十五碳三苯基膦盐的合成方法 Synthesis fifteen carbon triphenylphosphine salt

技术领域 Technical Field

[0001] 本发明涉及化学合成技术领域，尤其涉及十五碳三苯基膦盐的合成方法。 [0001] The present invention relates to the technical field of chemical synthesis, in particular, relates to a method for the synthesis of carbon-fifth triphenylphosphine salts.

背景技术 Background

[0002] 虾青素是非维生素A原的类胡萝卜素，广泛应用于保健品、药品、化妆品、食品及饲料添加剂等的生产中。 [0002] Astaxanthin non-provitamin A carotenoid, is widely used in the production of health care products, pharmaceuticals, cosmetics, food and feed additives, and the like. 在食品中，不仅可以着色，还可以有效地起到保鲜，防止变色、变味、变质的作用，也可以用于饮料、食品、调料等的着色。 In the food, not only can be colored, but also can effectively play preservation, to prevent discoloration, taste, bad role, but also can be used in beverage, food, spices, etc. coloring. 虾青素有艳丽的颜色，并可以与肌动蛋白非特意性结合，目前广泛应用于水产饲料中，可以改善养殖鱼类的皮肤和肌肉色泽， 增加鱼虾类的抗病能力。 Astaxanthin is known as bright colors, and can be non-specifically bind to the protein actin, now widely used in aquaculture feed, can improve the color of the skin and muscle of farmed fish, and increased disease resistance of fish and shrimp.

[0003] 虾青素的生产有两种方法， 一种是发酵提取法， 一种是化学合成法。 [0003] The astaxanthin production, there are two ways, one is fermentation extraction method, one is chemical synthesis. 发酵提取法由于产量小，成本高，在市场上占有量很小，目前90%以上的虾青素都是通过化学合成法得到。 Fermentation extraction method because the production of small, high cost, the market share of small, more than 90 percent of astaxanthin are obtained by chemical synthesis.

[0004] 现有工业上可行的虾青素的合成方法在文献Ep5748 ;Helv. chim. acta 64(1981) ，2436 ;US5455362 ;Pure. Appl. Chem. Vo174， No8， ppl369-1382， 2002中均做了描述，采用c9+c6 — C15 ;C15+C1Q+C15 — Q。 [0004] The synthesis method industrially viable existing astaxanthin in literature Ep5748;. Helv chim acta 64 (1981), 2436;. US5455362;... Pure Appl Chem Vo174, No8, ppl369-1382, 2002 in both He was described using c9 + c6 - C15; C15 + C1Q + C15 - Q. ，具体合成方法如下： [0005] , Specific synthesis methods are as follows: [0005]

[0006]0 [0006] 0

[0007] 在以上路线中，A为C9合成单元，即C9环己烯酮的羟基保护化合物，B与C为C6合成单元，即C6炔基化合物的羟基保护化合物，C9+C6 — C15，需经过脱保护，再氢化、溴化，再制成三苯基膦盐，然后与十碳双醛进行Wittig反应，得到虾青素。 [0007] In the above scheme, A is a C9 synthesis unit, i.e. C9 hydroxy protected compound of the cyclohexenone, B and C to C6 synthesizing unit, i.e., protected hydroxy compound C6 alkynyl compound, C9 + C6 - C15, need After deprotection, and then hydrogenated, bromide, triphenyl phosphine salt then made, and then with an aldehyde ten carbon double Wittig reaction to give astaxanthin. [0008] 上述方法反应路线长，收率不高，影响了规模化生产。 [0008] The above reaction scheme long, the yield is not high, the impact of large-scale production.

发明内容 DISCLOSURE

[0009] 本发明所要解决的技术问题在于克服上述不足之处，研究一种反应步骤短，收率高的方法。 [0009] The technical problem to be solved by the present invention is to overcome the deficiencies, study a short reaction step, high yield method.

