CN101575287B - Synthesizing method of simvastatin ammonium salt, midbody used thereby and preparation method thereof - Google Patents
Synthesizing method of simvastatin ammonium salt, midbody used thereby and preparation method thereof Download PDFInfo
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- CN101575287B CN101575287B CN 200810037175 CN200810037175A CN101575287B CN 101575287 B CN101575287 B CN 101575287B CN 200810037175 CN200810037175 CN 200810037175 CN 200810037175 A CN200810037175 A CN 200810037175A CN 101575287 B CN101575287 B CN 101575287B
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Abstract
The invention discloses a synthesizing method of a simvastatin ammonium salt indicated as a formula VI. The synthesizing method comprises the following steps: under the protection of an inert gas, in a C1-C4 low-grade fatty alcohol solvent and under the action of acid catalyst, a midbody indicated as a formula IV undergoes alcoholysis reaction, then undergoes hydrolysis under the action of alkali, then is added with acid for acidification and then undergoes amination reaction together with ammonia gas or ammonia liquid. The invention also discloses the novel midbody indicated as the formula IVand a preparation method thereof, wherein the preparation method of the novel midbody is as follows: the novel midbody is obtained in such a way that a midbody in a formula I reacts with 2,2-dimethylbutyrylchloride; in addition, the invention also discloses the novel midbody indicated as the formula I and a preparation method thereof, wherein the preparation method of the novel midbody is as follows: the novel midbody is obtained by causing diol-lactone indicated as a formula II and ortho-formate indicated as a formula III to undergo ester exchange reaction, wherein R is methyl or ethyl. The methods for preparing the simvastatin midbodies and the simvastatin ammonium salt have simple and convenient operation, mild conditions and higher yield rate.
Description
Technical field
The present invention relates to a kind of synthetic method of simvastatin ammonium salt and intermediate therefor and preparation method thereof.
Background technology
Simvastatin ammonium salt (VI) is the key intermediate of preparation 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, make impurity by effective separation, obtain the simvastatin ammonium salt of higher degree, then cyclization prepares Simvastatin, makes the finished product Simvastatin quality controllable, and purity is high.
Merck company report (US5159104) then prepares simvastatin ammonium salt through acidylate and deprotection with the 4-position hydroxyl selective protection of ethanoyl to diol lactone, and by its synthetic Simvastatin.Acetyl derivatives in this synthetic route is unstable under alkaline condition, easily produces during reaction and eliminates by product, and be difficult to remove from product.Of poor quality by the Simvastatin that this operational path makes, be not suitable for the suitability for industrialized production of Simvastatin.
Summary of the invention
Technical problem to be solved by this invention is easily to generate the by product that is difficult to remove for the method that overcomes existing synthetic Simvastatin, so that total product is of poor quality, be unsuitable for the defective of suitability for industrialized production, and provide a kind of the problems referred to above of avoiding, and simple to operate, novel method with higher industrial application value, and the used intermediate of the method and preparation method thereof.
Method of the present invention comprises the steps: under protection of inert gas, at C
1-C
4The lower aliphatic alcoholic solvent in, under the effect of acid catalyst, to carry out alcoholysis reaction suc as formula the intermediate shown in the IV, then under the effect of alkali, reaction is hydrolyzed, add afterwards acid and carry out acidifying, then with ammonia or ammoniacal liquor through the ammonium reaction, can make suc as formula the simvastatin ammonium salt shown in the VI.
Formula IV formula VI
Wherein, R is methyl or ethyl.
In the alcoholysis reaction, acid catalyst and consumption thereof, temperature of reaction and time conditions are the normal condition of the alcoholysis reaction of ketal in the organic synthesis field, optimum condition is as follows: the preferred tosic acid of described acid catalyst and/or hydrogenchloride, and what the consumption of an acidic catalyst was better is suc as formula 5～10% of the intermediate molar weight shown in the IV; What the temperature of alcoholysis reaction was better is 0～30 ℃, generally gets final product under natural room temperature; The reaction time better run out of with the TLC detecting reactant till.
