CN101538261B - Method for preparing (3R, 5S)-3, 5-O-isopropylidene-3, 5, 6-trihydroxy caproic acid hexylic acid derivative - Google Patents
Method for preparing (3R, 5S)-3, 5-O-isopropylidene-3, 5, 6-trihydroxy caproic acid hexylic acid derivativeDownload PDFInfo
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- CN101538261B CN101538261BCN2009100501150ACN200910050115ACN101538261BCN 101538261 BCN101538261 BCN 101538261BCN 2009100501150 ACN2009100501150 ACN 2009100501150ACN 200910050115 ACN200910050115 ACN 200910050115ACN 101538261 BCN101538261 BCN 101538261B
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Abstract
Description
Technical field
The present invention relates to a kind of preparation (3R, 5S)-3,5-O-isopropylidene-3,5, the method for 6-trihydroxy caproic acid verivate.
Background technology
(3R, 5S)-3,5-O-isopropylidene-3,5,6-trihydroxy caproic acid verivate are a kind ofly to be used to prepare as the suppressor factor of hypercholesterolemia and hyperlipidaemia Rosuvastatin (Rosuvastatin) for example, the key intermediate of pitavastatin (Pitavastatin).Structural formula is suc as formula shown in (1):
(1)
Wherein: R represents hydrogen, and is saturated-C1-C5-alkyl, unsaturated-C2-C5-alkyl or benzyl etc.
In the method for the said verivate of numerous preparations (1), prolonging carbochain is committed step, and the method for carbon current chain extension has US 5; 278; Use acetate tert-butyl lithium described in 313, this reagent must be at present with existing preparation, and need to use butyllithium to operate down at anhydrous, coldcondition; US 4,983, and employed in 759 is the expensive monobromo-acetic acid tert-butyl ester, and needs waterless operation; US 5,214, and employed propanedioic acid list tert-butyl ester magnesium salts in 197, this reagent need the multistep operation existing with existing preparation, and preparation process need waterless operation and the higher magnesium chloride of price.For these reasons, more than three kinds of carbochains prolong reagent and all be not suitable for large-scale production, therefore, how finding a kind of low price, the gentle carbochain of reaction conditions to prolong reagent, to be used for the production of key intermediate (1) significant.
Patent US 5,214, and 197 reports are starting raw material with the oxysuccinic acid, are that carbochain prolongation compositions and methods makes compound (1) (SchemeI) with propanedioic acid list tert-butyl ester magnesium salts.Its reaction scheme is following:
Prolonging carbochain at committed step compound (2) prepares and mainly contains two problems in the process of compound (4): 1) not purified after compound (2) and fmoc-2 imidazole (CDI) reaction; Cause the reaction of impurity effect back; 2) propanedioic acid list tert-butyl ester magnesium salts needs the multistep operation existing with existing preparation, and preparation process need waterless operation and the higher magnesium chloride of price.For these reasons, former route is not suitable for amplifying and produces.
Summary of the invention
The objective of the invention is to disclose a kind of preparation (3R, 5S)-3,5-O-isopropylidene-3,5, the method for 6-trihydroxy caproic acid verivate is to overcome the above-mentioned defective that prior art exists.
Method of the present invention comprises the steps:
1, protect the compound (2) of hydroxyl in solvent, to react L MALIC ACID and make (S)-2 with CDI, 2-dimethyl--5-oxo-1,3-dioxa-4-acetyl imidazole is compound (3);
The compound (2) of described L MALIC ACID protection hydroxyl can adopt TetrahedronLetters, Vol.28, and No.15, the method for pp1685-1688 bibliographical information prepares.
