CN102690201A - Simvastatin intermediate and preparation method thereof - Google Patents
Simvastatin intermediate and preparation method thereof Download PDFInfo
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- CN102690201A CN102690201A CN2012101868385A CN201210186838A CN102690201A CN 102690201 A CN102690201 A CN 102690201A CN 2012101868385 A CN2012101868385 A CN 2012101868385A CN 201210186838 A CN201210186838 A CN 201210186838A CN 102690201 A CN102690201 A CN 102690201A
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Abstract
The invention discloses an intermediate which is shown as a formula IV and a preparation method for the intermediate which is shown as the formula IV, wherein R is methyl or ethyl. The method comprises the following steps of: performing alcoholysis reaction of 4-acetyl simvastatin which is shows as a formula I and methyl alcohol or ethanol under the protection of inert gas and the action of an acid catalyst, wherein R is methyl or ethyl. The method for synthesizing the intermediate IV and a method for synthesizing simvastatin ammonium salt V by using the new intermediate IV are simple, mild in condition, short in time, and high in reaction yield, and a product is high in purity.
Description
The application is application number CN200810037174.X, and the applying date is on May 9th, 2008, and application name is called: the dividing an application of the patented claim of " a kind of compound method of simvastatin ammonium salt and used midbody and preparation method thereof ".
Technical field
The present invention relates to compound method and used midbody of a kind of simvastatin ammonium salt and preparation method thereof.
Background technology
Simvastatin ammonium salt (VI) is the key intermediate of preparation blood lipid-lowering medicine SV (VII).Utilize simvastatin ammonium salt and the simvastatin acid different solubilities in water and organic phase; Make effective constituent fully extract organic phase, be carried out to the process of ammonium salt crystallization again, impurity is effectively separated; Obtain the simvastatin ammonium salt of higher degree; Cyclization prepares SV then, makes the finished product SV quality controllable, and purity is high.
(Dabora RL such as Dabora; Tewalt GL.Process to simvastatin ester [P], US5159104,1992.p.5.) with 4-ethanoyl SV (I) through alcoholysis; Make midbody (VIII), further make simvastatin ammonium salt (V) again.In this operational path, lactone and acetic ester in three ester group parts of 4-ethanoyl SV (I) are carried out alcoholysis, and keep 2,2-methyl-butyric ester part, thus make midbody (VIII).This step reaction is because the alcoholysis reaction speed of acetic ester is slow, and length consuming time need 16h could generate midbody (VIII), and the side reaction of following is many, and impurity is many.And midbody (VIII) is an oily matter, can not remove through recrystallization method, because the structure of SV verivate is bigger, and all very similar, even therefore product is the impurity that solid also is difficult to remove through recrystallization method decorrelation.Because midbody (VIII) impurity is many, ammonium salt crystallization difficulty and purity were low when the step prepared ammonium salt under making, productive rate is low.
Summary of the invention
Technical problem to be solved by this invention is existingly to make midbody (VIII) by 4-ethanoyl SV (I) through alcoholysis in order to overcome; Further make in the operational path of simvastatin ammonium salt (V), because the first step reaction time consumption is long, and by product is many again; Make that finished product purity is low; The defective that productive rate is low, and a kind of method of new synthetic simvastatin ammonium salt (V) is provided, and the used new intermediate of this method and preparation method thereof.
Method of the present invention comprises the steps: under the protection of inert gas; In water-miscible organic solvent; Under the effect of alkali, will carry out acidifying with acid again suc as formula the reaction that is hydrolyzed of the midbody shown in the IV; Then with ammonia or ammoniacal liquor through the ammonium reaction, can make suc as formula the simvastatin ammonium salt shown in the V.
Wherein, R is methyl or ethyl.
In the hydrolysis reaction; Each condition such as alkali and consumption thereof, temperature of reaction and time is the normal condition of the hydrolysis reaction of ester compound in the organic synthesis field; Optimum condition is following: preferred sodium hydroxide of alkali and/or Pottasium Hydroxide, and what the consumption of alkali was preferable is 4 ~ 5 times suc as formula the midbody molar weight shown in the IV; What the temperature of hydrolysis reaction was preferable is 0 ~ 30 ℃, generally under natural room temperature, gets final product; The reaction time preferable run out of with the TLC detecting reactant till.
The used acid of acidifying is organic synthesis field acidifying acid commonly used, and preferable is hydrochloric acid.What the consumption of the acid that acidifying is used was preferable is that adjusting pH is 3 ~ 4 amount.What the acidifying temperature was preferable is 0 ~ 5 ℃.Can adopt ordinary method,, isolate acidizing product and carry out next step ammonium reaction like ethyl acetate extraction.