In the hydrolysis reaction, alkali and consumption thereof, temperature of reaction and time conditions are the normal condition of the hydrolysis reaction of ester compound in the organic synthesis field, optimum condition is as follows: the preferred sodium hydroxide of alkali and/or potassium hydroxide, and the consumption of alkali is better is suc as formula the intermediate molar weight shown in the IV 4～5 times; What the temperature of hydrolysis reaction was better is 0～30 ℃, generally gets final product under natural room temperature; The reaction time better run out of with the TLC detecting reactant till.
The used acid of acidifying is organic synthesis field acidifying acid commonly used, and better is hydrochloric acid.What the consumption of the acid that acidifying is used was better is that adjusting pH is 3～4 amount.What the temperature of acidifying was better is 0～5 ℃.Can adopt ordinary method, such as ethyl acetate extraction, isolate acidizing product and carry out next step ammonium reaction.
In the ammonium reaction, reactant and consumption thereof, temperature of reaction and time conditions are the normal condition of carboxylic acid ammoniumization reaction in the organic synthesis field, and optimum condition is as follows: what the consumption of ammoniacal liquor or ammonia was better is that adjusting pH is 7～8 amount; Better employing ammoniacal liquor reacts, and when adopting ammoniacal liquor, generally need adopt methyl alcohol as the diluting solvent of ammoniacal liquor by this area routine operation; What the temperature of ammonium reaction was better is 0～5 ℃.
What described inertia organic gas was better is nitrogen.Described C
1-C
4The lower aliphatic alcoholic solvent better be selected from methyl alcohol and/or ethanol, the consumption of solvent can be 5～10 times of reactant solubilized amount.
The invention still further relates in the aforesaid method used suc as formula the new intermediate shown in the IV, with and preparation method thereof: under protection of inert gas, in inert organic solvents or pyridine, under the catalysis of alkali, will be suc as formula the intermediate shown in the I with suc as formula 2 shown in the V, the 2-dimethyl-butyrylchlorine reacts;
Formula I formula V formula IV
Wherein, R is methyl or ethyl.
Wherein, reactant consumption, alkali and consumption thereof, temperature of reaction and time conditions are carboxylic acid halides and pure normal condition of reacting the reaction of preparation ester in the organic synthesis field, optimum condition is as follows: suc as formula 2 shown in the V, the consumption of 2-dimethyl-butyrylchlorine is better is suc as formula the intermediate molar weight shown in the I 4～8 times; What described alkali was better is tertiary amine (such as pyridine, DMAP (DMAP), triethylamine and xylidene(s)), and that better is DMAP (DMAP); When using inert organic solvents, the consumption of described alkali is better is suc as formula the intermediate molar weight shown in the I 1.2～1.5 times; When using pyridine solvent, what the consumption of alkali was better is suc as formula 10～20% of the intermediate molar weight shown in the I; Described inert organic solvents is better is in hexanaphthene, benzene, toluene and the methylene dichloride one or more, better with pyridine as solvent, it has the effect of acid binding agent and catalyzer simultaneously, the consumption of solvent can be 2～5 times of reactant solubilized amount; What the temperature of reaction was better is 40～50 ℃; The reaction time better run out of with the TLC detecting reactant till.What described rare gas element was better is nitrogen.
The invention still further relates in the aforesaid method used suc as formula the new intermediate shown in the 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 the II and the ortho-formiate derivative shown in formula III, get final product;
Formula II formula III formula I
Wherein, R is methyl or ethyl.
Wherein, the consumption of reactant, acid catalyst and consumption thereof, temperature of reaction and time conditions are the normal condition of transesterification reaction in the organic synthesis field, and optimum condition is as follows: suc as formula the consumption of the diol lactone shown in the II and the ortho-formiate derivative shown in formula III better be mol ratio 1: 3～1: 5; What the adding mode of described ortho-formiate derivative shown in formula III was better is to drip; In the preferred hydrogenchloride of acid catalyst, tosic acid and the methylsulfonic acid one or more, what the consumption of acid catalyst was better is suc as formula 10～20% of the diol lactone molar weight shown in the II; What the temperature of reaction was better is 0～5 ℃; The reaction time better run out of with the TLC detecting reactant till.Described inert organic solvents is better is in hexanaphthene, benzene, toluene and the methylene dichloride one or more, and the consumption of inert organic solvents can be 2～5 times of reactant solubilized amount.What described rare gas element was better is nitrogen.
