CN101747312B - Preparation method of (3R, 5S)-3,5,6-3-hydroxy-ethyl hexanoate derivative - Google Patents
Preparation method of (3R, 5S)-3,5,6-3-hydroxy-ethyl hexanoate derivative Download PDFInfo
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- CN101747312B CN101747312B CN 200810204427 CN200810204427A CN101747312B CN 101747312 B CN101747312 B CN 101747312B CN 200810204427 CN200810204427 CN 200810204427 CN 200810204427 A CN200810204427 A CN 200810204427A CN 101747312 B CN101747312 B CN 101747312B
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- ethyl ester
- acid
- caproic acid
- isopropylidene
- acid ethyl
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Abstract
The invention provides a preparation method of a (3R, 5S)-3,5,6-3-hydroxy-ethyl hexanoate derivative. In the method, (3R, 5S)-5,6-O-isopropylidene-3,5,6-3-hydroxy-ethyl hexanoate reacts with a benzaldehyde derivative in the presence of acid to prepare the (3R, 5S)-3,5,6-3-hydroxy-ethyl hexanoate derivative. The invention has the advantages of simple and short route, simple and convenient operation and high atom economy.
Description
Technical field
The present invention relates to statins synthetic intermediate (3R, 5S)-3,5, the preparation method of 6-trihydroxy caproic acid ethyl ester derivative
Background technology
6-position hydroxyl is without (3R, 5S)-3,5 of protection, and 6-trihydroxy caproic acid ethyl ester derivative is the intermediate of synthetic statins, and its chemical structure is suc as formula shown in the II, and the synthetic method of its analogue of bibliographical information has following a few class.
Nineteen ninety; Wess etc. [Tetrahedron Lett., 1990,31 (18): 2545-2548] are when synthetic Cerivastatin; (3R; 5S)-3,5-dihydroxy compound V makes VI through the 2,2-dimethoxypropane protection; VI makes 6-position hydroxyl without the (3R of protection through tetrabutyl ammonium fluoride desiliconization protecting group; 5S)-3,5,6-trihydroxy caproic acid ester derivative VII.
Nineteen ninety-five; [the Synthesis such as Beck; 1995 (8): 1014-1018] report (3R; 5S)-3,5-dihydroxy compound VIII makes IX through the 2,2-dimethoxypropane protection; IX takes off benzyl through the palladium charcoal and makes 6-position hydroxyl without the (3R of protection; 5S)-3,5,6-trihydroxy caproic acid ester derivative VII.
[WO2005047276, the 2005-05-26 such as Tararov; Adv.Synth.Catal., 2006,348 (18): 2633-2644.] report Ru[(R)-and BINAP] Cl2NEt3 is I with X asymmetry catalysis hydrogen, de% is greater than 99; I makes XI through the TERT-BUTYL DIMETHYL CHLORO SILANE protection, and XI is again in AcOH-H
2Lactonize among the O and make 6-position hydroxyl without (3R, 5S)-3,5 of protection, 6-trihydroxy caproic acid ester derivative XII.
Aforesaid method is at (the 3R of preparation 6-position hydroxyl without protection; 5S)-3; 5; during 6-trihydroxy caproic acid ester derivative, all need selective protection 3, the 5-dihydroxyl; and then slough 6-position hydroxyl protecting group; experience altogether two-step reaction and make, increased operating process and reagent cost, be not easy to the mass-producing preparation.
Summary of the invention
The technical issues that need to address of the present invention provide a kind of structural formula suc as formula the (3R of the 6-position hydroxyl shown in the II without protection; 5S)-3; 5; the preparation method of 6-trihydroxy caproic acid ethyl ester derivative; the defective that exists to overcome above-mentioned prior art provides the preparation method who more is conducive to large-scale production.
Wherein:
R
1Be the substituting group on the phenyl ring, such as hydrogen, methyl, nitro or contain the alkoxyl group of 1～6 carbon atom;
Provided by the present invention for the preparation of (3R, 5S)-3,5 of the 6-position hydroxyl shown in the formula II without protection, the technical scheme of 6-trihydroxy caproic acid ethyl ester derivative is as follows.