In the ammonium reaction, each condition such as reactant and consumption thereof, temperature of reaction and time is the normal condition of carboxylic acid ammoniumization reaction in the organic synthesis field, and optimum condition is following: what the consumption of ammoniacal liquor or ammonia was preferable is that adjusting pH is 7 ~ 8 amount; Preferable employing ammoniacal liquor reacts, and when adopting ammoniacal liquor, generally need adopt the diluting solvent of methyl alcohol as ammoniacal liquor by this area routine operation; What the temperature of ammonium reaction was preferable is 0 ~ 5 ℃.
Described water-miscible organic solvent is preferable is in methyl alcohol, ethanol and the acetonitrile one or more, and the consumption of water-miscible organic solvent can be 5 ~ 10 times of reactant solubilized amount.What described rare gas element was preferable is nitrogen.
The invention still further relates in the above-mentioned reaction used suc as formula the new intermediate shown in the IV; Its compound method comprises the steps: under the protection of inert gas; Under the effect of acid catalyst, will carry out alcoholysis reaction suc as formula the 4-ethanoyl SV shown in the I and methyl alcohol or ethanol.
Wherein, R is methyl or ethyl.
In the alcoholysis reaction; Acid catalyst and consumption thereof and temperature of reaction condition are the normal condition of the alcoholysis reaction (transesterification reaction) of ester compound in the organic synthesis field; Optimum condition is following: preferred tosic acid of described acid catalyst and/or hydrogenchloride, and what the consumption of acid catalyst was preferable is suc as formula 5 ~ 10% of the 4-ethanoyl SV molar weight shown in the I; Methyl alcohol or ethanol can be not only as solvents but also as reactant, and what consumption was preferable is 30 ~ 50 times suc as formula the 4-ethanoyl SV molar weight shown in the I; What the temperature of alcoholysis reaction was preferable is 0 ~ 30 ℃, generally under natural room temperature, gets final product; The reaction time preferable run out of with the TLC detecting reactant till, generally be about 2 hours.What described rare gas element was preferable is nitrogen.
Among the present invention, but make suc as formula the method for the 4-ethanoyl diol lactone preparation method reference shown in the I [Dabora RL, Tewalt GL.Process to simvastatin ester [P] .US 5159104,1992.p.5.].Agents useful for same of the present invention and raw material be all commercially available getting except that specifying.
Positive progressive effect of the present invention is: the new midbody (IV) that the present invention is obtained by the alcoholysis reaction of 4-ethanoyl SV (I); Thereby overcome prior art and prepared midbody (VIII) through alcoholysis by 4-ethanoyl SV (I); Long reaction time; By product is many, thereby influences the purity of follow-up synthetic simvastatin ammonium salt (V) and the defective of productive rate.The compound method of new intermediate of the present invention (IV) and simple to operate by the method for the synthetic simvastatin ammonium salt (V) of new intermediate of the present invention (IV), mild condition, the time is short, and reaction yield is higher, and purity is high.Total synthetic route is as follows:
Wherein, R is methyl or ethyl.
Embodiment
Mode through embodiment further specifies the present invention below, but does not therefore limit the present invention among the described scope of embodiments.
The preparation of embodiment 14-ethanoyl SV methyl esters (IV, R is a methyl)
Under nitrogen protection; 4-ethanoyl SV 5.0g (10.87mmol) is dissolved in methyl alcohol 20ml, and (15.84g 495mmol), adds tosic acid monohydrate 0.1g (0.53mmol); Room temperature (25 ℃) stirs, and the TLC detecting reactant runs out of (2.0h).Remove methyl alcohol under reduced pressure, residuum is used 3 * 10.0ml 5%NaHCO again with toluene 50ml dissolving
3The saturated NaCl solution washing of solution and 10.0ml, organic layer is used anhydrous MgSO
4After the drying, remove solvent under reduced pressure and get light yellow oil (4.9g, yield 91.6%), purity 96.5% (HPLC mensuration).
