[ CAS No. 127-47-9 ] {[proInfo.proName]}

Name: 127-47-9|(2E,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-yl acetate|2800000 IU/g
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Quality Control of [ 127-47-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 127-47-9 ]

CAS No. :	127-47-9	MDL No. :	MFCD00019413
Formula :	C₂₂H₃₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QGNJRVVDBSJHIZ-QHLGVNSISA-N
M.W :	328.49	Pubchem ID :	638034
Synonyms :	Retinol acetate;Vitamin A acetate;Ro 1-5275;NSC 122760;NSC 122045	Chemical Name :	(2E,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-yl acetate

Calculated chemistry of [ 127-47-9 ]

Physicochemical Properties

Num. heavy atoms :	24
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.5
Num. rotatable bonds :	7
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	104.41
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-3.87 cm/s

Lipophilicity

Log Po/w (iLOGP) :	4.35
Log Po/w (XLOGP3) :	6.25
Log Po/w (WLOGP) :	6.08
Log Po/w (MLOGP) :	4.72
Log Po/w (SILICOS-IT) :	6.2
Consensus Log Po/w :	5.52

Druglikeness

Lipinski :	1.0
Ghose :	None
Veber :	0.0
Egan :	1.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-5.35
Solubility :	0.00146 mg/ml ; 0.00000445 mol/l
Class :	Moderately soluble
Log S (Ali) :	-6.59
Solubility :	0.0000846 mg/ml ; 0.000000258 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-4.26
Solubility :	0.0182 mg/ml ; 0.0000553 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	4.21

Safety of [ 127-47-9 ]

Signal Word:	Danger	Class:	9
Precautionary Statements:	P201-P202-P281-P308+P313-P403-P501	UN#:	3082
Hazard Statements:	H360-H411	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 127-47-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 127-47-9 ]
Downstream synthetic route of [ 127-47-9 ]

[ 127-47-9 ] Synthesis Path-Upstream 1~3

1
[ 112-39-0 ]
[ 127-47-9 ]
[ 79-81-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium hydroxide In methanol at 55℃; for 3 h; Large scale	To 3000 kg of the compound of formula (la) which is known as Vitamin A acetate, in its crystalline form, 2750 kg of compound of formula (I la) which is known as methyl palmitate have been added. Afterwards 10 kg of NaOH have been dissolved in about 60 I of methanol, which was then added to the mixture of Vitamin A acetate and methyl palmitate. This reaction mixture was heated up to 55°C and the pressure was reduced to about 1500 - 2200 Pa. The reaction time was about 3 hours. During this process the main side product (methyl acetate) was removed continuously by distillation. The reaction was stopped by the addition of water and CO2. Afterwards the compound of formula (Ilia) which is known as Vitamin A palmitate was isolated from the reaction solution by extraction. The yield of compound of formula (Ilia) was 96percent.

Reference： [1] Patent: WO2014/23772, 2014, A1, . Location in patent: Page/Page column 9

2
[ 127-47-9 ]
[ 57-10-3 ]
[ 79-81-2 ]

Reference： [1] Journal of Nanoscience and Nanotechnology, 2011, vol. 11, # 9, p. 7593 - 7602
[2] Journal of Lipid Research, 2014, vol. 55, # 2, p. 319 - 328

3
[ 127-47-9 ]
[ 57-10-3 ]
[ 79-81-2 ]
[ 68-26-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21 In toluene at 20℃; for 15 h; Enzymatic reaction	Example 28; Preparation of Retinyl Palmitate in the Presence of Amberlyst A-21; Retinyl acetate (1.00 g; 3.04 mmol) was dissolved in 8.5 mL of toluene and palmitic acid (1.56 g; 6.09 mmol; 2.0 equiv) was added followed by 120 mg of Novozyme 435 and 0.5g of dried Amberlyst A-21. The reaction mixture was stirred at RT for 15 h, at which point a sample was removed and analyzed by HPLC, indicating 89.2percent conversion to retinyl palmitate with 9.1percent retinyl acetate and 1.7percent retinol. The reaction mixture was filtered and concentrated, then concentrated twice with heptane (10 mL each). The residue was dissolved in heptane (15 mL) and washed with 2.x.20 mL with a 1:1 mixture of 10percent aqueous potassium carbonate and methanol. The organic layer was washed further with a mixture of saturated sodium bicarbonate (2.5 mL), water (7.5 mL), and methanol (10 mL), dried (sodium sulfate) and concentrated to afford 1.25 g (78percent) of a yellow oil. Analysis of this product indicated 91.2percent retinyl palmitate (HPLC area percent), 0.4 wt percent palmitic acid, and 0.2percent retinol. HPLC (4.6.x.150 mm Zorbax SB-C8 column [Agilent], 3.5μ thickness, methanol eluent, detection at 350 nm): t_R5.52 min (retinyl palmitate); t_R2.32 min (retinyl acetate); t_R2.08 min (retinol).

Reference： [1] Patent: US7566795, 2009, B2, . Location in patent: Page/Page column 11

[ 127-47-9 ] Synthesis Path-Downstream 1~47

1
[ 108-24-7 ]
[ 68-26-8 ]
[ 127-47-9 ]

Yield	Reaction Conditions	Operation in experiment
99.5%	In hexane; at 35℃; for 1h;	Add 600g of vitamin A and 3L of n-hexane to the reactor, and add 207g of acetic anhydride dropwise with stirring.Control temperature 35 . After the dropwise addition, the reaction was carried out at 35 C for 1h. After the reaction was completed, the light components were distilled off under reduced pressure to obtain 690 g of vitamin A acetate solid with a content of 97% and a yield of 99.5%.
99.5%	In hexane; at 35℃; for 1h;	900g of vitamin A and 4L of n-hexane were added to the reactor, and 320g of acetic anhydride was added dropwise with stirring to control the temperature at 35 C. After the dropwise addition, the reaction was carried out at 35 C for 1h. After the reaction was completed, the light components were removed to obtain 1035 g of vitamin A acetate solid with a content of 97% and a yield of 99.5%.
76%	With triethylamine; In hexane; at 25℃; for 24h;Inert atmosphere; Darkness;	3) Under the protection of nitrogen, 100 mL of n-hexane, 15 mL of acetic anhydride, and 30 mL of triethylamine were sequentially added to the crude product, and the reaction was stirred at 25 C in the dark for 24 hours. After the reaction was completed, it was thoroughly washed 3 times with 95: 5 methanol-water; The n-hexane layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown-black oil, which was analyzed to contain 6.0 g of vitamin A acetate with a yield of 76%.

With pyridine; dmap; In toluene; at 20℃; for 4h;

0.02 g of the compound obtained in Example 1 and 5 ml of cyclohexane were added into a dry four-necked flask under nitrogen flow. After dissolving the mixture, 0.058 g (0.825 mmol) of potassium methoxide was added to the solution and the mixture was stirred at 400 C. for six hours. After confirming disappearance of the starting materials by TLC, the reaction mixture was added to a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride again and was dried over anhydrous magnesium sulfate. The solvent was removed from the organic layer to give a crude product as pale yellow oil. It was confirmed by NMR that the obtained compound contained, as a main component, retinol having only trans-configurations. In a dry four-necked flask, 0.01 g (0.035 mmol) of the above crude product was dissolved in 5 ml of toluene in an atmosphere of nitrogen. Then, after adding 0.003 g (0.035 mmol) of pyridine and 0.4 mg (0.004 mmol) of 4-dimethylaminopyridine, 0.004 g (0.035 mmol) of acetic anhydride was slowly added to the mixture at room temperature, and the mixture obtained was stirred at that temperature for four hours. After confirming disappearance of the starting materials by TLC, 5% of an aqueous solution of hydrochloric acid and toluene were added to the mixture. After washing the mixture with that aqueous solution and was separated into two layers. The organic layer obtained was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in order, and then dried over anhydrous magnesium sulfate. The dried organic layer was concentrated to give a crude product as yellow oil. The crude product obtained was purified by silica gel column chromatography. It was confirmed, by a comparison of its NMR with that of a standard sample of all trans-retinol acetate, that retinol acetate containing solely trans-configurations as a main component was obtained.