(3R shown in Formula I; 5S)-5; 6-O-isopropylidene-3,5,6-trihydroxy caproic acid ethyl ester react the (3R that makes shown in Formulae II with benzaldehyde derivative in the presence of acid; 5S)-3; 5,6-trihydroxy caproic acid ethyl ester derivative, a step realizes 5; it is unprotected 3 that the 6-ketal is converted into 6-position hydroxyl, the 5-acetal.
In the technical scheme shown in the background technology; (namely first with 3 with the selective protection of hydroxyl and deprotection reaction; the protection of 5-dihydroxyl; and then slough 6-position hydroxyl protecting group and experience altogether two-step reaction) proceed step by step; prepare 6-position hydroxyl without the (3R of protection with this; 5S)-3,5,6-trihydroxy caproic acid ethyl ester derivative.The present invention then in the presence of acid the reaction of I and benzaldehyde derivative make (3R shown in Formulae II; 5S)-3; 5; 6-trihydroxy caproic acid ethyl ester derivative; one step realized 5; it is unprotected 3 that the 6-ketal is converted into 6-position hydroxyl, the 5-acetal, and this process namely can be described as the zone conversion of hydroxyl protecting group.Thus, synthetic route of the present invention is brief, easy and simple to handle, and Atom economy is high.
Shown in the following formula III of the chemical structure of the described benzaldehyde derivative that adopts in this building-up reactions or the IV:
Usually, the substituting group among structural formula II I or the structural formula IV has as giving a definition:
R
1Be the substituting group on the phenyl ring, such as hydrogen, methyl, nitro or contain the alkoxyl group of 1～6 carbon atom, preferably, R
1Be hydrogen;
R
2Be methyl or ethyl.
In the present invention, the benzaldehyde derivative that adopts in the described reaction and (3R, 5S)-5,6-O-isopropylidene-3,5, the molar ratio of 6-trihydroxy caproic acid ethyl ester is 1: 1～3: 1.
The consumption that increases benzaldehyde derivative is conducive to add fast response, too much causes unnecessary waste and cost to increase but increase; The consumption that reduces benzaldehyde derivative is conducive to save production cost, and too much causes easily reaction not exclusively but reduce, for the separation and purification of product brings difficulty.
It will be understood by those skilled in the art that above-mentioned molar ratio provided by the present invention can be used for realizing technical scheme of the present invention, but other numerical value of not getting rid of outside this molar ratio scope also can be for the possibility that realizes technical solution of the present invention.When practical application, those skilled in the art can adjust concrete numerical value as required.Other numerical range that occurs herein also should be done same understanding.
In the present invention, the acid of adopting in the described reaction is selected from one or more following acid: tosic acid, camphorsulfonic acid, methanesulfonic, hydrochloric acid; Preferred camphorsulfonic acid and/or tosic acid.Its consumption is with respect to described (3R, 5S)-5,6-O-isopropylidene-3,5, and 6-trihydroxy caproic acid ethyl ester is 1～50mol%, is preferably 5～15mol%.
The present invention carries out in solvent, is fit to organic solvent of the present invention and is selected from one or more following solvents: methylene dichloride, chloroform, ethyl acetate, butylacetate; Preferred methylene dichloride is as reaction solvent.
Compared with prior art; it is brief, easy and simple to handle that the present invention has route; the Atom economy advantages of higher has been avoided first 3,5-dihydroxyl being protected; and then slough 6-position hydroxyl protection experience altogether two-step reaction prepare 6-position hydroxyl without the protection (3R; 5S)-3,5, the process of 6-trihydroxy caproic acid ester derivative; so that route of the present invention is brief, easy and simple to handle, Atom economy is high.
Embodiment
Further specify the present invention below by embodiment, but these embodiment do not consist of any restriction to the present invention.
