CN101148433B - Method for synthesizing pentadecanol - Google Patents
Method for synthesizing pentadecanol Download PDFInfo
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- CN101148433B CN101148433B CN2006101162600A CN200610116260A CN101148433B CN 101148433 B CN101148433 B CN 101148433B CN 2006101162600 A CN2006101162600 A CN 2006101162600A CN 200610116260 A CN200610116260 A CN 200610116260A CN 101148433 B CN101148433 B CN 101148433B
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- ethoxy
- pentadecanol
- tetramethyl
- methyl
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention provides improved synthesis process of important pentadecyl alcohol intermediate of astaxanthin. The process includes organic amine catalyzed condensation reaction and the subsequent deprotection reaction, has mild reaction conditions and yield over 98 %, and is suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical intermediate, particularly the synthetic method of astaxanthin intermediate pentadecanol.
Background technology
Astaxanthin is the carotenoid of non-provitamin A, is widely used in the production of healthcare products, medicine, makeup, food and fodder additives etc.In food, not only can be painted, can also play fresh-keepingly effectively, prevent variable color, spoiled, rotten effect, also can be used for the painted of beverage, food, condiment etc.In addition, astaxanthin has gorgeous color, and it can combine with the non-specially property of Actin muscle, is widely used at present in the aquatic feeds, can improve the skin and the muscle color and luster of cultured fishes, increases the resistance against diseases of fish and shrimp.
What the production method of astaxanthin was commonly used has following two kinds, and a kind of is the fermented extracted method, and a kind of is chemical synthesis.The fermented extracted method is little owing to output, the cost height, and occupancy volume is very little on market, thereby present astaxanthin more than 90% all is to obtain by chemical synthesis.
The synthetic method of existing industrial feasible astaxanthin is at document Ep5748; Helv.chim.acta64 (1981), 2436; US5455362; Pure.Appl.Chem.Vol74, No8, pp1369-1382 all is described in 2002, adopts C
9+ C
6→ C
15C
15+ C
10+ C
15→ C
40, concrete synthetic method is as follows: reaction formula
In above route; A is the C9 synthesis unit; be the hydroxyl protection compound of C9 cyclonene, B and C are the C6 synthesis unit, i.e. the hydroxyl protection compound of C6 alkynyl compounds; C9+C6 → C15; at Helv.chim.acta 64 (1981), in 2436 documents carrying out of system butyllithium and Grignard reagent relatively, clear and definite preferred butyllithium; in this case, theoretical yield is 85.6%.In US5455362, carry out the condensation reaction of C9+C6 → C15 with lithium amide, though reaction conditions than using the butyllithium gentleness, yield does not improve a lot yet.
Summary of the invention
Technical problem to be solved by this invention is the defective that overcomes above-mentioned prior art, and a kind of high yield reaction method of astaxanthin intermediate pentadecanol is provided.
Technical scheme of the present invention is: use the synthetic C of organic amine catalysis
15, described organic amine can be monoamine or diamines, all is the small molecules organic amine: triethylamine, propylene diamine, Tetramethyl Ethylene Diamine, quadrol or dimethylamine.
The invention provides the synthetic of a kind of synthetic method of astaxanthin intermediate pentadecanol and astaxanthin, this method is as shown in the formula expression:
Reaction formula two:
What the present invention solved is to improve C
9+ C
6→ C
15The yield that under butyllithium, prepares, the present invention under the catalysis of organic amino, the reaction conditions gentleness, yield is more than 98%.
C
9Unitary preparation:
3; 4-dihydroxyl-2,6,6-trimethylammonium-2-tetrahydrobenzene-1-ketone is dissolved in the dichloromethane solvent; mole proportioning 1: 4.5-5.0; at room temperature, add the tosic acid of catalytic amount, restir drips two hydroxy-protecting agent ethyl vinyl ethers; mol ratio is 1: 2; mixed stirring reaction 4 hours, the solution that adds dilute alkali neutralization gets C after extraction concentrates
9The unit.
