d,J=9.6Hz,1H),5.77(dd,J=6.4,10Hz,1H),5.49(m,1H),5.33(m,1H),5.29(s,1H),4.52(m,1H),4.18(t,J=7.2Hz,2H),4.08(m,1H),3.75(t,J=7.2Hz,2H),3.68(m,1H),3.75(m,1H),2.69-2.34(m,4H),2.23(d,J=12.4Hz,1H),1.25(2CH
3,6H),1.12(s,3H),1.12(s,3H),1.08(d,J=7.2Hz,3H),0.87(d,J=7.2Hz,3H),0.84(t,J=7.6Hz,3H)。
ES-MS(m/z)559(M+K),543(M+Na,100)。
B component (R
f=0.62, ethyl acetate: sherwood oil=1: 3):
1H-NMR(400MHz,CDCl
3)δ5.97(d,J=9.6Hz,1H),5.77(dd,J=6.4,10Hz,1H),5.49(m,1H),5.33(m,1H),5.29(s,1H),4.54(m,1H),4.16(t,J=7.2Hz,2H),4.09(m,1H),3.76(t,J=7.2Hz,2H),3.65(m,1H),3.56(m,1H),2.69-2.34(m,4H),2.23(d,J=12.4Hz,1H),1.25(2CH
3,6H),1.12(s,3H),1.12(s,3H),1.08(d,J=7.2Hz,3H),0.87(d,J=7.2Hz,3H),0.84(t,J=7.6Hz,3H)。
ES-MS(m/z)559(M+K),543(M+Na,100)。
Embodiment 12 prepares simvastatin ammonium salt by Simvastatin triethyl orthoformate derivative
Under nitrogen protection, by Simvastatin ethyl orthoformate derivative 2.3g(4.42mmol) be dissolved in methyl alcohol 50ml, add tosic acid monohydrate 0.08g(0.42mmol), stirring at room temperature, TLC detecting reactant runs out of reaction and finishes (1.0h).Add 2N NaOH solution 10.0ml, stirring at room temperature, TLC detecting reactant runs out of reaction and finishes (2.0h).Remove first alcohol and water under reduced pressure, when being concentrated into solid and separating out, add 5.0ml distilled water diluting, 0 ~ 5 DEG C of ice bath temperature control, with 3N HCl adjust pH to 6 ~ 7.Then add ethyl acetate 10.0ml, continue to regulate pH to 3 ~ 4, separate organic layer.After organic layer is cooled to 0 ~ 5 DEG C, use methyl alcohol and ammoniacal liquor (1: 1, V/V) mixing solutions to adjust pH to 7 ~ 8, insulated and stirred 2.0h, filters, and ethyl acetate and methyl alcohol (3: 1, V/V) washing for filter cake, be dried to obtain white solid (1.3g, 649%).
Claims (3)
1. the preparation method suc as formula the intermediate shown in I, it is characterized in that: under protection of inert gas, in inert organic solvents, under the effect of acid catalyst, will react suc as formula the diol lactone shown in II with suc as formula the ortho-formiate derivative shown in III;
The step of described reaction is as follows: first will react with methyl alcohol or ethanol suc as formula the diol lactone shown in II, add afterwards suc as formula the ortho-formiate derivative shown in III again and react; While adding methyl alcohol, subsequent reactions adds ortho-formiate trimethyl; While adding ethanol, subsequent reactions adds ortho-formiate triethyl;
Wherein, R is methyl or ethyl; Described methyl alcohol or the consumption of ethanol are 1～2 times suc as formula the diol lactone molar weight shown in II; The described temperature of reacting with methyl alcohol or ethanol suc as formula the diol lactone shown in II is 0～30 DEG C; The described temperature of reacting suc as formula the ortho-formiate derivative shown in III that adds is 0～5 DEG C; Described acid catalyst is one or more in hydrogenchloride, tosic acid and methylsulfonic acid; The consumption of described acid catalyst is suc as formula 10～20% of the diol lactone molar weight shown in II; Described suc as formula the diol lactone shown in II be mol ratio 1:3～1:5 suc as formula the consumption of the ortho-formiate derivative shown in III; The described mode that adds suc as formula the ortho-formiate derivative shown in III is dropping.
2. the method for claim 1, is characterized in that: till the described time of reacting with methyl alcohol or ethanol suc as formula the diol lactone shown in II is constant with the amount of HPLC detecting reactant and product; Described add the time of reacting suc as formula the ortho-formiate derivative shown in III to run out of with detecting reactant till.
3. the method for claim 1, is characterized in that: described rare gas element is nitrogen.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5159104A (en) * | 1991-05-01 | 1992-10-27 | Merck & Co., Inc. | Process to simvastatin ester |
| CN1083111A (en) * | 1992-02-07 | 1994-03-02 | 麦克公司 | The biochemical purification of simvastatin |
| CN1493570A (en) * | 1998-12-10 | 2004-05-05 | ��Ԩ��ѧ��ҵ��ʽ���� | Process for preparing |
| CN1951901A (en) * | 2006-10-26 | 2007-04-25 | 丽珠医药集团股份有限公司 | Process for producing simvastatin ammonium salt |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5159104A (en) * | 1991-05-01 | 1992-10-27 | Merck & Co., Inc. | Process to simvastatin ester |
| CN1083111A (en) * | 1992-02-07 | 1994-03-02 | 麦克公司 | The biochemical purification of simvastatin |
| CN1493570A (en) * | 1998-12-10 | 2004-05-05 | ��Ԩ��ѧ��ҵ��ʽ���� | Process for preparing |
| CN1951901A (en) * | 2006-10-26 | 2007-04-25 | 丽珠医药集团股份有限公司 | Process for producing simvastatin ammonium salt |
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