Embodiment 1
1) preparation (3R, 5S)-5,6-O-isopropylidene-3,5,6-trihydroxy caproic acid ethyl ester
(3R, 5S) of the present invention-5,6-O-isopropylidene-3,5,6-trihydroxy caproic acid ethyl ester can be with reference to [WO2005047276,2005-05-26 such as Tararov; Adv.Synth.Catal., 2006,348 (18): 2633-2644.] method of report is prepared, and its building-up process is shown below:
Use Ru[(R)-BINAP] Cl
2NEt
3Be (3R, 5S)-5 with compound asymmetric catalytic hydrogenation shown in the chemical formula X, 6-O-isopropylidene-3,5,6-trihydroxy caproic acid ethyl ester, de% is greater than 99; Wherein the preparation method of compounds X can be with reference to Chinese patent 200610025601.3 (2006-04-11).
2) preparation (3R, 5S)-3,5,6-trihydroxy caproic acid ethyl ester derivative
With step 1) in (3R, 5S)-5 that obtain, 6-O-isopropylidene-3,5,6-trihydroxy caproic acid ethyl ester (de%=99,3.0g, 12.9mmol), CSA (camphorsulfonic acid, 0.30g) and phenyl aldehyde (formula IV compound R
1=H, 3.45g, 32.5mmol) be dissolved in the methylene dichloride (50ml), stirring at room 30 hours is used saturated NaHCO
3The aqueous solution (40ml) washing, water layer extracts with methylene dichloride (30ml * 2), after organic layer merges successively through saturated common salt water washing, anhydrous MgSO
4Dry, concentrated, silica gel column chromatography (eluent: sherwood oil: ethyl acetate=2: 1) obtain the compound (R shown in the 2.83g Formulae II
1=H), yield 78.2%.[α]
D 21-15.60°(c?1.00，EtOH)；ESI-MS?m/z：[M+Na]
+?303.1；
1H-NMR(CDCl
3)：δ1.26(t，3H，CO
2CH
2C
H 3)，1.55-1.69(m，2H，CHC
H 2CH)，1.95(brs，1H，OH)，2.54(dd，1H，C
H 2CO
2)，2.73(dd，1H，C
H 2CO
2)，3.64-3.74(m，2H，HOC
H 2)，4.03(m，1H，HOCH
2C
H)，4.16(q，2H，CO
2C
H 2CH
3)，4.51(m，1H，C
HCH
2CO)，5.61(s，1H，PhC
H)，7.25-7.49(m，5H，Ph-H).
Embodiment 2
In the present embodiment, (3R, 5S)-5,6-O-isopropylidene-3,5, the preparation method of 6-trihydroxy caproic acid ethyl ester can be with reference to the step 1 of embodiment 1).(3R, the 5S) that then will prepare-5,6-O-isopropylidene-3,5,6-trihydroxy caproic acid ethyl ester (de%=99,3.0g, 12.9mmol), tosic acid (0.20g) and benzaldehyde dimethyl acetal (formula III compound R
1=H, R
2=CH
3, 3.93g, 25.8mmol) be dissolved in the methylene dichloride (50ml), stirring at room 30 hours is used saturated NaHCO
3The aqueous solution (40ml) washing, water layer extracts with methylene dichloride (30ml * 2), after organic layer merges successively through saturated common salt water washing, anhydrous MgSO
4Dry, concentrated, silica gel column chromatography (eluent: sherwood oil: ethyl acetate=2: 1) obtain the compound (R shown in the 2.87g Formulae II
1=H), yield 79.3%.[α]
D 21-15.60°(c1.00，EtOH)；ESI-MS?m/z：[M+Na]
+?303.1；
1H-NMR(CDCl
3)：δ1.26(t，3H，CO
2CH
2C
H 3)，1.55-1.69(m，2H，CHC
H 2CH)，1.95(br?s，1H，OH)，2.54(dd，1H，C
H 2CO
2)，2.73(dd，1H，C
H 2CO
2)，3.64-3.74(m，2H，HOC
H 2)，4.03(m，1H，HOCH
2C
H)，4.16(q，2H，CO
2C
H 2CH
3)，4.51(m，1H，C
HCH
2CO)，5.61(s，1H，PhC
H)，7.25-7.49(m，5H，Ph-H).