Amine catalytic preparation C
15The unit:
C
9Unit and C
6The unit is at inert solvent normal hexane, hexanaphthene, tetrahydrofuran (THF) or toluene, under the highly basic butyllithium, and under the catalysis of organic amine, reaction conditions gentleness-20 ℃～10 ℃, 1～4 hour reaction times, C
9Unit and C
6Unitary mol ratio is 1: 1～1.2, and yield is more than 98%.Described amine is small molecules organic amines such as triethylamine, propylene diamine, Tetramethyl Ethylene Diamine, quadrol or dimethylamine.
The acid hydrolysis deprotection:
Hydrolysis removes C under rare strong acid aqueous solution room temperature
15Unit hydroxyl protecting group ethyl vinyl ether obtains the target product pentadecanol, and described rare strong acid aqueous solution is 30% aqueous sulfuric acid, uses dichloromethane extraction after the hydrolysis, and concentrating under reduced pressure obtains pentadecanol after removing and desolvating.
The preparation of astaxanthin:
According to a conventional method, the hydrogenation of pentadecanol acetate zinc powder after the hydrogen bromide halogenation, adds triphenylphosphine and obtains pentadecane triphenyl phosphonium salt, obtains astaxanthin with ten carbon dialdehyde Wittig reaction again.
Embodiment 1:C
9Unitary preparation
With 170g (1.0mol) crystalline 3,4-dihydroxyl-2,6,6-trimethylammonium-2-tetrahydrobenzene-1-ketone is suspended in the 500ml methylene dichloride.At first in this suspension, add 500mg (2.9mmol) tosic acid, under room temperature (RT), in 2 hours time, add 144g (2.0mol) ethyl vinyl ether then.Then mixture is at room temperature stirred 4h, add the sodium hydroxide solution of 100ml5% concentration then.Tell following organic phase, water with the 100ml dichloromethane extraction once merges organic phase, uses the 200ml water washing, and concentrates on Rotary Evaporators.Resistates is dry under the condition of decompression (oil pump), obtains 2,4,6,6-tetramethyl--7,7a-dihydro-6H-benzo [1,3] dioxole-5-ketone, be yellow oil, detect it for pure, detect it with vapor-phase chromatography (GC) and be almost pure with tlc (TLC).
Embodiment 2: triethylamine catalytic preparation C
15The unit
The C9 unit 21.5 gram (0.1mol that embodiment 1 makes, 98%) and compound 121g (0.12mol, 96%) stir in the there-necked flask of 250ml with the normal hexane of 50ml, temperature is-10 ℃, drip the triethylamine of 1ml, logical nitrogen slowly drips 4.2N butyllithium hexane solution 36ml (0.15mol), keeps temperature of reaction to be-10 ℃～-5 ℃ approximately, dropwised in 30 minutes, continue to stir 1 hour, follow the tracks of with tlc (TLC) and detect C
9The unit reacts completely, and is warming up to room temperature, and the water that adds 50m1 stirs, layering, and water divides 2 washings with the normal hexane of 50ml, incorporates organic phase into, and organic phase is extremely neutral with the diluted acid water washing of 100ml.Organic phase is concentrating under reduced pressure under 50 ℃ of water-baths, obtains pink oily matter 45.2g.(90～100Pa), oily warm 100 ℃, boiling point is removed excessive compound 1 at 30～35 ℃ to pink oily matter, obtains the compound 3 of 38.7g, is 96% with vapor-phase chromatography (GC) detection level, and molar yield is 98.3% through high vacuum.