Reference： [1]Patent: CN110903190,2020,A .Location in patent: Paragraph 0019; 0065; 0072; 0073; 0078; 0081; 0088
[2]Patent: CN110950791,2020,A .Location in patent: Paragraph 0061; 0066; 0079; 0086
[3]Patent: CN110330451,2019,A .Location in patent: Paragraph 0095; 0099-0100; 0104
[4]Helvetica Chimica Acta,1931,vol. 14,p. 1431,1433
[5]Chemistry Letters,1985,p. 1883 - 1886
[6]Patent: US6348622,2002,B1 .Location in patent: Page column 13
[7]Green Chemistry,2016,vol. 18,p. 1240 - 1248

2
[ 127-47-9 ]
[ 603-35-0 ]
Vitamin A triphenylphosphonium sulfate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; aniline; In ethanol; at 10 - 25℃; for 26h;	Take 90g Vitamin A acetate oil (2,213,000 IU/g, 0.208mol) and 48.4g of aniline (0.52 mol) was dissolved in 1100ml of ethanol, dubbed vitamin A acetate-ethanol solution. 218.2 g of triphenylphosphine (0.832 mol) and 2300 ml of ethanol were separately added to the three-necked flask, and the temperature was lowered to below 10 C. 31.0 g of concentrated sulfuric acid (0.316 mol) was slowly added dropwise to the dropping funnel, and the dropping temperature was controlled to be 10 C or less, and stirring was continued for 2 hours. The vitamin A acetate-ethanol solution was added and reacted at 25 C for 24 hours to obtain a vitamin A triphenylphosphine chloride solution. Then, it was concentrated under reduced pressure, dissolved in 200 ml of acetone, placed in a refrigerator for 24 hours, crystallized, filtered, washed, and dried to obtain vitamin A triphenylphosphine sulfate (the same below).

Reference： [1]Justus Liebigs Annalen der Chemie,1977,p. 1146 - 1159
[2]Patent: CN108822015,2018,A .Location in patent: Paragraph 0037; 0038

3
[ 127-47-9 ]
[ 68-26-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In methanol; hexane; water;	Synthesis of vitamin A aldehyde from vitamin A acetate A 500-ml three-necked flask was charged under an atmosphere of nitrogen with 205 g of methanol, 50.2 g of vitamin A acetate (98% purity, 150 mmoles, ratio of all trans form: 98.6%), 24 g of a 50% aqueous sodium hydroxide solution, and the mixture was mechanically stirred at room temperature for 1 hour. The contents were transferred to a 1-liter separating funnel. To the contents 150 ml of hexane and 200 g of water were added and, after sufficient shaking, the mixture was separated. The organic layer separated was washed several times with water and the hexane was distilled off under reduced pressure, to obtain 47.06 g of a crude vitamin A.
	With sodium hydroxide; In methanol;	(1) Purification by Column Chromatography After the reaction of 11.6 g (33.67 mmol) of vitamin A acetate (purity 95.2%) with 5.6 g of an aqueous 50% sodium hydroxide solution in 80 g of methanol at room temperature for 1 hour, hexane and water were added to the reaction mixture and the organic layer was separated. After the obtained organic layer was washed with water, the organic solvent was removed by distillation under a reduced pressure to obtain 9.85 g of crude vitamin A.
	With sodium hydroxide; In methanol;	(2) Purification by Recrystallization After 2.8 g (8.37 mmol) of vitamin A acetate and 1.2 g of an aqueous 50% sodium hydroxide solution were reacted in 15 g of methanol at room temperature for 1 hour, hexane and water were added and separated. After the obtained organic layer was washed with water, the solvent was removed by distillation under a reduced pressure to obtain 2.98 g of crude vitamin A.