For the purity of product further is provided, better will react suc as formula the diol lactone shown in the II and methyl alcohol or ethanol first, the ortho-formiate derivative that adds again afterwards shown in formula III reacts.When adding methyl alcohol, subsequent reactions adds the ortho-formiate trimethyl; When adding ethanol, subsequent reactions adds the ortho-formiate triethyl.Each condition such as the consumption of reactant, acid catalyst and consumption thereof, temperature of reaction and time is with aforementioned, be the normal condition of transesterification reaction in the organic synthesis field, optimum condition is as follows: the consumption of methyl alcohol or ethanol is better is suc as formula the diol lactone molar weight shown in the II 1～2 times; Till the better amount substantially constant with HPLC detecting reactant and product of the time of reacting with methyl alcohol or ethanol, what temperature was better is 0～30 ℃, generally gets final product under natural room temperature.Each condition that the ortho-formiate derivative of adding shown in formula III reacts is with each condition of aforementioned direct reaction.
Among the present invention, but suc as formula the method for preparation method's reference [US4444784] of the diol lactone shown in the II, be hydrolyzed also under alkaline condition with lovastatin, cyclization gets final product.Other agents useful for same and raw material be commercially available getting all.
The present invention prepares the total synthetic route of simvastatin ammonium salt for adopting ring-type ortho-formiate form protection 1,3-dihydroxyl structure, and the product behind the hydroxyl protection is again by reaction preparation of a few step such as acidylate and deprotection simvastatin ammonium salt.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, and reaction yield is higher, purity is high, has higher industrial application value.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.
The preparation of embodiment 1 triol acid original acid A ester derivative (I, R are methyl)
Under nitrogen protection; diol lactone 2.0g (6.25mmo1) is suspended in toluene 20.0ml; add methyl alcohol 0.2g (6.25mmol) and tosic acid monohydrate 0.12g (0.63mmol); room temperature (25 ℃) stirring reaction is till the amount of HPLC detecting reactant and product is constant (2.0h).Behind 0～5 ℃ of the ice bath temperature control, slowly drip the toluene solution 10.0ml of trimethyl orthoformate, contain trimethyl orthoformate 2.7g (25.47mmol), 1.0h dropwises, and continues insulated and stirred.The TLC detecting reactant runs out of reaction and finishes (2.0h).Add afterwards triethylamine 0.13g (1.29mmol) neutralizing acid catalyzer, reaction solution is with the saturated NaCl solution washing of 2 * 10.0ml, the anhydrous MgSO of organic layer
4After the drying, remove solvent under reduced pressure and get light yellow oil (2.2g, 89.3%), purity is 95.4% (HPLC mensuration).
TLC shows that product is two components, is a pair of diastereomer, and it is as follows to measure structured data 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 are methyl)
Under nitrogen protection; diol lactone 2.0g (6.25mmol) is suspended in benzene 20.0ml; add methyl alcohol 0.4g (12.5mmol) and methylsulfonic acid (0.12g; 1.25mmol); room temperature (30 ℃) stirring reaction is till the amount of HPLC detecting reactant and product is constant (2.0h).Behind 4～5 ℃ of the ice bath temperature controls, slowly drip the toluene solution 10.0ml of trimethyl orthoformate, contain trimethyl orthoformate 2.0g (18.75mmol), 1.0h dropwises, and continues insulated and stirred.The TLC detecting reactant runs out of reaction and finishes (1.0h).Add afterwards triethylamine 0.13g (1.29mmol) neutralizing acid catalyzer, reaction solution is with the saturated NaCl solution washing of 2 * 10.0ml, the anhydrous MgSO of organic layer
4After the drying, remove solvent under reduced pressure and get light yellow oil (2.3g, 93.4%), purity is 93.6% (HPLC mensuration).