Embodiment 3:1,3 propylene diamine catalytic preparation C
15The unit
The C that embodiment 1 makes
9Unit 21.5 grams (0.1mol, 98%) and compound 221g (0.12mol, 96%) stir in the there-necked flask of 250ml with the hexanaphthene of 50ml, temperature is-10 ℃, drip 1,3 propylene diamine of 2ml, logical nitrogen, slowly drip 4.2N butyllithium cyclohexane solution 36ml (0.15mol), keep temperature of reaction for-20 ℃～-15 ℃ approximately, dropwised in 30 minutes, continue to stir 2 hours, follow the tracks of detection, C with tlc (TLC)
9The unit reacts completely, and is warming up to room temperature, and the water that adds 50ml stirs, layering, and water divides 2 washings with the hexanaphthene of 50ml, incorporates organic phase into, and organic phase is extremely neutral with the diluted acid water washing of 100ml.Organic phase is concentrating under reduced pressure under 50 ℃ of water-baths, obtains pink oily matter 45.5g.(90～100Pa), oily warm 100 ℃, boiling point is removed excessive compound 2 at 30～35 ℃ to pink oily matter, obtains the compound 4 of 38.9g, is 96% with vapor-phase chromatography (GC) detection level, and molar yield is 98.8% through high vacuum.
Embodiment 4: Tetramethyl Ethylene Diamine catalytic preparation C
15The unit
The C that embodiment 1 makes
9Unit 21.5 gram (0.1mol, 98%) and compound 121g (0.12mol, 96%) stir in the there-necked flask of 250ml with the THF of 50ml, temperature is-10 ℃, drip the Tetramethyl Ethylene Diamine of 1ml, logical nitrogen slowly drips 4.2N butyllithium hexane solution 36m1 (0.15mol), keeps temperature of reaction to be-15 ℃～-10 ℃ approximately, dropwised in 30 minutes, continue to stir 1.5 hours, follow the tracks of with tlc (TLC) and detect C
9The unit reacts completely, and is warming up to room temperature, and the water that adds 50ml stirs, layering, and water divides 2 washings with the THF of 50ml, incorporates organic phase into, and organic phase is extremely neutral with the diluted acid water washing of 100ml.Organic phase is concentrating under reduced pressure under 50 ℃ of water-baths, obtains pink oily matter 45.3g.(90～100Pa), oily warm 100 ℃, boiling point is removed excessive compound 1 at 30～35 ℃ to pink oily matter, obtains the compound 3 of 38.7g, is 97% with vapor-phase chromatography (GC) detection level, and molar yield is 99% through high vacuum.
Embodiment 5: quadrol catalytic preparation C
15The unit
The C that embodiment 1 makes
9Unit 21.5 gram (0.1mol, 98%) and compound 221g (0.12mol, 96%) stir in the there-necked flask of 250ml with the toluene of 50ml, temperature is-10 ℃, drip the quadrol of 1.5ml, logical nitrogen slowly drips 4.2N butyllithium hexane solution 36ml (0.15mol), keeps temperature of reaction to be-10 ℃～-5 ℃ approximately, dropwised in 30 minutes, continue to stir 4 hours, follow the tracks of with tlc (TLC) and detect C
9The unit reacts completely, and is warming up to room temperature, and the water that adds 50ml stirs, layering, and water divides 2 washings with the toluene of 50ml, incorporates organic phase into, and organic phase is extremely neutral with the diluted acid water washing of 100ml.Organic phase is concentrating under reduced pressure under 50 ℃ of water-baths, obtains pink oily matter 45.1g.(90～100Pa), oily warm 100 ℃, boiling point is removed excessive compound 2 at 40～42 ℃ to pink oily matter, obtains the compound 3 of 38.3g, is 96% with vapor-phase chromatography (GC) detection level, and molar yield is 97.3% through high vacuum.
Embodiment 6: dimethylamine catalytic preparation C
15The unit
The C that embodiment 1 makes
9Unit 21.5 gram (0.1mol, 98%) and compound 221g (0.12mol, 96%) stir in the there-necked flask of 250ml with the normal hexane of 50ml, temperature is-10 ℃, drip the dimethylamine of 2ml, logical nitrogen slowly drips 4.2N butyllithium hexane solution 36ml (0.15mol), and keeping temperature of reaction is about 0 ℃～5 ℃, dropwised in 30 minutes, continue to stir 1 hour, follow the tracks of with tlc (TLC) and detect C
9The unit reacts completely, and is warming up to room temperature, and the water that adds 50ml stirs, layering, and water divides 2 washings with the normal hexane of 50ml, incorporates organic phase into, and organic phase is extremely neutral with the diluted acid water washing of 100ml.Organic phase is concentrating under reduced pressure under 50 ℃ of water-baths, obtains pink oily matter 45.6g.(90～100Pa), oily warm 100 ℃, boiling point is removed excessive compound 2 at 30～35 ℃ to pink oily matter, obtains the compound 3 of 38.4g, is 96% with vapor-phase chromatography (GC) detection level, and molar yield is 97.5% through high vacuum.