1H-NMR(400MHz,CDCl
3)δ5.98(d,J=10.0Hz,1H),5.76(dd,J=6.4,9.2Hz,1H),5.49(s,1H),5.35(m,1H),4.93(m,1H),4.09(m,1H),3.70(s,3H),3.01(s,1H),2.66~2.53(AB?of?an?ABX,J=6.4,16.0Hz,2H),2.04(s,3H),1.12(s,6H),1.08(d,J=7.6Hz,3H),0.87(d,J=6.8Hz,3H),0.83(t,J=7.6Hz,3H)。
13C-NMR(100MHz,CDCl
3)δ177.59,172.76,170.66,132.83,131.61,128.39,128.32,72.25,67.86,65.63,51.61,42.90,41.09,40.54,37.67,36.50,33.00,32.95,31.43,30.57,27.28,24.69,24.63,23.83,23.00,21.16,13.76,9.18。
ES-MS(m/z)1007(2M+Na),517(M+2H+Na),516(M+H+Na),515(M+Na,100),399(M-H-CH
3COOH-CH
3OH)。
The preparation of embodiment 24-ethanoyl SV methyl esters (IV, R is a methyl)
Under nitrogen protection; 4-ethanoyl SV (formula I) 5.0g (10.87mmol) is dissolved in methyl alcohol 10.5g (328.1mmol), adds tosic acid monohydrate 0.2g (1.05mmol), room temperature (30 ℃) stirs; The TLC detecting reactant runs out of (1.5h); Remove methyl alcohol under reduced pressure, residuum is used 3 * 10.0ml 5%NaHCO again with toluene 50ml dissolving
3The saturated NaCl solution washing of solution and 10.0ml, organic layer is used anhydrous MgSO
4After the drying, remove solvent under reduced pressure and get light yellow oil (5.0g, yield 93.5%), purity 97.3% (HPLC mensuration).
The preparation of embodiment 34-ethanoyl SV methyl esters (IV, R is a methyl)
Under nitrogen protection; 4-ethanoyl SV (formula I) 5.0g (10.87mmol) is dissolved in methyl alcohol 13.9g (434.4mmol), adds 36wt% aqueous hydrochloric acid 0.06g (0.58mmol), 0 ℃ of stirring; The TLC detecting reactant runs out of (3.0h); Remove methyl alcohol under reduced pressure, residuum is used 3 * 10.0ml 5%NaHCO again with toluene 50ml dissolving
3The saturated NaCl solution washing of solution and 10.0ml, organic layer is used anhydrous MgSO
4After the drying, remove solvent under reduced pressure and get light yellow oil (4.8g, yield 89.7%), purity 96.3% (HPLC mensuration).
The preparation of embodiment 44-ethanoyl SV ethyl ester (IV, R is an ethyl)
Under nitrogen protection; 4-ethanoyl SV 5.0g (10.87mmol) is dissolved in ethanol 25.0g (543.5mmol); Add tosic acid monohydrate 0.1g (0.53mmol), room temperature (25 ℃) stirs, and the TLC detecting reactant runs out of (3.0h).Remove ethanol under reduced pressure, residuum is used 3 * 10.0ml 5%NaHCO again with toluene 50ml dissolving
3The saturated NaCl solution washing of solution and 10.0ml, organic layer is used anhydrous MgSO
4After the drying, remove solvent under reduced pressure and get light yellow oil (5.0g, yield 90.9%), purity 94.4% (HPLC mensuration).
1H-NMR(400MHz,CDCl
3)δ5.97(d,J=10.0Hz,1H),5.75(dd,J=6.4,9.2Hz,1H),5.45(s,1H),5.34(m,1H),4.91(m,1H),4.17(m,2H),4.05(m,1H),2.70~2.51(AB?of?an?ABX,J=6.4,16.0Hz,2H),2.05(s,3H),1.26(t,J=7.2Hz,3H),1.13(s,6H),1.09(d,J=7.6Hz,3H),0.88(d,J=6.8Hz,3H),0.82(t,J=7.6Hz,3H)。
ES-MS(m/z)1035(2M+Na),530(M+H+Na),529(M+Na,100)。
The preparation of embodiment 5 simvastatin ammonium salts (V)
Under nitrogen protection, 4-ethanoyl SV methyl esters 4.9g (9.96mmol) is dissolved in methyl alcohol 50ml, add 2N NaOH solution 20ml, room temperature (25 ℃) stirs, and the TLC detecting reactant runs out of and finishes reaction (2.0h).Remove the first alcohol and water under reduced pressure, when being concentrated into solid and separating out, add the 10.0ml distilled water diluting, 0 ~ 5 ℃ of ice bath temperature control is with 3N HCl adjust pH to 6 ~ 7.Add 20ml ETHYLE ACETATE then, 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 crystallization; Filter, filter cake is with ETHYLE ACETATE and methyl alcohol (3:1, V/V) washing; Dry simvastatin ammonium salt (3.0g, yield 66.7%), 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.