[0010] 本发明提供了一种虾青素重要中间体三苯基膦盐的合成方法。 [0010] The present invention provides a method for synthesizing astaxanthin important intermediates triphenylphosphine salt. 该方法如下： The method is as follows:

[0011] 反应式二： [0011] Scheme II:

[0012]<formula>formula see original document page 6</formula> [0013] 化合物1和化合物2为C6单元。 [0012] <formula> formula see original document page 6 </ formula> [0013] Compounds 1 and 2 for the C6 unit. [0014] Cg单元的制备： [0014] Cg unit Preparation:

[0015] 3，4-二羟基-2，6，6-三甲基-2-环己烯-1-酮溶于二氯甲烷溶剂中，摩尔配比1 : 4.5〜5.0，在室温下，加入催化剂量的对甲苯磺酸，再搅拌滴加双羟基保护剂乙烯基乙醚，摩尔比为l : 2，混合搅拌反应4小时，加稀碱溶液中和，萃取浓縮后得(:9单元。 [0016] 化合物3和4的制备 [0015] 3,4-dihydroxy-2,6,6-trimethyl-2-cyclohexen-1-one is dissolved in methylene chloride solvent, the molar ratio of 1: 4.5~5.0, at ambient temperature, was added a catalytic amount of p-toluenesulfonic acid, and then added dropwise with stirring bis vinyl ether hydroxy protecting agent, the molar ratio of l: 2, mixing the reaction mixture was stirred for 4 hours and dilute alkali solution, extracted and concentrated to give (: 9 units Preparation of [0016] Compound 3 and 4

[0017] C9单元和C6单元采用丁基锂在强碱低温下縮合得到化合物3和4。 [0017] C9 cells and C6 cells using butyllithium at low temperature condensation of a strong base to give compound 3 and 4. [OO1 S] 氢化（化合物5和6的制备） [OO1 S] hydride (compound of Preparation 5 and 6)

[0019] C9单元溶于有机溶剂，在乙酸酸性条件下批次加锌粉氢化炔基得到化合物5和6。 [0019] C9 unit in an organic solvent, under acidic conditions, acetic acid plus zinc hydrogenation batch obtained alkynyl Compound 5 and 6. [0020] 三苯基膦盐的制备 [0020] The preparation of triphenylphosphine salt

[0021] 所述三苯基瞵盐的制备，是以化合物5、化合物6为原料。 [0021] Preparation of the salt of triphenylphosphine, based on compound 5, compound 6 as starting material.

[0022] 所述的反应体系中应含有水和与水混溶的有机溶剂，优选甲醇、乙醇、异丙醇等低 [0022] The reaction system should contain water and a water-miscible organic solvent, preferably methanol, ethanol, isopropanol, etc. Low

级醇类或其混合物。 Grade alcohols or mixtures thereof. 醇类与水的比例可以在o : ioo到95 : 5之间，优选在50 : 50到 The ratio of alcohol to water can be in o: ioo to 95: Between 5, preferably 50: 50 to

80 : 20之间。 80: 20 between.

[0023] 所述的反应温度在-20°C到30°C ，优选在0°C到l(TC之间，反应时间可以在半小时到20小时之间。 The reaction temperature [0023], wherein at -20 ° C to 30 ° C, preferably between 0 ° C and l (TC, reaction time can be between half an hour to 20 hours.

[0024] 所述的滴加方式可以是醇的悬浮液滴加浓硫酸，醇的悬浮液滴加预先配制好的醇浓硫酸液。 Dropwise manner [0024] The alcohol may be added dropwise concentrated sulfuric acid, added dropwise alcohol Chunnong sulfuric acid solution previously prepared.

[0025] 实施例l:Cg单元的制备（2，2，4，6，6-五甲基-7，7a-二氢-6H-苯并[1，3]间二氧杂环戊烯_5-酮） [0025] Example l: Preparation of Cg unit (2,2,4,6,6-pentamethyl--7,7a- -6H- dihydro-benzo [1,3] dioxole _ 5-one)

[0026] 将170g(1.0mo1)晶状的3， 4_ 二羟基_2， 6， 6_三甲基_2_环己烯_1_酮悬浮于500ml 二氯甲烷中。 [0026] The 3, 4 _ dihydroxy _2 170g (1.0mo1) crystalline, 6, 6_ trimethyl cyclohexene _1_ _2_ one was suspended in 500ml of dichloromethane. 首先向该悬浮液中加入500mg(2.9mmo1)对甲苯磺酸，然后在室温（RT) 下在2小时的时间内加入144g(2.0mo1)乙烯基乙醚。 First To this suspension was added 500mg (2.9mmo1) p-toluenesulfonic acid, and then a period of 2 hours was added 144g (2.0mo1) vinyl ether at room temperature (RT) under. 然后将混合物在室温下搅拌4h，然后加入100ml5X浓度的氢氧化钠溶液。 The mixture was then stirred for 4h at room temperature, followed by addition of sodium hydroxide solution 100ml5X. 分出下面的有机相，水相用100ml 二氯甲烷萃取一次，合并有机相，用200ml水洗涤，并在旋转蒸发仪上浓縮。 Lower organic phase was separated, the aqueous phase was extracted once with 100ml of methylene chloride, and the combined organic phase was washed with 200ml water, and concentrated on a rotary evaporator. 残余物在减压（油泵）的条件下干燥，得到2， 2， 4， 6， 6-五甲基-7， 7a- 二氢-6H-苯并[1， 3]间二氧杂环戊烯_5_酮，为黄色油状物，用薄层色谱法（TLC)检测其为纯的，用气相色谱法（GC)检测其几乎为纯的。 The residue under reduced pressure (oil pump) is dried to give 2, 2, 4, 6, 6-pentamethyl -7, 7a- dihydro -6H- benzo [1, 3] dioxol ene _5_ one as a yellow oil, by thin layer chromatography (TLC) is detected as a pure, almost pure detected by gas chromatography (GC). [0027] 实施例2 :制备化合物3 [0027] Example 2: Preparation of Compound 3