Embodiment 7: the preparation of pentadecanol
The compound 338.7g (0.098mol) that embodiment 2 is obtained is dissolved in the methylene dichloride of 100ml, to the water that wherein adds 35ml, the sulfuric acid that adds 18ml30% concentration then, at room temperature stir and spend the night, tell the organic phase of lower floor, water layer is washed at twice with the methylene dichloride of 25ml, incorporate organic phase into, the NaHCO3 of adding 35ml5% concentration and the water of 35ml are respectively washed once in organic phase, concentrating under reduced pressure organic phase in Rotary Evaporators then, dry oily resistates under high vacuum gets Compound I 21.5g.
Embodiment 8: the preparation of pentadecanol
The compound 338.9g (0.099mol) that embodiment 3 is obtained is dissolved in the methylene dichloride of 100ml, to the water that wherein adds 35ml, the sulfuric acid that adds 18ml30% concentration then, at room temperature stir and spend the night, tell the organic phase of lower floor, water layer is washed at twice with the methylene dichloride of 25ml, incorporate organic phase into, the NaHCO3 of adding 35ml5% concentration and the water of 35ml are respectively washed once in organic phase, concentrating under reduced pressure organic phase in Rotary Evaporators then, dry oily resistates under high vacuum gets Compound I I21.6g.
Embodiment 9: the preparation of astaxanthin
Compound I 26g (0.1mol, 96%) is dissolved in the methylene dichloride of 100ml, is cooled to 0 ℃, add 18g (0.3mol) acetate, stir, added zinc powder 0.5g (adding 8.8g altogether) then at 0 ℃ of interval in 10 minutes in batches, after in the end a collection of zinc powder adds, stirred 45 minutes at 0 ℃.Filter zinc acetate, filter cake is washed secondary with methylene dichloride, uses 25ml at every turn, incorporates in the filtrate, and filtrate water washes twice, each water 50ml.Dripping 25g concentration at 0 ℃ in 30 minutes is the 47%HBr aqueous solution, stirs 30 minutes, and adding 100ml water is told organic phase, and water respectively washes twice with the methylene dichloride of 25ml, incorporates organic phase into, adds the NaHCO of entry 100ml and 5g again
3Solid stirs, layering, and the organic phase water 100ml of lower floor washing adds 1ml1, the 2-butylene oxide ring in organic phase.Be cooled to below 10 ℃, add the 25g triphenylphosphine, stirred 12 hours under the room temperature.Be cooled to below 10 ℃, add ten carbon dialdehyde 7g (0.04mol, 95%), drips 40%NaOH aqueous solution 10ml, stirred 3 hours down at 10 ℃, constantly there is red crystals to separate out, filter, each 50ml washed twice of crystal water is incorporated in the filtrate, add each 50ml extracting twice of methylene dichloride again in filtrate, organic phase water 50ml washs once.Under normal pressure, steam methylene dichloride, add methyl alcohol simultaneously,, be cooled to below 10 ℃ suspension returning 4 hours to 65 ℃ of boiling points, filter crystal, merge the crystal drying, astaxanthin 16.7g, the HPLC detection level is 95.6%.