The preparation of embodiment 6 simvastatin ammonium salts (V)
Under nitrogen protection, 4-ethanoyl SV methyl esters 4.9g (9.96mmol) is dissolved in acetonitrile 50ml, add 2N NaOH solution 25ml, room temperature (30 ℃) stirs, and the TLC detecting reactant runs out of and finishes reaction (2.0h).Remove the first alcohol and water under reduced pressure, when being concentrated into solid and separating out, add the 10.0ml distilled water diluting, 0 ~ 1 ℃ of ice bath temperature control is with 3N HCl adjust pH to 6 ~ 7.Add 20ml ETHYLE ACETATE then, continue to regulate pH to 3, tell organic layer.After organic layer is cooled to 0 ~ 1 ℃ with methyl alcohol and ammoniacal liquor (1:1, V/V) mixing solutions is transferred pH to 7, insulated and stirred 2.0h crystallization; Filter, filter cake is with ETHYLE ACETATE and methyl alcohol (3:1, V/V) washing; Dry simvastatin ammonium salt (2.9g, yield 64.3%), mp 158.0-159.8 ℃ of getting.
The preparation of embodiment 7 simvastatin ammonium salts (V)
Under nitrogen protection, 4-ethanoyl SV methyl esters 4.9g (9.96mmol) is dissolved in ethanol 50ml, add 2N KOH solution 22ml, 0 ℃ of stirring, the TLC detecting reactant runs out of and finishes reaction (4h).Remove the first alcohol and water under reduced pressure, when being concentrated into solid and separating out, add the 10.0ml distilled water diluting, 4 ~ 5 ℃ of ice bath temperature controls are with 3N HCl adjust pH to 6 ~ 7.Add 20ml ETHYLE ACETATE then, continue to regulate pH to 4, tell organic layer.Logical ammonia was transferred pH to 8 after organic layer was cooled to 4 ~ 5 ℃, and insulated and stirred 2.0h crystallization filters, and filter cake is with ETHYLE ACETATE and methyl alcohol (3:1, V/V) washing, dry simvastatin ammonium salt (3.1g, yield 68.7%), mp 158.0-159.8 ℃ of getting.
The preparation of embodiment 8 simvastatin ammonium salts (V)
Under nitrogen protection, 4-ethanoyl SV ethyl ester 5.0g (9.88mmol) is dissolved in ethanol 50ml, add 2N KOH solution 20ml, 25 ℃ of stirrings, the TLC detecting reactant runs out of and finishes reaction (2h).Remove the second alcohol and water under reduced pressure, when being concentrated into solid and separating out, add the 10.0ml distilled water diluting, 4 ~ 5 ℃ of ice bath temperature controls are with 3N HCl adjust pH to 6 ~ 7.Add 20ml ETHYLE ACETATE then, 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; Filter, filter cake is with ETHYLE ACETATE and methyl alcohol (3:1, V/V) washing; Dry simvastatin ammonium salt (2.9g, yield 64.8%), mp158.0-159.8 ℃ of getting.
Claims (7)
1. suc as formula the midbody shown in the IV;
Wherein, R is methyl or ethyl.
2. as claimed in claim 1 suc as formula the intermediates preparation shown in the IV, it is characterized in that: under the protection of inert gas, under the effect of acid catalyst, will carry out alcoholysis reaction suc as formula the 4-ethanoyl SV shown in the I and methyl alcohol or ethanol;
Wherein, R is methyl or ethyl.
3. method as claimed in claim 2 is characterized in that: described acid catalyst is tosic acid and/or hydrogenchloride; The consumption of described acid catalyst is suc as formula 5 ~ 10% of the 4-ethanoyl SV molar weight shown in the I.
4. method as claimed in claim 2 is characterized in that: described methyl alcohol or ethanol are not only as solvent but also as reactant, and consumption is 30 ~ 50 times suc as formula the 4-ethanoyl SV molar weight shown in the I.
5. method as claimed in claim 2 is characterized in that: the temperature of described alcoholysis reaction is 0 ~ 30 ℃.
6. method as claimed in claim 2 is characterized in that: till the time of described reaction runs out of with detecting reactant.
7. method as claimed in claim 2 is characterized in that: described rare gas element is a nitrogen.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103787881A (en) * | 2013-11-22 | 2014-05-14 | 成都摩尔生物医药有限公司 | Simvastatin ammonium salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103787881A (en) * | 2013-11-22 | 2014-05-14 | 成都摩尔生物医药有限公司 | Simvastatin ammonium salt |
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