	With sodium hydroxide; In methanol;	EXAMPLE 2 Synthesis of Vitamin A Aldehyde using 2,2-dimethyl-4-pentenal After the reaction of 2.8 g (8.37 mmol) of vitamin A acetate (purity 98%) with 1.2 g of an aqueous 50% sodium hydroxide solution in 15 g of methanol at room temperature for 1 hour, hexane and water were added to the reaction mixture and the organic layer was separated. After the obtained organic layer was washed with water, the organic solvent was removed by distillation under a reduced pressure to obtain 3.05 g of crude vitamin A.
	With potassium methanolate; In cyclohexane; at 40℃; for 6h;	0.02 g of the compound obtained in Example 1 and 5 ml of cyclohexane were added into a dry four-necked flask under nitrogen flow. After dissolving the mixture, 0.058 g (0.825 mmol) of potassium methoxide was added to the solution and the mixture was stirred at 400 C. for six hours. After confirming disappearance of the starting materials by TLC, the reaction mixture was added to a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride again and was dried over anhydrous magnesium sulfate. The solvent was removed from the organic layer to give a crude product as pale yellow oil. It was confirmed by NMR that the obtained compound contained, as a main component, retinol having only trans-configurations. In a dry four-necked flask, 0.01 g (0.035 mmol) of the above crude product was dissolved in 5 ml of toluene in an atmosphere of nitrogen. Then, after adding 0.003 g (0.035 mmol) of pyridine and 0.4 mg (0.004 mmol) of 4-dimethylaminopyridine, 0.004 g (0.035 mmol) of acetic anhydride was slowly added to the mixture at room temperature, and the mixture obtained was stirred at that temperature for four hours. After confirming disappearance of the starting materials by TLC, 5% of an aqueous solution of hydrochloric acid and toluene were added to the mixture. After washing the mixture with that aqueous solution and was separated into two layers. The organic layer obtained was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in order, and then dried over anhydrous magnesium sulfate. The dried organic layer was concentrated to give a crude product as yellow oil. The crude product obtained was purified by silica gel column chromatography. It was confirmed, by a comparison of its NMR with that of a standard sample of all trans-retinol acetate, that retinol acetate containing solely trans-configurations as a main component was obtained.
	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21; Pamolyn 380 conjugated linoleic acid; In toluene; at 20℃; for 15h;Enzymatic reaction;Product distribution / selectivity;	Example 26; Preparation of the Conjugated Linoleic Acid Ester of Retinol (Retinyl-CLA) with Pamolyn 380 Conjugated Linoleic Acid in the Presence of Amberlyst A-21; Retinyl acetate (1.00 g; 3.04 mmol) was dissolved in 8.5 mL of toluene and Pamolyn 380 conjugated linoleic acid (1.71 g; 6.09 mmol; 2.0 equiv) was added followed by 120 mg of Novozyme 435 and 0.5g of dried Amberlyst A-21. The reaction mixture was stirred at RT for 15 h, at which point a sample was removed and analyzed by HPLC, indicating 87.2% conversion to retinyl-CLA with 10.9% retinyl acetate and 2.0% retinol. The reaction mixture was filtered and concentrated, then concentrated twice with heptane (10 mL each). The residue was dissolved in heptane (15 mL) and washed with 2×20 mL with a 1:1 mixture of 10% aqueous potassium carbonate and methanol. The organic layer was washed further with a mixture of saturated sodium bicarbonate (2.5 mL), water (7.5 mL), and methanol (10 mL), dried (sodium sulfate) and concentrated to afford 1.34 g (80%) of a yellow oil. Analysis of this product indicated 90.5% retinyl-CLA (HPLC area percent), 0.4 wt % conjugated linoleic acid, and 0.13% retinol. HPLC (4.6×150 mm Zorbax SB-C8 column [Agilent], 3.5mu thickness, methanol eluent, detection at 350 nm): tR 4.39, 4.88, 5.65, 6.06 min (retinyl-CLA isomers); tR 2.32 min (retinyl acetate); tR 2.08 min (retinol).
	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21; Tonalin FFA conjugated linoleic acid; In toluene; at 20℃; for 15h;Enzymatic reaction;Product distribution / selectivity;	Example 27; Preparation of the Conjugated Linoleic Acid Ester of Retinol (Retinyl-CLA) with Tonalin FFA Conjugated Linoleic Acid in the Presence of Amberlyst A-21; Retinyl acetate (1.00 g; 3.04 mmol) was dissolved in 8.5 mL of toluene and Tonalin FFA conjugated linoleic acid (1.71 g; 6.09 mmol; 2.0 equiv) was added followed by 120 mg of Novozyme 435 and 0.5g of dried Amberlyst A-21. The reaction mixture was stirred at RT for 15 h, at which point a sample was removed and analyzed by HPLC, indicating 88.6% conversion to retinyl-CLA with 9.7% retinyl acetate and 1.7% retinol. The reaction mixture was filtered and concentrated, then concentrated twice with heptane (10 mL each). The residue was dissolved in heptane (15 mL) and washed with 2×20 mL with a 1:1 mixture of 10% aqueous potassium carbonate and methanol. The organic layer was washed further with a mixture of saturated sodium bicarbonate (2.5 mL), water (7.5 mL), and methanol (10 mL), dried (sodium sulfate) and concentrated to afford 1.29 g (77%) of a yellow oil. Analysis of this product indicated 92.8% retinyl-CLA (HPLC area percent), 0.8 wt % conjugated linoleic acid, and 0.1% retinol.
		Vitamin A-acetate 9 oily concentrate (approx. 0.327 g all-trans retinyl acetate/g oil) (40.00 g, 39.82 mmol) was melted into a round-bottomed flask, and was suspended in 90% (v/v) aqueous ethanol (150 mL) containing sodium hydroxide (5.00 g, 125.00 mmol). The yellow mixture was refluxed for 25 min to achieve saponification to all-trans retinol 10. The clear yellow solution was cooled at 5 C for 30 min, and was mixed with glacial acetic acid (7.2 mL, 125.90 mmol) resulting in pH 5-7. This solution was diluted with water (200 mL), and was extracted with ethyl acetate (EtOAc, 200 mL). The isolated EtOAc phase was washed with water (200 mL). Black, precipitated (active) manganese dioxide powder (63.00 g, MnO2 content ~90%) was suspended in the isolated EtOAc phase, which contained mainly 10, and the mixture was stirred at a temperature of 20 C under light and air exclusion for 5 h. The suspension was occasionally shaken. Afterwards the black suspension was filtered through three layers of filter paper, and the black filter residue was rinsed with EtOAc (150 mL). To remove the finely suspended MnO2 residues, the filtrate, transferred into a separation funnel, was mixed with a freshly prepared solution of l-ascorbic acid (10.00 g, 56.78 mmol) and sodium hydroxide (4.54 g, 113.50 mmol) in water (200 mL). The mixture was shaken vigorously for 1 min. A heavy precipitate of manganese(II) compounds evolved in the aqueous phase, which was dissolved by addition of glacial acetic acid (6.5 mL, 113.66 mmol) and repeated shaking. Finally, the separated EtOAc phase was washed twice with water (2 × 200 mL). The EtOAc phase, containing mainly all-trans retinal 11, was mixed with a solution of thiosemicarbazide (5.73 g, 62.88 mmol) in 90% (v/v) aqueous ethanol (220 mL, prepared by short refluxing). The solution was refluxed for 20 min. The clear, deep yellow solution was then frozen at -25 C for 4 h. After adding 100 ml of water, the volume of the cloudy yellow solution was reduced in vacuo until heavy crystallization started. The crystallizing suspension was additionally frozen at -25 C for 3 h. The evolved orange-yellow crystals were filtered and dried. The orange-yellow filtrate was evaporated to a volume of ca. 150 mL, until it crystallized again. For completion of crystallization, it was frozen at -25 C for 1 h. The evolved orange, fine crystalline precipitate of all-trans retinal thiosemicarbazone was filtered and dried. All crude products were combined (12.00 g) and dissolved in acetone (120 mL) by gentle warming. After 1 h freezing at -25 C water (60 mL) was added, and the crystallizing suspension was frozen at -25 C for 4 h. The evolved orange-yellow crystals were filtered and dried (10.50 g). This material was dissolved in acetone (130 mL) by gentle warming. A solution of sodium hydroxide (1.76 g, 44.00 mmol) in water (7 mL) was added under stirring. Immediately a lemon yellow precipitate of crude compound 12 formed. The precipitating suspension was cooled at 5 C for 2 h. The evolved lemon yellow precipitate of the crude 12 was filtered and dried. The crude product 12 (11.40 g, 66%) was suspended in 80% (v/v) aqueous acetone (600 mL). The suspension was refluxed for 15 min. Afterwards, the orange solution was cooled at 5 C for 5 h, and then was frozen at -25 C for 6 h. The evolved yellow-orange crystalline material (fine needles and accompanying shiny plates) (9.58 g) was filtered and dried. A part of this material (2.00 g) was dissolved in acetone (70 mL) by gentle warming. A solution of sodium hydroxide (0.25 g, 6.25 mmol) in water (1 mL) was added under stirring. Immediately a lemon yellow precipitate formed. The precipitating suspension was frozen at -25 C for 2 h. The evolved lemon yellow precipitate of 12 (2.13 g, 99% for this procedure) was filtered and dried over CaCl2 in vacuo.
	With potassium methanolate; In methanol; at 30℃; for 3h;Inert atmosphere;	3.28 kg of vitamin A acetate and 16.5 g of potassium methoxide were added to 33 L of methanol under nitrogen protection, and the reaction was carried out at 30 C for about 3hour;After completion of the reaction, it was concentrated to dryness under reduced pressure at 40 C to give a yellow oil as a vitamin A alcohol.The obtained vitamin A alcohol was mixed with 2.80 kg of methyl palmitate.The mixture was heated to 60 C and then the pressure was reduced to about 100 Pa for about 3 hours.The reaction was terminated by nitrogen gas, and 20 L of n-hexane and 165 g of activated carbon were added.After decolorizing for 30 minutes, the silica gel was filtered, and the filtrate was concentrated to dryness under reduced pressure.A pale yellow oil of 4.93 kg was obtained with a yield of 94%.The obtained oil was analyzed according to the method of the United States Pharmacopoeia USP28, and the result showed that the purity of vitamin A palmitate was 1.77 million IU/g.
	With sodium hydroxide; In ethanol; at 20 - 26℃; for 0.5h;	1) Take 300g (0.92mol) of vitamin A acetate dissolved in 1600ml of absolute ethanol, add 480ml of sodium hydroxide solution with a mass concentration of 35%, and hydrolyze at 20-26 C for 30 minutes.

Reference： [1]European Journal of Organic Chemistry,2011,p. 6704 - 6712
[2]Journal of the Chemical Society. Perkin transactions II,1984,p. 1361 - 1368
[3]Tetrahedron,1980,vol. 36,p. 1179 - 1182
[4]Tetrahedron,1996,vol. 52,p. 405 - 424
[5]Nucleosides and Nucleotides,1998,vol. 17,p. 2127 - 2133
[6]Chemical Physics Letters,2003,vol. 369,p. 380 - 385
[7]Patent: US5312978,1994,A
[8]Patent: US5087762,1992,A
[9]Patent: US5087762,1992,A
[10]Patent: US5087762,1992,A
[11]Patent: US6348622,2002,B1 .Location in patent: Page column 12-13
[12]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 10-11
[13]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 11
[14]Journal of Physical Chemistry B,2010,vol. 114,p. 13904 - 13910
[15]European Journal of Medicinal Chemistry,2011,vol. 46,p. 1656 - 1664
[16]Synthesis,2011,p. 2205 - 2207
[17]Organic Preparations and Procedures International,2013,vol. 45,p. 325 - 327
[18]Patent: CN108623507,2018,A .Location in patent: Paragraph 0017-0028
[19]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2020,vol. 227
[20]Dyes and Pigments,2020,vol. 175
[21]Patent: CN111087335,2020,A .Location in patent: Paragraph 0020; 0029-0030

4
(+-)-9-acetoxy-3.7-dimethyl-1-<2.2.6-trimethyl-cyclohexen-(6)-yl>-nonatrien-(2ξ.5<i>c</i>.7ξ)-ol-(4) [ No CAS ]
[ 127-47-9 ]

Reference： [1]Patent: US2451739,1947,
[2]Helvetica Chimica Acta,1962,vol. 45,p. 548 - 561

5
[ 127-47-9 ]
[ 472-86-6 ]

Reference： [1]Chemical Physics Letters,2003,vol. 369,p. 380 - 385

6
[ 37905-02-5 ]
[ 127-47-9 ]

Reference： [1]Journal of Organic Chemistry,1986,vol. 51,p. 3834 - 3838
[2]Journal of Organic Chemistry,1986,vol. 51,p. 3834 - 3838
[3]Journal of Organic Chemistry,1986,vol. 51,p. 3834 - 3838
[4]Chemistry Letters,1985,p. 1883 - 1886

7
[ 127-47-9 ]
[ 4192-77-2 ]
retinol cinnamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With immobilized lipase from Candida antarctica Novozym 435; 2,6-di-tert-butyl-4-methyl-phenol; at 50℃; under 150.015 Torr; for 28h;	2 ml Ethylcinnamat (11,9 mmol), 100 mg Retinolacetat (0,3 mmol), 200 mg Butylhydroxytoluol (BHT) als Antioxidans und 100 mg immobilisierte Lipase von Candida antarctica Novozym 435 wurden unter Ruehren und Lichtausschluss in einem Reaktor zusammengefuegt. Die Reaktion lief bei 50 C und 200 mbar Vakuum ab. Nach 28 Stunden war die Umsetzung von Retinolacetat zu Retinolcinnamat vollstaendig erfolgt, der Endpunkt wurde durch eine HPLC-analyse ermittelt.