Said solvent is selected from chlorinated solvent, ether solvent, esters solvent or nitrile solvents;
Preferred methylene dichloride of said chlorinated solvent or chloroform etc.; The preferred THF of said ether solvent, dioxane, ether, propyl ether, isopropyl ether or MTBE; Said esters solvent ethyl acetate or butylacetate etc., preferred acetonitrile of said nitrile solvents or propionitrile;
In this step reaction, the mole dosage of CDI is 1-3 a times of compound (2), preferred 1.5 times;
Temperature of reaction is 10～70 ℃, preferred 20～40 ℃;
Reaction times is 1～5 hour;
2, with compound (3) and Michaelis acid in solvent, the basic catalyst of catalytic amount reacts down, makes (S)-2-(4 '-oxo-3 ', 4 '-O-isopropylidene-3 ', 4 '-dihydroxyl-1 '-hydroxyl-alkene)-propanedioic acid ring Asia isopropyl ester, be compound (4);
Said solvent is selected from chlorinated solvent, ether solvent, esters solvent or nitrile solvents;
Preferred methylene dichloride of said chlorinated solvent or chloroform etc.; The preferred THF of said ether solvent, dioxane, ether, propyl ether, isopropyl ether or MTBE; Said esters solvent ethyl acetate or butylacetate etc., preferred acetonitrile of said nitrile solvents or propionitrile;
Said basic catalyst is selected from secondary amine or tertiary amine etc., preferred imidazoles, pyridine, triethylamine or diisopropyl ethyl amine;
The mole dosage of basic catalyst is 1-3 a times of compound (3), preferred 1 times;
The weight consumption of Michaelis acid is 1-3 a times of compound (3), preferred 1 times;
The temperature of reaction is 0～80 ℃, preferred 0～50 ℃, and reaction times 1～48h, preferred 3～15h;
3, compound (4) and excessive ROH are reacted under reflux state make (S)-3,6-dioxo-5,6-isopropylidene-5,6-dihydroxyl hecanoic acid t-butyl ester is compound (5);
Said ROH serves as reactant and solvent, and wherein, R is saturated-C1-C5-alkyl or benzyl, preferred ROH is methyl alcohol, ethanol, Virahol, the trimethyl carbinol or phenylcarbinol, the trimethyl carbinol most preferably, reaction times 2～20h, preferred 5h;
4, be raw material with compound (5) then, preparation target compound (1), this process is a prior art, can be with reference to U.S. Pat 5,214,197 disclosed methods, the present invention repeats no more.
Reaction expression is following:
Wherein: R represents saturated-C1-C5-alkyl or benzyl;
The present invention uses Michaelis acid to carry out the Claisen condensation as carbochain prolongation reagent, and the Michaelis acid value is honest and clean to be easy to get, and stable being prone to preserves; Reaction can carried out near the room temperature or under the higher temperature; Reaction conditions is gentle, and through the effect of basic catalyst, the usage quantity of all ingredients, Michaelis acid and compound (3) is minimum; The quality of product and productive rate are high, are convenient to industrializing implementation.
Embodiment
Embodiment 1
1, (S)-2,2-dimethyl--5-oxo-1, the preparation of 3-dioxa-4-acetyl imidazole (3):
19.5g compound (2) is dissolved in the 150ml methylene dichloride, adds 18.2g fmoc-2 imidazole (CDI), behind 25 ℃ of reaction 2h, concentrate and obtain the 25g yellow solid; Recrystallization obtains 21.3g white plates solid (S)-2 then, 2-dimethyl--5-oxo-1,3-dioxa-4-acetyl imidazole (3).mp：126.9～128.3℃。
MS：225(M+1)
1H-NMR(CDCl3)：8.18(s，1H)，7.48(s，1H)，7.13(s，1H)，4.91(m，1H)，3.28-3.54(dd，2H)，1.57-1.65(d，6H)
2, the preparation of the inferior isopropyl ester of (S)-2-(4 '-oxo-3 ', 4 '-O-isopropylidene-3 ', 4 '-dihydroxyl-1 '-hydroxyl-alkene)-propanedioic acid ring (4):
21.3g compound (3), the acid of 13.6g Michaelis and 6.5g imidazoles are dissolved in the 250ml methylene dichloride, and 25 ℃ of stirring reaction 15h concentrate and obtain 24.2g yellow oil bullion.
