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 derivative Download PDFInfo
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- CN101538261B CN101538261B CN2009100501150A CN200910050115A CN101538261B CN 101538261 B CN101538261 B CN 101538261B CN 2009100501150 A CN2009100501150 A CN 2009100501150A CN 200910050115 A CN200910050115 A CN 200910050115A CN 101538261 B CN101538261 B CN 101538261B
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- 238000000034 method Methods 0.000 title claims abstract description 22
- -1 caproic acid hexylic acid derivative Chemical class 0.000 title claims abstract description 21
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 239000002904 solvent Substances 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 229940116298 l- malic acid Drugs 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 150000002825 nitriles Chemical class 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 2
- 150000003335 secondary amines Chemical group 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 6
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 abstract 2
- XLWBIEWPSIQQTL-YFKPBYRVSA-N CC(=O)[C@@H]1OC(C)(C)OC1=O Chemical compound CC(=O)[C@@H]1OC(C)(C)OC1=O XLWBIEWPSIQQTL-YFKPBYRVSA-N 0.000 abstract 2
- 239000000463 material Substances 0.000 abstract 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 abstract 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 abstract 1
- 150000002440 hydroxy compounds Chemical class 0.000 abstract 1
- 235000011090 malic acid Nutrition 0.000 abstract 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 abstract 1
- NUKZAGXMHTUAFE-UHFFFAOYSA-N methyl hexanoate Chemical compound CCCCCC(=O)OC NUKZAGXMHTUAFE-UHFFFAOYSA-N 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 239000012141 concentrate Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 3
- 159000000003 magnesium salts Chemical class 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 229940043232 butyl acetate Drugs 0.000 description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- SHZIWNPUGXLXDT-UHFFFAOYSA-N ethyl hexanoate Chemical compound CCCCCC(=O)OCC SHZIWNPUGXLXDT-UHFFFAOYSA-N 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 229960002797 pitavastatin Drugs 0.000 description 2
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229960000672 rosuvastatin Drugs 0.000 description 2
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- LSZFPMUWINOMFL-UHFFFAOYSA-N C(C)(C)(C)[Li].C(C)(=O)O Chemical compound C(C)(C)(C)[Li].C(C)(=O)O LSZFPMUWINOMFL-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002512 suppressor factor Substances 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing (3R, 5S)-3, 5-O-isopropylidene-3, 5, 6-trihydroxy caproic acid hexylic acid derivative, including the following steps: (1) L-malic acid protected hydroxy compound and carbonyl diimidazole (CD I) react in solvent to obtain (S)-2,2- dimethyl-5-oxo-1, 3-dioxa-4-acetyl imidazole; (2) the (S)-2,2- dimethyl-5-oxo-1, 3-dioxa-4-acetyl imidazole and Meldrum's acid react in the solvent under the existence of basic catalyst to prepare (S)-2-(4'-oxo-3', 4'-O-isopropylidene-3', 4'-dihydroxy-1'-hydroxy-alkene)-malonic acid cyclic isopropylidene ester; (3) the (S)-2-(4'-oxo-3',4'-O-isopropylidene-3',4'-dihydroxy-1'-hydroxy-alkene)-malonic acid cyclic isopropylidene ester reacts with methanol to prepare (S)-3, 6-dioxo-5, 6-isopropylidene-5, 6-dihydroxy tert-butyl ester hexanoate; and a target compound can be obtained after further reaction. The method has the advantages of easy acquisition of materials, moderate reaction condition, less material consumption, high product quality and yield and easy implementation of industrialization.
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-C
1-C
5-alkyl, unsaturated-C
2-C
5-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-C
1-C
5-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-C
1-C
5-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(CDCl
3)：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(CDCl
3)：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+NH
4 +)
1H-NMR(DMSO-d
6)：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(CDCl
3)：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(CDCl
3)：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+NH
4 +)
1H-NMR(DMSO-d
6)：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(CDCl
3)：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(CDCl
3)：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+NH
4 +)
1H-NMR(DMSO-d
6)：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-d
6)：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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| CN2009100501150A CN101538261B (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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| 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
- 2009-04-28 CN CN2009100501150A patent/CN101538261B/en active Active
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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