Reference： [1]Patent: EP1369411,2003,A1 .Location in patent: Page 15

8
1-acetoxy-5-hydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-9-(4-methylphenylsulfonyl)-nona-2,6-diene [ No CAS ]
[ 127-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	With titanium tetrachloride; In tetrahydrofuran; at 20℃; for 12h;	0.5 g (0.995 mmol) of 1-acetoxy-5-hydroxy-3,7-dimethyl-9-(2,6,6-trimethylcyclohexene-1-yl)-9-(4-methylphenylsulfonyl)-nona-2,6-diene (compound III-1) and 10 ml of tetrahydrofuran were added into a dry four-necked flask in an atmosphere of nitrogen. After dissolving compound [III-1], 0.095 g (0.497 mmol) of titanium tetrachloride was added slowly to the solution at room temperature. After stirring at the temperature for twelve hours, disappearance of the starting material was confirmed by TLC. The reaction mixture was added to 1% aqueous solution of sodium hydroxide and was extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated to give a crude product. The crude product obtained was purified by silica gel chromatography to give a compound as pale yellow oil.

Reference： [1]Patent: US6348622,2002,B1 .Location in patent: Page column 12

9
[ 138871-46-2 ]
[ 26586-02-7 ]
[ 127-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate; In water; N,N-dimethyl-formamide; toluene;	Example 1 Preparation of Vitamin A Acetate Under a nitrogen gas atmosphere, a 250 ml brown flask was charged with a solution of 10.0 g (27.4 mmol, 93.2% in purity) of 3-methyl-5-(2, 6, 6,-trimethyl-cyclohexen-1-yl)-1,3-pentadienylphosphonic acid diethyl ester in 40 ml of toluene, cooled to -35(. Then, a solution of 5.0 g (52 mmol) sodium tert-butoxide in the mixture of 20 ml of DMF and 10 ml of toluene was added dropwise slowly over a period of 10 minutes, and the mixture was stirred successively at the same temperature for 2 hours. A solution of 5.0 g (35.2 mmol) 4-acetoxy-2-methyl-2-butenal in 40 ml of toluene was added dropwise to the solution at -35 C., and the mixture was stirred at this temperature for 10 minutes. 50 ml of water was added to the reaction mixture the organic phase was separated and washed with 50 ml of saturated brines dried over anhydrous magnesium sulfate Removal of the solvent by evaporation under reduced pressure gave 11.0 g of yellow oil. The yellow oil was analyzed by high performance liquid chromatography (HPLC) under the following conditions: Column: Nuclesosil 50-54.6*250 mm Eluent: cyclohexane-diethyl ether 50:1 (v/v) Flowing Rate: 0.80 ml/min Detection: UV310 nm The analysis results showed the content of all trans-vitamin A acetate was 90.3%, the total content of I 1-cis and 13 cis isomers was 5.4% and the content of 9-cis isomer was 1.0%.

Reference： [1]Patent: US2002/151742,2002,A1

10
[ 138871-48-4 ]
[ 26586-02-7 ]
[ 127-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium chloride; potassium tert-butylate; In tetrahydrofuran; water; N,N-dimethyl-formamide; Petroleum ether;	Example 2 Preparation of Vitamin A Acetate Under a nitrogen gas atmosphere, a 250 ml brown flask was charged with a solution of 10.0 g (27,4 mmol, 93.5% in purity) of 3-methyl-5-(2, 6 6-trimethyl-cyclohexen-1-yl)-1,4-pentadienylphosphonic acid diethyl ester in 40 ml of tetrahydrofuran, cooled to -45 C. Then, with stirring, a solution of 4.0 g (35.7 mmol) of potassium tert-butoxide in the mixture of 20 ml of DMF and 20 ml of TBF was added dropwise slowly at the same temperature over a period of 20 minutes, 2 hours later, a solution of 50 g (35.2 mmol) 4-acetoxy-2-methyl-2-butenal in 40 ml of TH.F was Wadded dropwise to the solution at -45 C. Successively, the mixture was stirred at this temperature for 10 minutes. Then 150 ml of water and 200 ml of petroleum ether was added to the reaction mixture, the organic phase was separated and washed with 100 ml of saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate. Removal of the solvent by evaporation under reduced pressure gave 10.5 g of yellow oil. In the same way as in example 1, the resulting vitamin A acetate was quantified by HPLC, the content of all trans-vitamin A acetate was 85.0%, the total content of 11-cis and 13-cis isomers was 7.1% and the content of 9-cis isomer was 1.3%.
	With sodium chloride; sodium t-butanolate; In 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1,3-pentadienylphosphonic acid diethyl ester; water; N,N-dimethyl-formamide; toluene;	Example 3 Preparation of Vitamin A Acetate Under a nitrogen gas atmosphere, a 250 ml brown flask was charged with the mixture of 5.0 g (93.2% in purity) of 3-methyl-5-(2, 6, 6-trimethyl-1-cyclohexen-1-yl)-1, 3-pentadienylphosphonic acid diethyl ester and 5.0 g (93.5% in purity) of 3-methyl-5(2, 6, 6-trimethyl-1-cyclohexen-1-yl)-1, 4-pentadienylphosphonic acid diethyl ester dissolved in 40 ml of toluene, cooled to -35 C. Then, with stirring, a solution of 50 g sodium tert-butoxide in the mixture of 20 ml of DMF and 10 ml of toluene was added dropwise slowly at the same temperature over a period. of about 30 minutes, and the mixture was stirred for further 2 hours. A solution of 5.0 g 4-acetoxy-2-methyl-2-butenal in 40 ml of toluene was added dropwise to the stirred mixture with the temperature being maintained at -35 C. After addition was completed, the mixture was stirred at the same temperature for further 10 minutes. Then 100 ml of water was added to the reaction mixture, the organic phase was separated and washed with 50 ml of saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate. Removal of the solvent by evaporation under reduced pressure gave 11.0 g of yellow oil. In the same way as in example 1, the resulting vitamin A acetate was quantified by HPLC, the content of all trans-vitamin A acetate was 89.2%, the total content of 11-cis and 13-cis isomers was 6.7% and the content of 9-cis isomer was 1.0%

Reference： [1]Patent: US2002/151742,2002,A1
[2]Patent: US2002/151742,2002,A1

11
[ 26586-02-7 ]
[ 128759-88-6 ]
[ 127-47-9 ]