Get part bullion column chromatography and obtain the pure article of the inferior isopropyl ester (4) of faint yellow oily thing (S)-2-(4 '-oxo-3 ', 4 '-O-isopropylidene-3 ', 4 '-dihydroxyl-1 '-hydroxyl-alkene)-propanedioic acid ring.
MS：300(M)
1H-NMR(CDCl3)：15.66(s，1H)，4.97(m，1H)，3.77-3.82(m，1H)，3.60-3.66(m，1H)，1.75(d，6H)，1.62(s，3H)，1.57(s，3H)
3, (S)-3,6-dioxo-5,6-isopropylidene-5, the preparation of 6-dihydroxyl hecanoic acid t-butyl ester (5):
In 22.2g compound (4) bullion, add the 200mL trimethyl carbinol and make it dissolving; Backflow
5h concentrates and obtains yellow oil 17.1g.Get part bullion column chromatography and obtain faint yellow oily thing (S)-3,6-dioxo-5,6-isopropylidene-5, the pure article of 6-dihydroxyl hecanoic acid t-butyl ester (5).
MS：290(M+NH4+)
1H-NMR(DMSO-d6)：4.79-4.82(m，1H)，3.52(s，2H)，3.15-3.23(m，1H)，2.98-3.06(m，1H)，1.52(s，6H)，1.41(s，9H)
Be raw material with compound (5) then, with reference to U.S. Pat 5,214,197 disclosed methods prepare target compound (1).
Embodiment 2
1, (S)-2,2-dimethyl--5-oxo-1, the preparation of 3-dioxa-4-acetyl imidazole (3):
20g compound (2) is dissolved in the 200ml acetonitrile, adds 18.6g fmoc-2 imidazole (CDI), behind 70 ℃ of reaction 1h, concentrate and obtain the 25g yellow solid; Recrystallization obtains 15.4g white plates solid (S)-2 then, 2-dimethyl--5-oxo-1,3-dioxa-4-acetyl imidazole (3).mp：127～128.3℃。
MS：225(M+1)
1H-NMR(CDCl3)：8.18(s，1H)，7.48(s，1H)，7.13(s，1H)，4.91(m，1H)，3.28-3.54(dd，2H)，1.57-1.65(d，6H)
2, the preparation of the inferior isopropyl ester of (S)-2-(4 '-oxo-3 ', 4 '-O-isopropylidene-3 ', 4 '-dihydroxyl-1 '-hydroxyl-alkene)-propanedioic acid ring (4):
15.4g compound (3), the acid of 19.8g Michaelis and 11.1ml pyridine are dissolved in the 200ml THF, and 0 ℃ of stirring reaction 48h concentrates and obtains 10.3g yellow oil bullion.
Get part bullion column chromatography and obtain the pure article of the inferior isopropyl ester (4) of faint yellow oily thing (S)-2-(4 '-oxo-3 ', 4 '-O-isopropylidene-3 ', 4 '-dihydroxyl-1 '-hydroxyl-alkene)-propanedioic acid ring.
MS：300(M)
1H-NMR(CDCl3)：15.66(s，1H)，4.97(m，1H)，3.77-3.82(m，1H)，3.60-3.66(m，1H)，1.75(d，6H)，1.62(s，3H)，1.57(s，3H)
3, (S)-3,6-dioxo-5,6-isopropylidene-5, the preparation of 6-dihydroxyl hecanoic acid t-butyl ester (5):
In 9.3g compound (4) bullion, add the 100mL trimethyl carbinol and make it dissolving, backflow 2h concentrates and obtains yellow oil 3.8g.Get part bullion column chromatography and obtain faint yellow oily thing (S)-3,6-dioxo-5,6-isopropylidene-5, the pure article of 6-dihydroxyl hecanoic acid t-butyl ester (5).
MS：290(M+NH4+)
1H-NMR(DMSO-d6)：4.79-4.82(m，1H)，3.52(s，2H)，3.15-3.23(m，1H)，2.98-3.06(m，1H)，1.52(s，6H)，1.41(s，9H)
Be raw material with compound (5) then, with reference to U.S. Pat 5,214,197 disclosed methods prepare target compound (1).