The preparation of embodiment 3 triol acid original acid A ester derivatives (I, R are methyl)
Under nitrogen protection; diol lactone 2.0g (6.25mmol) is suspended in toluene 20.0ml; add methyl alcohol 0.2g (6.25mmol) and 25wt% methanol hydrochloride solution 0.14g (0.96mmol); 0 ℃ of stirring reaction is till the amount of HPLC detecting reactant and product is constant (2.0h).Behind 0～1 ℃ of the ice bath temperature control, slowly drip the toluene solution 10.0ml of trimethyl orthoformate, contain trimethyl orthoformate 3.3g (31.25mmol), 1.0h dropwises, and continues insulated and stirred, and the TLC detecting reactant runs out of reaction and finishes (1.0h).Add afterwards triethylamine 0.13g (1.29mmol) neutralizing acid catalyzer, reaction solution is with the saturated NaCl solution washing of 2 * 10.0ml, the anhydrous MgSO of organic layer
4After the drying, remove solvent under reduced pressure and get light yellow oil (2.3g, 93.4%), purity is 93.2% (HPLC mensuration).
The preparation of embodiment 4 Simvastatin original acid A ester derivatives (IV, R are methyl)
Under nitrogen protection; with triol acid original acid A ester derivative (I; R is methyl) 2.2g (5.58mmol) is dissolved in dry pyridine 7.0ml; add DMAP 0.14g (1.15mmol) and 2; 2-dimethyl-butyrylchlorine 6.0g (44.61mmol); be heated to about 45 ℃, insulation reaction, TLC detecting reactant run out of reaction and finish (48h).Remove solvent and excessive acyl chlorides under reduced pressure, residuum 15.0ml acetic acid ethyl dissolution is 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 the drying, remove solvent under reduced pressure and get light yellow oil (2.3g, 83.8%), purity is 91.5% (HPLC mensuration).
TLC shows that product is two components, is a pair of diastereomer, and it is as follows to measure structured data 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 are methyl)
Under nitrogen protection; with triol acid original acid A ester derivative (I; R is methyl) 2.2g (5.58mmol) is dissolved in hexanaphthene 7.0ml; add triethylamine 0.84g (8.32mmol) and 2; 2-dimethyl-butyrylchlorine 3.0g (22.3mmol); be heated to about 40 ℃, insulation reaction, TLC detecting reactant run out of reaction and finish (72h).Remove solvent and excessive acyl chlorides under reduced pressure, residuum 15.0ml acetic acid ethyl dissolution is 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 the drying, remove solvent under reduced pressure and get light yellow oil (2.1g, 76.5%), purity is 89.4% (HPLC mensuration).
The preparation of embodiment 6 Simvastatin original acid A ester derivatives (IV, R are methyl)
Under nitrogen protection; with triol acid original acid A ester derivative (I; R is methyl) 2.2g (5.58mmol) is dissolved in toluene 7.0ml; add pyridine (0.53g; 6.71mmol) and 2,2-dimethyl-butyrylchlorine 4.5g (33.45mmol), be heated to about 50 ℃; insulation reaction, TLC detecting reactant run out of reaction and finish (72h).Remove solvent and excessive acyl chlorides under reduced pressure, residuum 15.0ml acetic acid ethyl dissolution is 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 the drying, remove solvent under reduced pressure and get light yellow oil (2.2g, 80.1%), purity is 88.7% (HPLC mensuration).
Embodiment 7 prepares simvastatin ammonium salt (VI) by Simvastatin trimethyl orthoformate derivative
Under nitrogen protection; with Simvastatin trimethyl orthoformate derivative (IV; R is methyl) 2.3g (4.67mmol) is dissolved in methyl alcohol 50ml; add tosic acid monohydrate 0.09g (0.47mmol); room temperature (25 ℃) stirs, and the TLC detecting reactant runs out of reaction and finishes (1.0h).Add 2NNaOH solution 10.0ml, room temperature (25 ℃) stirs, and the TLC detecting reactant runs out of reaction and finishes (2.0h).Remove the first alcohol and water under reduced pressure, when being concentrated into solid and separating out, add the 5.0ml distilled water diluting, 0～5 ℃ of ice bath temperature control is with 3N HCl adjust pH to 6～7.Then add ethyl acetate 10.0ml, continue to regulate pH to 3～4, tell organic layer.Usefulness methyl alcohol and ammoniacal liquor after organic layer is cooled to 0～5 ℃ (1: 1, V/V) mixing solutions is transferred pH to 7～8, insulated and stirred 2.0h crystallization, filter, and filter cake usefulness ethyl acetate and methyl alcohol (3: 1, V/V) washing, dry white solid (1.4g, 66.2%), mp 158.0-159.8 ℃ of getting.