[0028] 实施例1制得的C9单元21. 5克(0. lmol，98% )和化合物121g(0. 12mol，96% ) 用50ml的正己烷在250ml的三口瓶中搅拌，温度为_10°C ，通氮气，缓慢滴加4. 2N 丁基锂正己烷溶液36ml (0. 15mol)，保持反应温度为约_10°C〜_5°C，30分钟滴加完毕，继续搅拌1小时，用薄层色谱法（TLC)跟踪检测，C9单元已经反应完全，升温至室温，加入50ml的水搅拌，分层，水相用50ml的正己烷分2次洗涤，并入有机相，有机相用100ml的稀酸水洗涤至中性。 [0028] Example 1 was 21.5 g C9 unit implementation (0. lmol, 98%) and compound 121g (0. 12mol, 96%) in 250ml three-necked flask stirred with 50ml of hexane, temperature _ 10 ° C, nitrogen was slowly added dropwise n-hexane solution 4. 2N butyllithium 36ml (0. 15mol), maintaining the reaction temperature of about _10 ° C~_5 ° C, 30 completion of the dropwise addition, stirring was continued for 1 hour tracking detection by thin layer chromatography (TLC), C9 unit has been completely reacted, warmed to room temperature, added 50ml of water was stirred, layers were separated, the aqueous phase was extracted with 50ml of n-hexane was washed 2 times, into the organic phase, the organic phase washed to neutrality with 100ml of acid water. 有机相在5(TC水浴下减压浓縮，得到淡红色的油状物45. 2g。淡红色的油状物经高真空（90〜lOOPa)，油温IO(TC，沸点在30〜35°C ，除去过量的化合物l，得到38. 7g的化合物3，用气相色谱法（GC)检测含量为96%。 [0029] 实施例3 :制备化合物4 The organic phase 5 (TC water bath under concentrated under reduced pressure to give a reddish oil 45. 2g. Reddish oil under high vacuum (90~lOOPa), oil IO (TC, boiling point 30~35 ° C to remove excess compound l, 3 compound obtained 38. 7g, detected by gas chromatography (GC) content of 96% [0029] Example 3: Preparation of Compound 4

[0030] 实施例1制得的C9单元21. 5克(0. lmol，98% )和化合物221g(0. 12mol，96% ) 用50ml的正己烷在250ml的三口瓶中搅拌，温度为_10°C ，通氮气，缓慢滴加4. 2N 丁基锂正己烷溶液36ml (0. 15mol)，保持反应温度为约_10°C〜_5°C，30分钟滴加完毕，继续搅拌1小时，用薄层色谱法（TLC)跟踪检测，C9单元已经反应完全，升温至室温，加入50ml的水搅拌，分层，水相用50ml的正己烷分2次洗涤，并入有机相，有机相用100ml的稀酸水洗涤至中性。 [0030] Example 1 was C9 unit 21.5 g (0. lmol, 98%) and compound 221g (0. 12mol, 96%) was stirred with 50ml of n-hexane in 250ml three-necked flask, temperature _ 10 ° C, nitrogen was slowly added dropwise n-hexane solution 4. 2N butyllithium 36ml (0. 15mol), maintaining the reaction temperature of about _10 ° C~_5 ° C, 30 completion of the dropwise addition, stirring was continued for 1 hour tracking detection by thin layer chromatography (TLC), C9 unit has been completely reacted, warmed to room temperature, added 50ml of water was stirred, layers were separated, the aqueous phase was extracted with 50ml of n-hexane was washed 2 times, into the organic phase, the organic phase washed to neutrality with 100ml of acid water. 有机相在5(TC水浴下减压浓縮，得到淡红色的油状物45. 5g。淡红色的油状物经高真空（90〜lOOPa)，油温IO(TC，沸点在30〜35°C ，除去过量的化合物2，得到38. 9g的化合物4，用气相色谱法（GC)检测含量为96%。 [0031 ] 实施例4 :氢化得化合物5 The organic phase 5 (TC water bath under concentrated under reduced pressure to give a reddish oil 45. 5g. Reddish oil under high vacuum (90~lOOPa), oil IO (TC, boiling point 30~35 ° C 4, removal of excess compound 2 to give compound 38. 9g 4, detected by gas chromatography (GC) content of 96% [0031] Example: hydrogenating the compound 5.