Yield	Reaction Conditions	Operation in experiment
7.1%	With dimethyl sulfoxide; In tetrahydrofuran; hexane; water;	EXAMPLE 8 Preparation of vitamin A acetate 60% Sodium hydride (1.18 g, 29.5 mmol) was placed in a 200 ml flask in which the atmosphere had been replaced with nitrogen gas, and washed with n-hexane (5 ml) three times. Then, dimethyl sulfoxide (15 ml) was added and the mixture was stirred at 65 C. for 45 minutes to give dimsylsodium. After cooling, tetrahydrofuran (50 ml) was added, and the mixture was cooled to -50 to -70 C. Then, diethyl 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienyl-phosphonate (5.0 g, purity: 93.6%, 13.75 mmol) was dissolved in tetrahydrofuran (50 ml). This solution was added dropwise to the above dimsylsodium solution over about 25 minutes while maintaining the temperature at -50 to -70 C. After stirring for 20 minutes, a solution of 4-acetoxy-2-methyl-2-buten-1-al (2.5 g, 17.59 mmol) in tetrahydrofuran (50 ml) was added dropwise to the above solution over about 20 minutes while maintaining the temperature at -50 to -70 C. The mixture was stirred at the same temperature for 20 minutes. After completion of the reaction, the reaction mixture was added to hexane (400 ml), and water was added to separate the mixture into two layers. The organic layer was separated and the aqueous layer was extracted with hexane (200 ml). The extract and the organic layer were combined, washed with 10% (by weight) aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off. Evaporation of the solvent gave a yellow oil (5.2 g). This oil was assayed by high performance liquid chromatography according to the same manner as that described in Example 1. The results showed that the yield of the resulting vitamin A acetate (all-trans form) was 70.2%, the total yield of the 11-cis and 13-cis isomers was 7.1%, the yield of the 9-cis isomer was 2.6%.
7.9%	In di-isopropyl ether; water;	EXAMPLE 7 Preparation of vitamin A acetate Diisopropyl ether (200 ml) was placed in a 300 ml flask in which the atmosphere had been replaced with nitrogen gas. Potassium t-butoxide (5.0 g, 44.56 mmol) was added, and the mixture was stirred and cooled to -40 to -50 C. To this mixture was added dropwise a solution of diethyl 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonate (10.0 g, purity: 93.6%, 27.50 mmol) in diisopropyl ether (25 ml) over about 30 minutes while maintaining the temperature at -40 to -50 C. Then, to this solution was added dropwise a solution of 4-acetoxy-2-methyl-2-buten-1-al (5.0 g, 35.17 mmol) in diisopropyl ether (25 ml) over about 30 minutes while maintaining the temperature at -40 to -50 C. The mixture was stirred at the same temperature for additional 30 minutes. After completion of the reaction, water was added and the mixture was allowed to stand. The organic layer was separated and the aqueous layer was extracted with diisopropyl ether (50 ml). This extract and the organic layer were combined, washed with water and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off. Evaporation of the solvent under reduced pressure gave a yellow oil (9.3 g). This oil was assayed by high performance liquid chromatography according the same manner as that described in Example 1. The results showed that the yield of the resulting vitamin A acetate (all-trans form) was 78.4%, the total yield of the 11-cis and 13-cis isomers was 7.9%, and the yield of the 9-cis isomer was 2.9%.
7.0%	In N-methyl-acetamide; water; toluene;	EXAMPLE 4 Preparation of vitamin A acetate Diethyl 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonate (10 g, purity: 93.2%, 27.4 mmol) was placed in a 300 ml flask in which the atmosphere had been replaced with nitrogen gas, and dissolved in toluene (40 ml). The solution was cooled to -45 C. A solution of sodium t-butoxide (7.5 g, 78.0 mmol) in a mixed solution of toluene (75 ml) and dimethylformamide (45 ml) and a solution of 4-acetoxy-2-methyl-2-buten-1-al (5.0 g, 35.2 mmol) in toluene (40 ml) were added dropwise simultaneously over about 25 minutes to the above solution cooled to -45 C. After completion of the addition, the mixture was stirred at -45 C. for 5 minutes, and water (45 ml) was added. The organic layer was separated and washed with water (200 ml) twice. Evaporation of the solvent under reduced pressure gave a yellow solid (10.3 g). This solid was assayed by high performance liquid chromatography according the same manner as that described in Example 1. The results showed that the yield of the vitamin A acetate (all-trans form) was 90.2%, the yield of the total of the 11-cis and 13-cis isomers was 7.0%, and the yield of the 9-cis isomer was 1.0%.

6.9%	With nitrogen; In N-methyl-acetamide; di-isopropyl ether; water;	EXAMPLE 2 Preparation of vitamin A acetate Diethyl 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonate (8.0 g, purity: 93.4%, 21.95 mmol) was placed in a 300 ml flask in which the atmosphere had been replaced with nitrogen gas, dissolved in diisopropyl ether (160 ml), and the solution was cooled to -65 C. A solution of potassium t-butoxide (4.0 g, 35.65 mmol) in a mixed solution of diisopropyl ether (20 ml) and dimethylformamide (8 ml) was added dropwise to the above cooled solution over about 15 minutes while maintaining the temperature at -65 C. One to two minutes later, a solution of 4-acetoxy-2-methyl-2-buten-1-al (4.0 g, 28.14 mmol) in diisopropyl ether (20 ml) was added dropwise over about 15 minutes. After completion of the addition, the mixture was stirred at the same temperature for 5 minutes, water (200 ml) was added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with diisopropyl ether (40 ml). The extract and the above organic layer were combined. The mixture was washed with water and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and evaporation of the solvent under reduced pressure gave a yellow oil (8.1 g). This oil was assayed by high performance liquid chromatography according the same manner as that described in Example 1. The results showed that the yield of the resulting vitamin A acetate (all-trans form) was 83.2%. The yield of the total of the 11-cis and 13-cis isomers was 6.9%, and the yield of the 9-cis isomer was 1.3%.
6.5%	In N-methyl-acetamide; di-isopropyl ether; water;	EXAMPLE 5 Preparation of vitamin A acetate Diethyl 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonate (10 g, purity: 93.2%, 27.4 mmol) was placed in a 300 ml flask in which the atmosphere had been replaced with nitrogen gas, and dissolved in diisopropyl ether (40 ml). The solution was cooled to -45 C. A solution of sodium t-butoxide (7.5 g, 78.0 mmol) in a mixed solution of diisopropyl ether (75 ml) and dimethylformamide (45 ml) and a solution of 4-acetoxy-2-methyl-2-buten-1-al (5.0 g, 35.2 mmol) in diisopropyl ether (40 ml) was added dropwise simultaneously to the above cooled solution over about 25 minutes. After completion of the addition, the mixture was stirred at -45 C. for 5 minutes, and water (45 ml) was added. The organic layer was separated and washed with water (200 ml) twice. Evaporation of the solvent under reduced pressure gave a yellow solid (10.1 g). This solid was assayed by high performance liquid chromatography according the same manner as that described in Example 1. The results showed that the yield of the vitamin A acetate (all-trans form) was 85.0%, the total yield of the 11-cis and 13-cis isomers was 6.5%, and the yield of the 9-cis isomer was 1.3%.
5.6%	In tetrahydrofuran; hexane; water;	EXAMPLE 6 Preparation of vitamin A acetate Diethyl 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienylphosphonate (8.0 g, purity: 93.4%, 21.95 mmol) was placed in a 300 ml flask in which the atmosphere had been replaced with nitrogen gas, and dissolved in tetrahydrofuran (160 ml). The solution was cooled to -65 C. Potassium t-butoxide (4.0 g, 35.65 mmol) was dissolved in tetrahydrofuran (20 ml). 4-Acetoxy-2-methyl-2-buten-1-al (4.0 g, 28.14 mmol) was dissolved in tetrahydrofuran (20 ml). The above potassium t-butoxide solution was added dropwise to the previously cooled solution of the phosphonic acid diester over about 15 minutes while maintaining the temperature at -65 C. Dropwise addition of the above 4-acetoxy-2-methyl-2-butenal solution was started one to two minutes after beginning of the dropwise addition of the potassium t-butoxide solution, and the addition was carried out over about 15 minutes while maintaining the temperature at -65 C. After completion of the addition, the mixture was stirred at the same temperature for 5 minutes, water was added, hexane (160 ml) was added, and the resulting mixture was allowed to stand. The organic layer was separated and the aqueous layer was extracted with hexane (40 ml). This extract and the organic layer were combined, and the mixture was washed with water and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off. Evaporation of the solvent under reduced pressure gave a yellow oil (8.2 g). This oil was assayed by high performance liquid chromatography according the same manner as that described in Example 1. The results showed that the yield of the resulting vitamin A acetate (all-trans form) was 80.4%, the total yield of the 11-cis and 13-cis isomers was 5.6%, and the yield of the 9-cis isomer was 1.6%.