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; with Simvastatin trimethyl orthoformate derivative (IV; R is methyl) 2.3g (4.67mmol) is dissolved in ethanol 50ml; add tosic acid monohydrate 0.045g (0.234mmol); room temperature (30 ℃) stirs, and the TLC detecting reactant runs out of reaction and finishes (3.0h).Add 2N KOH solution 9.0ml, room temperature (30 ℃) stirs, and the TLC detecting reactant runs out of reaction and finishes (3.0h).Remove the first alcohol and water under reduced pressure, when being concentrated into solid and separating out, add the 5.0ml distilled water diluting, 4～5 ℃ of ice bath temperature controls are with 3N HCl adjust pH to 6～7.Then add ethyl acetate 10.0ml, continue to regulate pH to 4, tell organic layer.Usefulness methyl alcohol and ammoniacal liquor after organic layer is cooled to 4～5 ℃ (1: 1, V/V) mixing solutions is transferred pH to 8, insulated and stirred 2.0h crystallization, filter, and filter cake usefulness ethyl acetate and methyl alcohol (3: 1, V/V) washing, dry white solid (1.3g, 61.5%), mp 158.0-159.8 ℃ of getting.
Embodiment 9 prepares simvastatin ammonium salt (VI) by Simvastatin trimethyl orthoformate derivative
Under nitrogen protection; with Simvastatin trimethyl orthoformate derivative (IV; R is methyl) 2.3g (4.67mmol) is dissolved in propyl carbinol 50ml; add 25wt% methanol hydrochloride solution 0.07g (0.47mmol); 0 ℃ of stirring, TLC detecting reactant run out of reaction and finish (1h).Add 2NNaOH solution 11.7ml, 0 ℃ of stirring, the TLC detecting reactant runs out of reaction and finishes (2h).Remove the first alcohol and water under reduced pressure, when being concentrated into solid and separating out, add the 5.0ml distilled water diluting, 0～1 ℃ of ice bath temperature control is with 3N HCl adjust pH to 6～7.Then add ethyl acetate 10.0ml, continue to regulate pH to 3, tell organic layer.Logical ammonia was transferred pH to 7 after organic layer was cooled to 0～1 ℃, and insulated and stirred 2h crystallization filters, filter cake with ethyl acetate and methyl alcohol (3: 1, V/V) washing, dry white solid (1.2g, 56.7%), mp158.0-159.8 ℃.
The preparation of embodiment 10 triol acid ethyl orthoformate derivatives (I, R are ethyl)
Under nitrogen protection; diol lactone 2.0g (6.25mmol) is suspended in toluene 20.0ml; add ethanol 0.3g (6.52mmol) and tosic acid monohydrate 0.24g (1.26mmol); the stirring at room reaction is till the amount of HPLC detecting reactant and product is constant (2.0h).Behind 0～5 ℃ of the ice bath temperature control, slowly drip the toluene solution 10.0ml of triethyl orthoformate, contain triethyl orthoformate 3.7g (25.00mmol), 1.0h dropwises, and continues insulated and stirred, and the TLC detecting reactant runs out of reaction and finishes (2.0h).Add afterwards triethylamine 0.13g (1.29mmol) neutralizing acid catalyzer, reaction solution is with the saturated NaCl solution washing of 2 * 10.0ml, the anhydrous MgSO of organic layer
4After the drying, remove solvent under reduced pressure and get light yellow oil (2.3g, 87.2%), purity is 95.8% (HPLC mensuration).