Embodiment 3
1) preparation (3R, 5S)-5,6-O-isopropylidene-3,5,6-trihydroxy caproic acid ethyl ester
(3R of the present invention, 5S)-5,6-O-isopropylidene-3,5,6-trihydroxy caproic acid ethyl ester also can be by the Raney-Ni[(R of following preparation method with the tartrate modification, R)-and TA-NaBr-MRNi-U] be (3R with the compounds X asymmetric catalytic hydrogenation, 5S)-5,6-O-isopropylidene-3,5,6-trihydroxy caproic acid ethyl ester, de% are 48.
The preparation of catalyzer (R, R)-TA-NaBr-MRNi-U:
The preparation of Raney-Ni-U: 45.0g sodium hydroxide is dissolved in the 200ml water, add 19.0g alumel (nickel content: 40～50%) under the ice-water bath in batches, added in about 15 minutes, be stirred to and be warming up to 100 ℃ of lower stirrings 1 hour after the bubble emitting rate slows down slowly, be chilled to room temperature, under magnet is auxiliary, pour out water layer, use again the distilled water wash catalyzer, each 300ml is until neutral.Gained Raney-Ni is soaked in the 200ml distilled water, with ultrasonic wave (200W, 59kHz) washing 3 minutes, pours out water layer, and this operation repeats twice, namely makes Raney-Ni-U.
Modify the preparation of solution: in (R, R)-tartrate (12.0g), Sodium Bromide (120.0g) water-soluble (1200ml), use again the NaOH aqueous solution (about 100ml) the adjusting pH to 3.2 of 1N to get final product.
(R, R)-and the preparation of TA-NaBr-MRNi-U: above-mentioned gained modified descend modification 30 minutes in 100 ℃ after 50% of solution mixes with Raney-Ni-U, pour out water layer, with the 200ml distilled water wash once, again with remaining 50% modification solution in 100 ℃ of lower modifications 30 minutes, pour out water layer, use again distilled water (100ml * 2), methyl alcohol (100ml * 2), THF (100ml * 2) washing, namely make catalyzer (R, R)-and TA-NaBr-MRNi-U, be kept among the THF for subsequent use.
(3R, 5S)-5,6-O-isopropylidene-3,5, the preparation of 6-trihydroxy caproic acid ethyl ester (I):
With compound (20.0g shown in the formula X, 86.9mmol), catalyzer (R, R)-TA-NaBr-MRNi-U (4.0g, weight in wet base), THF (200ml) and Glacial acetic acid (2ml) are put in the hydriding reactor of 500ml, be 8.0Mpa at hydrogen pressure, temperature is 100 ℃ of lower hydrogenations 24 hours, adds ethyl acetate (400ml) dilute reaction solution after being chilled to room temperature, through saturated NaHCO
3The aqueous solution (100ml), saturated aqueous common salt (100ml) washing are used ethyl acetate (100ml) extraction once again after the gained water layer merges, organic layer merges by anhydrous MgSO
4Drying, the concentrated 19.31g oily matter that to get, de% is 48, yield 97.3%.ESI-MSm/z：[M+Na]
+?255.1；
1H-NMR(CDCl
3)：δ1.26(m，3H，CO
2CH
2C
H 3)，1.35(s，3H，C(C
H 3)
2)，1.39-1.42(s+s，3H，C(C
H 3)
2)，1.71-1.79(m，2H，CHC
H 2CH)，2.43-2.57(m，2H，C
H 2CO
2Et)，3.19(s，0.74H，OH?for(3S，5S))，3.39(s，0.26H，OH?for(3R，5S))，3.55-3.60(m，1H，OC
H 2CH)，4.09(dd，1H，OC
H 2CH)，4.17(m，2H，CO
2C
H 2CH
3)，4.20(m，1H，C
HOH)，4.30(m，1H，OCH
2C
H).