Reference： [1]Patent: US5424478,1995,A
[2]Patent: US5424478,1995,A
[3]Patent: US5424478,1995,A
[4]Patent: US5424478,1995,A
[5]Patent: US5424478,1995,A
[6]Patent: US5424478,1995,A

12
[ 128-37-0 ]
[ 103905-08-4 ]
[ 127-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; ammonium chloride; acetic anhydride; sodium hydrogencarbonate; triethylamine; In hexane; di-isopropyl ether; cyclohexane; argon;	EXAMPLE 21 STR57 A 50 ml flask purged with argon gas was charged with 0.4913 g (0.970 mmole) of 1-acetoxy-6-chloro-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,7-nonadiene (15) obtained in Example 12, (A) and 15 ml of cyclohexane. The mixture was stirred for a while, and 0.66 g (10 mmoles) of potassium hydroxide (purity 85%) was added. The mixture was stirred at 65 C. for 1.5 hours, and further at the refluxing temperature for 2 hours. After cooling, 30 ml of diisopropyl ether and 15 ml of a saturated aqueous solution of ammonium chloride were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with 20 ml of diisopropyl ether. The extract was combined with the organic layer, and the mixture was washed with a saturated aqueous solution of ammonium chloride, and dried over anhydrous magnesium sulfate. The organic solvent was evaporated from the organic layer, and the residue, together with 5 ml of a 0.05% by weight hexane solution of 2,6-di-t-butyl-4-methylphenol and 1.1 ml of triethylamine, was put in a 100 ml flask purged with argon. Under ice bath cooling, 0.68 ml of acetic anhydride was added to the mixture. The mixture was stirred at room temperature for 1 day. To the reaction mixture were added 50 ml of hexane and 10 ml of a saturated aqueous solution of sodium bicarbonate. The mixture was stirred for a while, and the hexane layer was separated. The hexane layer was washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous magnesium sulfate. Hexane was evaporated from the hexane solution to give 0.3577 g of a red oily product. The resulting vitamin A acetate was quantified by high-performance liquid chromatography in the same way as in Example 16.

Reference： [1]Patent: US4825006,1989,A

13
1-acetoxy-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,6,8-nonatriene [ No CAS ]
[ 865-33-8 ]
[ 127-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; acetic anhydride; sodium hydrogencarbonate; triethylamine; In hexane; di-isopropyl ether; cyclohexane; argon;	EXAMPLE 27 STR70 A 50 ml flask purged with argon gas was charged with 0.4812 g (1.02 mmoles) of 1-acetoxy-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,6,8-nonatriene (19), 15 ml of cyclohexane and 0.70 g (10 mmoles) of potassium methoxide, and the mixture was stirred at 38 C. for 2 hours. The reaction mixture was partitioned between 30 ml of diisopropyl ether and 15 ml of a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with 20 ml of diisopropyl ether, and the extract was combined with the organic layer. The mixture was washed with a saturated aqueous solution of ammonium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed from the organic layer, and the residue, together with 4 ml of a 0.05% by weight hexane soilution of 2,6-di-t-butyl-4-methylphenol and 1.1 ml of triethylamine, was put in a 100 ml flask purged with argon gas. To the mixture was added 0.68 ml of acetic anhydride, and the entire mixture was stirred at room temperature for one day. The reaction mixture was stirred for a while together with 50 ml of hexane and 10 ml of a saturated aqueous solution of sodium bicarbonate, and the hexane layer was separated. The hexane layer was washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous magnesium sulfate. Hexane was evaporated from the hexane solution to give 0.3276 g of a red oily product. The FD-MASS analysis of the oily product revealed a peak at m/e=328. This led to the determination that the main component of the oily product was vitamin A acetate (7) The resulting vitamin A acetate was quantified by high-performance liquid chromatography using methyl stearate as an internal standard.

Reference： [1]Patent: US4825006,1989,A

14
[ 59830-43-2 ]
[ 68-26-8 ]
[ 127-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; ammonia; sodium; In diethyl ether; isopropyl alcohol;	EXAMPLE 8 Sodamide was prepared by the addition of 0.12 g. of sodium to 4 ml. of ammonia containing a crystal of ferric nitrate. When the blue solution had decolorized 1-hydroxy-3,7-dimethyl-4-(phenylsulfonyl)-9-(2,6,6-trimethylcyclohexen-1-yl)-nona-2,6,8-triene, (0.13 g.) was added at -80C. in 2 ml. of diethyl ether. The solution was warmed to reflux (-33C.) and kept there 5 minutes. Ammonium chloride (0.5 g.) was added followed by 15 ml. of diethyl ether. The ammonia was evaporated and the organic solution was washed with brine and dried and concentrated to afford 0.25 g. of an orange oil containing vitamin A alcohol and displaying a UV in isopropanol at lambdamax = 328 mmu. Acetylation was carried out as described in Example 7 utilizing 0.2 g. of the crude vitamin A alcohol. This afforded 0.218 g. of crude vitamin A acetate having a UV in isopropanol at lambda max = 325-7 (epsilon = 21,180). Liquid chromatography indicated a vitamin A acetate content of 29%.

Reference： [1]Patent: US3960967,1976,A

15
[ 59830-43-2 ]
[ 127-47-9 ]
[ 68-26-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; sodium; In diethyl ether; water; tert-butyl alcohol;	EXAMPLE 10 Sodamide was prepared by the addition of 0.48 g. of sodium to 20 ml. o anhydrous ammonia containing a crystal of ferric nitrate. When the color was discharged, a solution of 0.54 g. of 1-hydroxy-3,7-dimethyl-4-(phenylsulfonyl)-9-(2,6,6-trimethylcyclohexen-1-yl)-nona-2,6,8-triene in 10 ml. of anhydrous diethyl ether was added, followed by 2.15 ml. of t-butanol added in two portions. Total reaction time at -33C. was 11/2 hours. Solid ammonium chloride (2.5 g.) was added and the ammonia was evaporated. Water was added and the residue was extracted with diethyl ether. of combined extracts were washed with brine, dried and concentrated to give 0.399 g. of crude vitamin A alcohol. Acetylation of the vitamin A alcohol as described in Example 7 afforded 0.364 g. of crude vitamin A acetate having a UV in isopropanol at lambdamax = 324-4 mmu (epsilon=22,935). Liquid chromatography indicated a vitamin A acetate content of 47% of which 45% was the all trans isomer.
	In tert-butyl alcohol;	EXAMPLE 9 1-hydroxy-3,7-dimethyl-4-(phenylsulfonyl)-9-(2,6,6-trimethylcyclohexen-1-yl)-nona-2,6,8-triene, (0.295 g.) was dissolved in 2.0 ml. of t-butanol and 0.6 g. of potassium t-butoxide was added. The mixture was then stirred for 1/2 hour at room temperature, refluxed for 1 hour and poured into water. The aqueous mixture was extracted with diethyl ether and washed with brine and dried to give 0.242 g. of crude vitamin A alcohol. Acetylation of the crude vitamin A alcohol was carried out by the procedure of Example 7 to afford 0.195 g. of crude vitamin A acetate having a UV in isopropanol at lambda max = 320-2 mmu (epsilon = 18,200).

Reference： [1]Patent: US3960967,1976,A
[2]Patent: US3960967,1976,A

16
[ 59830-46-5 ]
[ 127-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; ammonia; sodium; In diethyl ether; water; tert-butyl alcohol;	EXAMPLE 14 Preparation of vitamin A acetate Sodamide was prepared by dissolving 0.014 g. of sodium to 5 ml. of ammonia containing a crystal of ferric nitrate. To the decolorized suspension was added 0.89 g. of t-butanol followed by a solution of 0.030 g. of the 1-hydroxy-3,7-dimethyl-4-(p-trifluoromethylphenylsulfonyl)-9-(2,6,6-trimethylcyclohexen-1-yl)-nona-2,6,8-triene in 20 ml. of diethyl ether. The reaction mixture was stirred for 11/2 hours at reflux and 0.5 g. of ammonium chloride was added followed by 5 ml. of diethyl ether. The ammonia was evaporated and the residue was added to water and extracted with diethyl ether. The extracts were washed with brine and dried and concentrated to give 0.016 g. of a yellow oil containing vitamin A alcohol. The crude vitamin A alcohol product was acetylated by the procedure of Example 7 to give 0.011 g. of crude vitamin A acetate product which had a UV absorption in isopropanol at lambdamax = 323-7.