TLC shows that product is two components, is a pair of diastereomer, and it is as follows to measure structured data 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 are ethyl)
Under nitrogen protection; triol acid ethyl orthoformate derivative 2.3g (5.45mmol) is dissolved in dry pyridine 7.0ml; add DMAP 0.065g (0.54mmol) and 2; 2-dimethyl-butyrylchlorine 5.9g (43.87mmol); be heated to about 45 ℃; insulation reaction, TLC detecting reactant run out of reaction and finish (48 hours).Remove solvent and excessive acyl chlorides under reduced pressure, residuum 15.0ml acetic acid ethyl dissolution is 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 the drying, remove solvent under reduced pressure and get light yellow oil (2.3g, 81.2%), purity is 92.5% (HPLC mensuration).
TLC shows that product is two components, is a pair of diastereomer, and it is as follows to measure structured data 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(2CH3，6H)，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; Simvastatin ethyl orthoformate derivative 2.3g (4.42mmol) is dissolved in methyl alcohol 50ml; add tosic acid monohydrate 0.08g (0.42mmol), stirring at room, TLC detecting reactant run out of reaction and finish (1.0h).Add 2N NaOH solution 10.0ml, stirring at room, TLC detecting reactant run out of reaction and finish (2.0h).Remove the first alcohol and water under reduced pressure, when being concentrated into solid and separating out, add the 5.0ml distilled water diluting, 0～5 ℃ of ice bath temperature control is with 3N HCl adjust pH to 6～7.Then add ethyl acetate 10.0ml, continue to regulate pH to 3～4, tell organic layer.After organic layer is cooled to 0～5 ℃ with methyl alcohol and ammoniacal liquor (1: 1, V/V) mixing solutions is transferred pH to 7～8, insulated and stirred 2.0h filters, filter cake with ethyl acetate and methyl alcohol (3: 1, V/V) washing, dry white solid (1.3g, 64.9%).
Claims (10)
1. a synthetic method for preparing suc as formula the simvastatin ammonium salt shown in the VI is characterized in that comprising the steps: under protection of inert gas, at C
1-C
4The lower aliphatic alcoholic solvent in, under the effect of acid catalyst, to carry out alcoholysis reaction suc as formula the intermediate shown in the IV, then under the effect of alkali, reaction is hydrolyzed, add afterwards acid and carry out acidifying, then with ammonia or ammoniacal liquor through the ammonium reaction, can make suc as formula the simvastatin ammonium salt shown in the VI;
Wherein, R is methyl or ethyl.
2. the method for claim 1, it is characterized in that: in the alcoholysis reaction, described acid catalyst is tosic acid and/or hydrogenchloride, the consumption of an acidic catalyst is suc as formula 5～10% of the intermediate molar weight shown in the IV.
3. the method for claim 1, it is characterized in that: in the hydrolysis reaction, described alkali is sodium hydroxide and/or potassium hydroxide, the consumption of alkali is 4～5 times suc as formula the intermediate molar weight shown in the IV.
4. the method for claim 1, it is characterized in that: the temperature of described alcoholysis reaction and/or hydrolysis reaction is 0～30 ℃.
5. the method for claim 1 is characterized in that: the consumption of the acid that described acidifying is used is 3～4 amount for regulating pH.
6. the method for claim 1 is characterized in that: in the ammonium reaction, the consumption of described ammoniacal liquor or ammonia is 7～8 amount for regulating pH.
7. the method for claim 1, it is characterized in that: the temperature of described acidifying and/or ammonium reaction is 0～5 ℃.
8. the method for claim 1 is characterized in that: described C
1-C
4The lower aliphatic alcoholic solvent be methyl alcohol and/or ethanol.
9. the method for claim 1 is characterized in that: in the alcoholysis reaction or in the hydrolysis reaction, till the time of reaction runs out of with detecting reactant.
10. the method for claim 1, it is characterized in that: described rare gas element is nitrogen.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1083111A (en) * | 1992-02-07 | 1994-03-02 | 麦克公司 | The biochemical purification of simvastatin |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1083111A (en) * | 1992-02-07 | 1994-03-02 | 麦克公司 | The biochemical purification of simvastatin |
| 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 |
Non-Patent Citations (3)
| Title |
|---|
| 张永塘 * |
| 彭永延 * |
| 段丽辉.辛伐他汀的合成工艺改进.《中国药物化学杂志》.2010,(第3期), * |
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