Claims (2)
1. the synthetic method of a pentadecanol is characterized in that this method comprises the following steps:
(1) C
9Unitary preparation; 3; 4-dihydroxyl-2,6,6-trimethylammonium-2-tetrahydrobenzene-1-ketone is dissolved in the dichloromethane solvent; mole proportioning 1: 4.5-5.0; at room temperature, add the tosic acid of catalytic amount, restir drips two hydroxy-protecting agent ethyl vinyl ethers; mol ratio is 1: 2; mixed stirring reaction 4 hours, the solution that adds dilute alkali neutralization gets C after extraction concentrates
9The unit; Described C
9The unit is 2,4,6,6-tetramethyl--7,7a-dihydro-6H-benzo [1,3] dioxole-5-ketone;
(2) amine catalytic preparation C
15Unit: C
9Unit and C
6The unit under the highly basic butyllithium, under the catalysis of organic amine ,-20 ℃～10 ℃, reacted C 1～4 hour at inert solvent normal hexane, hexanaphthene, tetrahydrofuran (THF) or toluene
9Unit and C
6Unitary mol ratio is 1: 1～1.2; Described C
6The unit is 3-(1-ethoxy ethoxy)-3-Methyl-1-pentene-4-alkynes and 5-(1-ethoxy ethoxy)-3-methyl-pirylene,
Described C
15The unit is 5-[3-(1-ethoxy ethoxy)-3-methyl-4-amylene-1-alkynyl]-2,4,6,6-tetramethyl--5,6,7,7a-tetrahydrochysene-pure and mild the 5-[5-of 6H-benzo [1,3] dioxole-5-(1-ethoxy ethoxy)-3-methyl-pirylene base]-2,4,6,6-tetramethyl--5,6,7,7a-tetrahydrochysene-6H-benzo [1,3] dioxole-5-alcohol;
(3) acid hydrolysis deprotection base: in 30% aqueous sulfuric acid, under room temperature, hydrolysis removes C
15Unit hydroxyl protecting group ethyl vinyl ether is used dichloromethane extraction again, and concentrating under reduced pressure obtains pentadecanol after removing and desolvating.
2. the synthetic method of a kind of pentadecanol according to claim 1 is characterized in that wherein step (2) amine catalytic preparation C
15Amine described in the unitary reaction is triethylamine, propylene diamine, Tetramethyl Ethylene Diamine, quadrol or dimethylamine.
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| CN101148433B true CN101148433B (en) | 2011-01-12 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015067709A1 (en) * | 2013-11-07 | 2015-05-14 | Dsm Ip Assets B.V. | Process for the purification of astaxanthin |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102002033B (en) * | 2010-12-23 | 2013-11-20 | 厦门金达威集团股份有限公司 | Protection method for astaxanthin intermediate |
| CN103288613B (en) * | 2013-05-24 | 2015-07-29 | 广州巨元生化有限公司 | Utilize the method for 2,6,6-trimethylammonium-3,4-dihydroxyl-2-tetrahydrobenzene-1-ketone synthesizing astaxanthin intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1098101A (en) * | 1993-07-05 | 1995-02-01 | Basf公司 | The preparation of astaxanthin, prepare it new intermediate with and preparation |
| US20060183947A1 (en) * | 2004-10-01 | 2006-08-17 | Lockwood Samuel F | Methods for the synthesis of astaxanthin |
-
2006
- 2006-09-20 CN CN2006101162600A patent/CN101148433B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1098101A (en) * | 1993-07-05 | 1995-02-01 | Basf公司 | The preparation of astaxanthin, prepare it new intermediate with and preparation |
| US20060183947A1 (en) * | 2004-10-01 | 2006-08-17 | Lockwood Samuel F | Methods for the synthesis of astaxanthin |
Non-Patent Citations (2)
| Title |
|---|
| Erich Widmer, et al..Technische Verfahren zur Synthese von Carotinoiden undverwandten Verbindungen aus 6-Oxo-isophoron. II. Ein neuesKonzept für die Synthese von (3RS, 3‘RS)-Astaxanthin.Helv. chim. acta64 7.1981,64(7),2436-2446. |
| Erich Widmer, et al..Technische Verfahren zur Synthese von Carotinoiden undverwandten Verbindungen aus 6-Oxo-isophoron. II. Ein neuesKonzept für die Synthese von (3RS, 3‘RS)-Astaxanthin.Helv. chim. acta64 7.1981,64(7),2436-2446. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015067709A1 (en) * | 2013-11-07 | 2015-05-14 | Dsm Ip Assets B.V. | Process for the purification of astaxanthin |
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