Reference： [1]Patent: US3960967,1976,A

17
[ 127-47-9 ]
[ 68269-24-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium chlorate; sodium iodide; sulfuric acid; In dichloromethane; water;	EXAMPLE 3 0.1 mole of vitamin A acetate is introduced into 850 ml of methylene chloride. A solution of 79.5 g of sodium chlorate (0.75 mole) and 1.125 g (7.51 mmoles, corresponding to 7.5 mole %, based on vitamin A acetate) of sodium iodide in 300 ml of water is added. After cooling to 10 C., the mixture is acidified with 0.015 g of concentrated sulfuric acid and is stirred at 10 C. for 18 hours. The phases are then separated and the organic phase is washed with 400 ml of saturated sodium bicarbonate solution and then with water. After drying and concentrating, an oily raw material which contains 57% by weight of 4-oxo-vitamin A acetate is obtained. The ketone can be obtained pure by column chromatography. 220 Mc/s--1 H--NMR spectrum (CDCl3); delta values: 1.4 s (6H); 1.8 s (3H); 2.5 t (2H); 6.1-6.7 m (5H). Mass spectrum: m/e: 282 (M--CH3 COOH); 43 (H3 C--CO). IR spectrum: bands at 1,735 cm-1 and 1,655 cm-1.

Reference： [1]Patent: US4209450,1980,A

18
[ 337913-25-4 ]
(2Z,4Z)-3,7-dimethyl-6-hydroxy-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate [ No CAS ]
argon [ No CAS ]
[ 127-47-9 ]

Yield	Reaction Conditions	Operation in experiment
94.9%	In N-methyl-acetamide;	Example 1 Synthesis of (all-E)-3,7-dimethyl-9-(2',6', 6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate ((all-E)-vitamin A acetate) from (2Z,4Z)-3,7-dimethyl-6-hydroxy-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate In a 100 ml round-bottomed flask equipped with a magnetic bar stirrer and flushed with argon were introduced 1020 mg (2.94 mmol) of (2Z,4Z)-3,7-dimethyl-6-hydroxy-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate and 30 ml of dimethylformamide. The stirred (350 rpm) homogeneous solution was cooled down to 0 C. (ice bath), and 1250 mg (8.82 mmol) of phosphorous pentoxide were rapidly added to the mixture. Then, the reaction mixture was stirred (350 rpm) at 0 C. (ice bath) for about 16 hours. After that reaction, the yield of (all-E)-vitamin A acetate was calculated on the basis of RP-HPLC to be 917.6 mg (94.9% yield based on the amount of starting material used; content: 83.8% all-E, 15.3% 2Z, 1.0% 2Z,4Z).

Reference： [1]Patent: US6215009,2001,B1

19
(2Z,4Z)-3,7-dimethyl-6-hydroxy-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate [ No CAS ]
argon [ No CAS ]
[ 127-47-9 ]

Yield	Reaction Conditions	Operation in experiment
95.8%	In N-methyl-acetamide;	Example 2 Synthesis of (all-E)-3,7-dimethyl-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl 1)-nona-2,4,6,8-tetraenyl acetate ((all-E)-vitamin A acetate) from (2Z,4Z)-3,7-dimethyl-6-hydroxy-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate In a 100 ml round-bottomed flask equipped with a magnetic bar stirrer and flushed with argon were introduced 1020 mg (2.94 mmol) of (2Z,4Z)-3,7-dimethyl-6-hydroxy-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate and 30 ml of dimethylformamide. The stirred (350 rpm) homogeneous solution was cooled down to 0 C. (ice bath), and 900.0 mg (5.88 mmol) of 1:1-dimethylformamide-sulphur trioxide-complex were rapidly added to the mixture. Then, the reaction mixture was stirred (350 rpm) at 0 C. (ice bath) for about 20 hours. After that reaction, the yield of (all-E)-vitamin A acetate was calculated on the basis of RP-HPLC to be 926.0 mg (95.8% yield based on the amount of starting material used; content: 83.0% all-E, 15.7% 2Z, 1.2% 2Z,4Z).
94.1%	In N-methyl-acetamide;	Example 3 Synthesis of (all-E)-3,7-dimethyl-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate ((all-E)-vitamin A acetate) from (2Z,4Z)-3,7-dimethyl-6-hydroxy-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate In a 100 ml round-bottomed flask equipped with a magnetic bar stirrer and flushed with argon were introduced 1020 mg (2.94 mmol) of (2Z,4Z)-3,7-dimethyl-6-hydroxy-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate and 30 ml of dimethylformamide. The stirred (350 rpm) homogeneous solution was cooled down to 0 C. (ice bath), and 1920 mg (5.88 mmol) of p-toluenesulphonic acid anhydride were rapidly added to the mixture. Then, the reaction mixture was stirred (350 rpm) at 0 C. (ice bath) for about 16 hours. After that reaction, the yield of (all-E)-vitamin A acetate was calculated on the basis of RP-HPLC to be 909.4 mg (94.1% yield based on the amount of starting material used; content: 81.5% all-E, 17.2% 2Z, 1.3% 2Z,4Z).
93.9%	In N-methyl-acetamide;	Example 4 Synthesis of (all-E)-3,7-dimethyl-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate ((all-E)-vitamin A acetate) from (2Z,4Z)-3,7-dimethyl-6-hydroxy-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate In a 100 ml round-bottomed flask equipped with a magnetic bar stirrer and flushed with argon were introduced 1020 mg (2.94 mmol) of (2Z,4Z)-3,7-dimethyl-6-hydroxy-9-(2',6',6'-trimethylcyclohex-1'-en-1'-yl)-nona-2,4,6,8-tetraenyl acetate and 30 ml of dimethylformamide. The stirred (350 rpm) homogeneous solution was cooled down to -45 C. to -50 C. (ice bath), and 534 mul (913.6 mg, 3.24 mmol) of trifluoromethanesulphonic acid anhydride were added to the mixture within 3-5 minutes. Then, the reaction mixture was stirred (350 rpm) at -45 C. to -50 C. for about 6 hours. After that reaction, the yield of (all-E)-vitamin A acetate was calculated on the basis of RP-HPLC to be 908.0 mg (93.9% yield based on the amount of starting material used; content: 88.3% all-E, 11.3% 2Z, 0.4% 2Z,4Z).

Reference： [1]Patent: US6215009,2001,B1
[2]Patent: US6215009,2001,B1
[3]Patent: US6215009,2001,B1

20
[ 112-80-1 ]
[ 127-47-9 ]
[ 631-88-9 ]
[ 68-26-8 ]

Yield	Reaction Conditions	Operation in experiment
69%	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21; In toluene; at 20℃; for 15h;Enzymatic reaction;Product distribution / selectivity;	Example 29; Preparation of Retinyl Oleate in the Presence of Amberlyst A-21; Retinyl acetate (1.00 g; 3.04 mmol) and dried Amberlyst A-21 (0.5 g) were combined with 8.5 mL of toluene. Oleic acid (1.72 g; 6.09 mmol; 2.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 15 h, at which point a sample was removed and analyzed by HPLC, indicating 89.2% conversion to retinyl oleate with 9.0% retinyl acetate and 1.9% retinol. The reaction mixture was filtered and concentrated, then concentrated twice with heptane (10 mL each). The residue was dissolved in heptane (15 mL) and washed with 2×20 mL with a 1:1 mixture of 10% aqueous potassium carbonate and methanol. The organic layer was washed further with a mixture of saturated sodium bicarbonate (2.5 mL), water (7.5 mL), and methanol (10 mL), dried (sodium sulfate) and concentrated to afford 1.16 g (69%) of a yellow oil. HPLC (4.6×150 mm Zorbax SB-C8 column [Agilent], 3.5mu thickness, methanol eluent, detection at 350 nm): TR 5.65 min (retinyl oleate); TR 2.32 min (retinyl acetate); TR 2.08 min (retinol).