With (3R, 5S)-5,6-O-isopropylidene-3,5,6-trihydroxy caproic acid ethyl ester (4.0g, 17.4mmol), CSA (camphorsulfonic acid, 0.30g) and phenyl aldehyde (be formula IV compound R
1=H, 3.69g, 34.8mmol) be dissolved in the methylene dichloride (60ml), stirring at room 30 hours is used saturated NaHCO
3The aqueous solution (40ml) washing, water layer extracts with methylene dichloride (30ml * 2), after organic layer merges successively through saturated common salt water washing, anhydrous MgSO
4Dry, concentrated, silica gel column chromatography (eluent: sherwood oil: ethyl acetate=2: 1) obtain the compound (R shown in the 1.84g Formulae II
1=H), yield 51.5%.[α]
D 21-15.60°(c1.00，EtOH)；ESI-MS?m/z：[M+Na]
+?303.1；
1H-NMR(CDCl
3)：δ1.26(t，3H，CO
2CH
2C
H 3)，1.55-1.69(m，2H，CHC
H 2CH)，1.95(br?s，1H，OH)，2.54(dd，1H，C
H 2CO
2)，2.73(dd，1H，C
H 2CO
2)，3.64-3.74(m，2H，HOC
H 2)，4.03(m，1H，HOCH
2C
H)，4.16(q，2H，CO
2C
H 2CH
3)，4.51(m，1H，C
HCH
2CO)，5.61(s，1H，PhC
H)，7.25-7.49(m，5H，Ph-H).
Claims (8)
1. one kind by (3R, 5S)-5,6-O-isopropylidene-3,5, and 6-trihydroxy caproic acid ethyl ester preparation (3R, 5S)-3,5, the method for 6-trihydroxy caproic acid ethyl ester derivative,
It is characterized in that (3R, 5S) shown in the formula I-5,6-O-isopropylidene-3,5,6-trihydroxy caproic acid ethyl ester make (3R shown in the formula II with the benzaldehyde derivative reaction with structure shown in following formula III or the IV under the catalysis of acid, 5S)-3,5,6-trihydroxy caproic acid ethyl ester derivative;
Shown in the following formula III of the chemical structure of described benzaldehyde derivative or the IV:
Wherein:
R
1Be the substituting group on the phenyl ring, be selected from hydrogen, methyl, nitro or contain the alkoxyl group of 1～6 carbon atom;
R
2Be methyl or ethyl.
2. method according to claim 1 is characterized in that, used benzaldehyde derivative and (3R, 5S)-5, and 6-O-isopropylidene-3,5, the molar ratio of 6-trihydroxy caproic acid ethyl ester is 1: 1～3: 1.
3. method according to claim 1 and 2 is characterized in that, described acid is selected from one or more following acid: tosic acid, camphorsulfonic acid, methanesulfonic, hydrogenchloride.
4. method according to claim 3 is characterized in that, described acid is preferably camphorsulfonic acid and/or tosic acid.
5. method according to claim 3 is characterized in that, the consumption of described acid is with respect to (3R, 5S)-5,6-O-isopropylidene-3,5, and 6-trihydroxy caproic acid ethyl ester is 1～50mol%.
6. method according to claim 5 is characterized in that, the consumption of described acid is with respect to (3R, 5S)-5,6-O-isopropylidene-3,5, and 6-trihydroxy caproic acid ethyl ester is 5～10mol%.
7. method according to claim 1 and 2 is characterized in that, described reaction is carried out in organic solvent, and this organic solvent is selected from one or more following solvents: methylene dichloride, chloroform, ethyl acetate, butylacetate.
8. method according to claim 7 is characterized in that, described reaction is carried out in methylene dichloride.
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| CN101747312B true CN101747312B (en) | 2013-02-06 |
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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 |
| CN1878763A (en) * | 2003-11-11 | 2006-12-13 | 拉蒂奥法姆有限责任公司 | Method for the production of statins |
-
2008
- 2008-12-11 CN CN 200810204427 patent/CN101747312B/en not_active Expired - Fee Related
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 |
| CN1878763A (en) * | 2003-11-11 | 2006-12-13 | 拉蒂奥法姆有限责任公司 | Method for the production of statins |
Non-Patent Citations (1)
| Title |
|---|
| G. Wess, et al.STEREOSELECTIVE SYNTHESIS OF HR 780 A NEW HIGHLY POTENT HMG-COA REDUCTASE INHIBITOR.《Tetrahedron Letters》.1990,第31卷(第18期),2545-2548. * |
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