[0032] 将化合物339. 5g(0. lmol，96% )溶于100ml的二氯甲烷中，冷却至0°C，加入18g(0. 3mo1)乙酸，搅拌，然后在(TC间隔IO分钟分批加入锌粉O. 5g(总共加入8. 8g)，在最后一批锌粉加入后，在(TC搅拌45分钟。过滤乙酸锌，滤饼用二氯甲烷洗二次，每次用25ml， 并入滤液中，滤液用水洗两次，每次用水50ml。滤液减压浓縮，得35. 5g，用气相色谱法（GC) 检测含量为95%。 [0032] Compound 339. 5g (0. Lmol, 96%) was dissolved in 100ml of dichloromethane, cooled to 0 ° C, was added 18g (0. 3mo1) acetic acid, followed by stirring, and then (TC IO min min intervals Zinc powder was added in O. 5g (total added 8. 8g), after the last batch of zinc powder was added, in (TC was stirred for 45 min., zinc acetate was filtered, the filter cake with dichloromethane and washed twice, each time with 25ml, incorporated into the filtrate, and the filtrate was washed with water twice, each time with water 50ml. The filtrate was concentrated under reduced pressure to give 35. 5g, detected by gas chromatography (GC) content of 95%.

[0033] 实施例5 :三苯基膦盐及虾青素的制备 Preparation of triphenylphosphine salts and astaxanthin: [0033] Example 5

[0034] 将三苯基膦26. 2g(0. lmol)和化合物540g(0. lmol，95% )放入甲醇100ml搅拌， 冷却至Ot:，通氮气，慢慢滴加浓硫酸（98%，0. lmo1)5. 5ml，滴好为白色悬浮液，保持l(TC 以下搅拌3小时，溶液逐渐变清亮，最后为透明液。加入水50ml，用正己烷萃取3次，每次100ml，取水相，在10。C以下加入十碳双醛7g(0. 04mol，95% )，滴加40% NaOH水溶液12ml， 在l(TC下搅拌3小时，不断有红色晶体析出，过滤，晶体用水各50ml洗涤两次，并入滤液中， 再在滤液中加入二氯甲烷各50ml萃取两次，有机相用水50ml洗涤一次。在常压下蒸出二氯甲烷，同时加入甲醇至沸点65t:，将悬浮液回流4小时，冷却至l(rC以下，过滤得晶体，合并晶体干燥，得虾青素18. 2g， HPLC检测含量为98. 8% 。[0035] 实施例6 :三苯基膦盐及虾青素的制备 [0034] Triphenylphosphine 26. 2g (0. Lmol) and the compound 540g (0. Lmol, 95%) was stirred into 100ml of methanol, cooled to Ot :, nitrogen, was slowly added dropwise concentrated sulfuric acid (98% , 0. lmo1) 5. 5ml, preferably white suspension dropwise, maintaining l (TC hereinafter stirred for 3 hours, the solution gradually becomes clear, and finally as a clear liquid. Water was added 50ml, extracted three times with n-hexane, each time 100ml, water phase was added at 10.C the following ten carbon dialdehyde 7g (0. 04mol, 95%), 40% NaOH aqueous solution was added dropwise 12ml, stirring at the l (TC 3 hours continuously red crystals precipitated, filtered, washed with water crystals Each 50ml washed twice, into the filtrate, and then added to each 50ml of methylene chloride in the filtrate was extracted twice, the organic phase was washed once with water 50ml. of methylene chloride was distilled off at atmospheric pressure, while adding methanol to the boiling point 65t :, The suspension was refluxed for 4 hours, cooled to l (rC or less, and filtered to give crystals, crystals combined and dried to give astaxanthin 18. 2g, HPLC content of 98.8% is detected [0035] Example 6: Triphenylphosphine The preparation of salts and astaxanthin