Embodiment 3
1, (S)-2,2-dimethyl--5-oxo-1, the preparation of 3-dioxa-4-acetyl imidazole (3):
20g compound (2) is dissolved in the 200ml THF, adds 55.8g fmoc-2 imidazole (CDI), behind 10 ℃ of reaction 5h, concentrate and obtain the 28g yellow solid; Recrystallization obtains 18g white plates solid (S)-2 then, 2-dimethyl--5-oxo-1,3-dioxa-4-acetyl imidazole (3).mp：126.5～128.4℃。
MS：225(M+1)
1H-NMR(CDCl3)：8.18(s，1H)，7.48(s，1H)，7.13(s，1H)，4.91(m，1H)，3.28-3.54(dd，2H)，1.57-1.65(d，6H)
2, the preparation of the inferior isopropyl ester of (S)-2-(4 '-oxo-3 ', 4 '-O-isopropylidene-3 ', 4 '-dihydroxyl-1 '-hydroxyl-alkene)-propanedioic acid ring (4):
18g compound (3), the acid of 34.7g Michaelis and 24.3g triethylamine are dissolved in the 250ml acetonitrile, and 80 ℃ of stirring reaction 1h concentrate and obtain 7.2g yellow oil bullion.
Get part bullion column chromatography and obtain the pure article of the inferior isopropyl ester (4) of faint yellow oily thing (S)-2-(4 '-oxo-3 ', 4 '-O-isopropylidene-3 ', 4 '-dihydroxyl-1 '-hydroxyl-alkene)-propanedioic acid ring.
MS：300(M)
1H-NMR(CDCl3)：15.66(s，1H)，4.97(m，1H)，3.77-3.82(m，1H)，3.60-3.66(m，1H)，1.75(d，6H)，1.62(s，3H)，1.57(s，3H)
3, (S)-3,6-dioxo-5,6-isopropylidene-5, the preparation of 6-dihydroxyl hecanoic acid t-butyl ester (5):
In 6.2g compound (4) bullion, add the 100mL trimethyl carbinol and make it dissolving, backflow 20h concentrates and obtains yellow oil 3.4g.Get part bullion column chromatography and obtain faint yellow oily thing (S)-3,6-dioxo-5,6-isopropylidene-5, the pure article of 6-dihydroxyl hecanoic acid t-butyl ester (5).
MS：290(M+NH4+)
1H-NMR(DMSO-d6)：4.79-4.82(m，1H)，3.52(s，2H)，3.15-3.23(m，1H)，2.98-3.06(m，1H)，1.52(s，6H)，1.41(s，9H)
Be raw material with compound (5) then, with reference to U.S. Pat 5,214,197 disclosed methods prepare target compound (1).
Embodiment 4
(S)-3,6-dioxo-5,6-isopropylidene-5, the preparation of 6-dihydroxyl NSC 8882 (5)
Make compound (4) according to embodiment 1.
In 10g compound (4) bullion, add 100mL ethanol and make it dissolving; Backflow
5h concentrates and obtains yellow oil 4.6g.Get part bullion column chromatography and obtain faint yellow oily thing (S)-3,6-dioxo-5,6-isopropylidene-5, the pure article of 6-dihydroxyl NSC 8882 (5).
1H-NMR(DMSO-d6)：4.79-4.82(m，1H)，4.22(q，2H)，3.52(s，2H)，3.15-3.23(m，1H)，2.98-3.06(m，1H)，1.52(s，6H)，1.3(t，3H)
Embodiment 5
(S)-3,6-dioxo-5,6-isopropylidene-5, the preparation of 6-dihydroxyl methyl caproate (5)
Make compound (S)-3 according to embodiment 4,6-dioxo-5,6-isopropylidene-5,6-dihydroxyl methyl caproate (5).
Claims (5)
1. preparation (3R, 5S)-3,5-O-isopropylidene-3,5, the method for 6-trihydroxy caproic acid verivate is characterized in that, comprises the steps:
(1) protect the compound (2) of hydroxyl in solvent, to react L MALIC ACID and make (S)-2 with fmoc-2 imidazole (CDI), 2-dimethyl--5-oxo-1,3-dioxa-4-acetyl imidazole is compound (3);
(2) with compound (3) and Michaelis acid in solvent, basic catalyst reacts down, makes (S)-2-(4 '-oxo-3 ', 4 '-O-isopropylidene-3 ', 4 '-dihydroxyl-1 '-hydroxyl-alkene)-propanedioic acid ring Asia isopropyl ester, be compound (4);
The mole dosage of Michaelis acid is 1-3 a times of compound (3), and the temperature of reaction is 0～80 ℃, reaction times 1～48h;
Said basic catalyst is selected from secondary amine or tertiary amine, and the mole dosage of basic catalyst is 1-3 a times of compound (3);
(3) with compound (4) and ROH reaction, make (S)-3,6-dioxo-5,6-isopropylidene-5,6-dihydroxyl hecanoic acid t-butyl ester is compound (5);
(4) be raw material with compound (5) then, preparation target compound (1), reaction expression is following:
Wherein, ROH is the trimethyl carbinol.
2. method according to claim 1 is characterized in that, in the step (1), said solvent is selected from chlorinated solvent, ether solvent, esters solvent or nitrile solvents.
3. method according to claim 1 is characterized in that, in the step (1), the mole dosage of CDI is 1-3 a times of compound (2), and temperature of reaction is 10～70 ℃, and the reaction times is 1～5 hour.
4. method according to claim 1 is characterized in that, in the step (2), said solvent is selected from chlorinated solvent, ether solvent, esters solvent or nitrile solvents.
5. method according to claim 1 is characterized in that, in the step (3), compound (4) and excessive ROH is reacted reaction times 2～20h under reflux state.
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| CN2009100501150ACN101538261B (en) | 2009-04-28 | 2009-04-28 | Method for preparing (3R, 5S)-3, 5-O-isopropylidene-3, 5, 6-trihydroxy caproic acid hexylic acid derivative |
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| CN102617540A (en)* | 2012-04-19 | 2012-08-01 | 江苏施美康药业有限公司 | Method for preparing (S)-3,6-dioxo-5,6-isopropylidene-5,6-dyhydroxyl hexanoic acid tert-butyl ester |
| CN105566257B (en)* | 2016-01-04 | 2017-10-17 | 成都丽凯手性技术有限公司 | A kind of industrialized process for preparing of high-optical-purity acetyl group tetrahydrofuran |
| CN108409561B (en)* | 2017-05-11 | 2022-03-29 | 厦门本素药业有限公司 | Preparation method of 5-aminolevulinic acid hydrochloride and intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0374922A2 (en)* | 1988-12-21 | 1990-06-27 | Kanegafuchi Chemical Industry Co., Ltd. | Process for the production of 3,5,6-trihydroxyhexanoic acid derivative |
| US5214197A (en)* | 1990-07-06 | 1993-05-25 | Kanegafuchi Chemical Industry Co., Ltd. | 2,4-dihydroxyadipic acid derivative |
- 2009
- 2009-04-28CNCN2009100501150Apatent/CN101538261B/enactiveActive
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0374922A2 (en)* | 1988-12-21 | 1990-06-27 | Kanegafuchi Chemical Industry Co., Ltd. | Process for the production of 3,5,6-trihydroxyhexanoic acid derivative |
| US5214197A (en)* | 1990-07-06 | 1993-05-25 | Kanegafuchi Chemical Industry Co., Ltd. | 2,4-dihydroxyadipic acid derivative |
Non-Patent Citations (3)
| Title |
|---|
| -keto esters.《J.Org.Chem.》.1978,第43卷(第10期),2087-2088. |
| Yuji Oikawa et al..Meldrum’s acid in organic synthesis.2, A General and Versatile synthesis of ß |
| Yuji Oikawa et al..Meldrum’s acid in organic synthesis.2, A General and Versatile synthesis of ß-keto esters.《J.Org.Chem.》.1978,第43卷(第10期),2087-2088.* |
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