[0036] 将三苯基膦26. 2g(0. lmol)和化合物640g(0. lmol，95% )放入乙醇50ml搅拌， 冷却至Ot:，通氮气，慢慢滴加浓硫酸（98%，0. lmol，5. 5ml)甲醇（50ml)溶液，滴好为白色悬浮液，保持l(TC以下搅拌12小时，溶液逐渐变清亮，最后为透明液。加入水25ml，用正己烷萃取3次，每次100ml，取水相，在l(TC以下加入十碳双醛7g(0. 04mol， 95% )，滴力口40% NaOH水溶液12ml，在l(TC下搅拌3小时，不断有红色晶体析出，过滤，晶体用水各50ml洗涤两次，并入滤液中，再在滤液中加入二氯甲烷各50ml萃取两次，有机相用水50ml洗涤一次。在常压下蒸出二氯甲烷，同时加入甲醇至沸点65t:，将悬浮液回流4小时，冷却至l(rC 以下，过滤得晶体，合并晶体干燥，得虾青素18. 5g， HPLC检测含量为98. 5% 。 [0037] 实施例7 :三苯基膦盐及虾青素的制备 [0036] Triphenylphosphine 26. 2g (0. Lmol) and the compound 640g (0. Lmol, 95%) into 50ml of ethanol was stirred and cooled to Ot :, nitrogen, was slowly added dropwise concentrated sulfuric acid (98% , 0. lmol, 5. 5ml) in methanol (50ml) solution, preferably white suspension dropwise, maintaining l (TC hereinafter stirred for 12 hours, the solution gradually becomes clear, and finally as a clear liquid. Water was added 25ml, extracted with n-hexane 3 times 100ml, water phase in l (TC was added the following ten carbon dialdehyde 7g (0. 04mol, 95%), 40% NaOH dropwise power port aqueous 12ml, stirring at the l (TC 3 hours continuously red Crystals precipitated was filtered, washed twice with 50ml each of water crystals, the filtrate was incorporated, and then added to each 50ml of methylene chloride in the filtrate was extracted twice, the organic phase was washed once with water 50ml. of methylene chloride was distilled off at atmospheric pressure, at the same time Methanol was added to the boiling point 65t :, The suspension was refluxed for 4 hours, cooled to l (rC or less, and filtered to give crystals, crystals combined and dried to give astaxanthin 18. 5g, HPLC content of 98.5% is detected. [0037] Example 7: Preparation of triphenylphosphine salts and astaxanthin

[0038] 将三苯基膦26. 2g(0. lmol)和化合物540g(0. lmol，95% )放入异丙醇75ml搅拌， 冷却至Ot:，通氮气，慢慢滴加浓硫酸（98%，0. lmol)5. 5ml，滴好为白色悬浮液，保持10°C 以下搅拌20小时，溶液逐渐变清亮，最后为透明液。 [0038] Triphenylphosphine 26. 2g (0. Lmol) and the compound 540g (0. Lmol, 95%) was stirred into 75ml of isopropanol, cooled to Ot :, nitrogen, was slowly added dropwise concentrated sulfuric acid ( 98%, 0. lmol) 5. 5ml, preferably white suspension dropwise, maintaining below 10 ° C for 20 hours, the solution gradually becomes clear, and finally as a clear liquid. 在10°C以下加入十碳双醛7g (0. 04mol， 95% )，滴加40% NaOH水溶液20ml，在l(TC下搅拌3小时，不断有红色晶体析出，过滤，晶体用水各50ml洗涤两次，并入滤液中，再在滤液中加入二氯甲烷各50ml萃取两次，有机相用水50ml洗涤一次。在常压下蒸出二氯甲烷，同时加入甲醇至沸点65t:，将悬浮液回流4小时，冷却至l(TC以下，过滤得晶体，合并晶体干燥，得虾青素16. 7g， HPLC检测含量为95. 6%。 Was added at below 10 ° C ten carbon dialdehyde 7g (0. 04mol, 95%), 40% NaOH aqueous solution was added dropwise 20ml, stirring at the l (TC 3 hours continuously red crystals precipitated, filtered, washed with 50ml each of water crystals twice, incorporated into the filtrate, and then added to each 50ml of methylene chloride in the filtrate was extracted twice, the organic phase was washed once with water 50ml. of methylene chloride was distilled off at atmospheric pressure, while adding methanol to the boiling point of the suspension 65t :, was refluxed for 4 hours, cooled to l (TC hereinafter, filtered to give crystals, crystals combined and dried to give astaxanthin 16. 7g, HPLC content of 95.6% is detected.