Reference： [1]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 11-12

21
[ 127-47-9 ]
[ 57-10-3 ]
[ 79-81-2 ]
[ 68-26-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21; In toluene; at 20℃; for 15.0h;Enzymatic reaction;Product distribution / selectivity;	Example 28; Preparation of Retinyl Palmitate in the Presence of Amberlyst A-21; Retinyl acetate (1.00 g; 3.04 mmol) was dissolved in 8.5 mL of toluene and palmitic acid (1.56 g; 6.09 mmol; 2.0 equiv) was added followed by 120 mg of Novozyme 435 and 0.5g of dried Amberlyst A-21. The reaction mixture was stirred at RT for 15 h, at which point a sample was removed and analyzed by HPLC, indicating 89.2% conversion to retinyl palmitate with 9.1% retinyl acetate and 1.7% retinol. The reaction mixture was filtered and concentrated, then concentrated twice with heptane (10 mL each). The residue was dissolved in heptane (15 mL) and washed with 2×20 mL with a 1:1 mixture of 10% aqueous potassium carbonate and methanol. The organic layer was washed further with a mixture of saturated sodium bicarbonate (2.5 mL), water (7.5 mL), and methanol (10 mL), dried (sodium sulfate) and concentrated to afford 1.25 g (78%) of a yellow oil. Analysis of this product indicated 91.2% retinyl palmitate (HPLC area percent), 0.4 wt % palmitic acid, and 0.2% retinol. HPLC (4.6×150 mm Zorbax SB-C8 column [Agilent], 3.5mu thickness, methanol eluent, detection at 350 nm): tR 5.52 min (retinyl palmitate); tR 2.32 min (retinyl acetate); tR 2.08 min (retinol).

Reference： [1]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 11

22
[ 127-47-9 ]
[ 1077-28-7 ]
retinyl lipoate [ No CAS ]
[ 68-26-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21; In toluene; at 20℃; for 21h;Enzymatic reaction; Sonication;Product distribution / selectivity;	Example 30; Preparation of Retinyl Lipoate in the Presence of Amberlyst A-21; Retinyl acetate (1.00 g; 3.04 mmol) and lipoic acid (1.26 g; 6.09 mmol; 2.0 equiv) were combined with dried Amberlyst A-21 (0.5 g). Toluene (3.5 mL) was added and the mixture was sonicated and 120 mg of Novozyme 435 was added. The reaction mixture was stirred at RT for 21 h, at which point a sample was removed and analyzed by HPLC, indicating 85.3% conversion to retinyl lipoate with 12.8% retinyl acetate and 1.9% retinol. The reaction mixture was filtered and concentrated, and the residue was dissolved in 1:1 ethyl acetate:heptane (20 mL). The solution was washed with 10 mL of a 10% aqueous potassium carbonate followed by 10 mL of a mixture of saturated sodium bicarbonate (5 mL) and water (5 mL). The organic solution was dried (sodium sulfate) and concentrated to afford 1.06 g (71%) of a yellow oil.HPLC (4.6×150 mm Zorbax SB-C8 column [Agilent], 3.5mu thickness, methanol eluent, detection at 350 nm): TR 2.68 min (retinyl lipoate); TR 2.32 min (retinyl acetate); TR 2.08 min (retinol).

Reference： [1]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 12

23
[ 60-33-3 ]
[ 127-47-9 ]
retinyl linoleate [ No CAS ]
[ 68-26-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21; In toluene; at 20℃; for 2 - 50h;Enzymatic reaction;Product distribution / selectivity;	Example 4; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 71.7% conversion to retinyl linoleate with 17.7% retinyl acetate and 10.6% retinol. Stirring for an additional 2 days afforded no further change.; Example 4; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 71.7% conversion to retinyl linoleate with 17.7% retinyl acetate and 10.6% retinol. Stirring for an additional 2 days afforded no further change.; Example 9; Preparation of Retinyl Linoleate with 5 Equiv of Linoleic Acid in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (140 mg; 5.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 87.4% conversion to retinyl linoleate with 9.2% retinyl acetate and 3.4% retinol. Stirring overnight afforded no further change.; Example 15; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid and Product Isolation; Retinyl acetate (4.11 g; 12.5 mmol) and linoleic acid (7.01 g; 25.0 mmol; 2.0 equiv) were dissolved in 35 mL of toluene. Novozyme 435 (1.0 g) and dried Amberlyst A-21 (2.1 g) were added, and the reaction mixture was evacuated and filled with nitrogen ten times. The reaction mixture was stirred in the dark at ambient temperature for 5.5 h, at which point HPLC analysis indicated 90.3% conversion to retinyl linoleate (9.1% retinyl acetate and 0.6% retinol). The reaction mixture was filtered and concentrated, then concentrated twice with heptane (10 mL each). The residue was dissolved in heptane (50 mL) and washed with 2×80 mL with a 1:1 mixture of 10% aqueous potassium carbonate and methanol. The organic layer was washed further with a mixture of saturated sodium bicarbonate (10 mL), water (30 mL), and methanol (40 mL), dried (sodium sulfate) and concentrated to afford 5.14 g (75%) of a yellow oil. A portion of this material (4.00 g) was dissolved in 40 mL of heptane and washed with 20 mL of methanol. The heptane layer was concentrated to afford 3.77 g (71% overall) of retinyl linoleate. Analysis of this product indicated 90.9% retinyl linoleate (HPLC area percent), 0.26 wt % linoleic acid, and 0.06 wt % retinol. The initial aqueous extracts (using a 1:1 mixture of 10% aqueous potassium carbonate and methanol) were acidified to pH 1 with 25 mL of 3 M HCl. The resulting mixture was extracted with 20 mL of heptane. The organic solution was dried with sodium sulfate and concentrated to afford 3.91 g (56% of initial charge) of recovered linoleic acid, which was suitable for re-use.
	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); In toluene; at 20 - 50℃; for 1 - 2h;Enzymatic reaction;Product distribution / selectivity;	Example 1; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred and heated at 50 C. for 1 h, at which point a sample was removed and analyzed by HPLC, indicating 49.8% conversion to retinyl linoleate with 39.8% retinyl acetate and 10.4% retinol.HPLC (4.6×150 mm Zorbax SB-C8 column [Agilent], 3.5mu thickness, methanol eluent, detection at 350 nm): tR 4.77 min (retinyl linoleate); tR 2.32 min (retinyl acetate); tR 2.08 min (retinol).; Example 5; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (56 mg; 2.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at ambient temperature for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 63.4% conversion to retinyl linoleate with 30.5% retinyl acetate and 4.8% retinol.; Example 8; Preparation of Retinyl Linoleate with 5 Equiv of Linoleic Acid; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (140 mg; 2.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at ambient temperature for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 78.7% conversion to retinyl linoleate with 17.6% retinyl acetate and 3.7% retinol.
	With Lipozyme TI IM; Amberlyst A-21; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity;	Example 24; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipozyme TI IM in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipozyme TI IM (Novozyme). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 14.6% conversion to retinyl linoleate with 84.7% retinyl acetate and 0.7% retinol.

	With Lipozyme TI IM; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity;	Example 23; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipozyme TI IM; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipozyme TI IM (Novozyme). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 2.0% conversion to retinyl linoleate with 94.9% retinyl acetate and 3.2% retinol.
	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlite IRA-95; In toluene; at 20℃; for 2 - 50h;Enzymatic reaction;Product distribution / selectivity;	Example 3; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid in the Presence of Amberlite IRA-95; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlite IRA-95. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 2 h, at which point a sample was removed and analyzed by HPLC, indicating 72.3% conversion to retinyl linoleate with 16.3% retinyl acetate and 11.3% retinol. Stirring for an additional 2 days afforded no further change.
	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21; In acetonitrile; at 20℃; for 23h;Enzymatic reaction; Sonication;Product distribution / selectivity;	Example 12; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid in Acetonitrile with Amberlyst A-21; Retinyl acetate (500 mg; 1.52 mmol) was dissolved in 3.5 mL of acetonitrile with sonication. Dried Amberlyst A-21 (0.25 g) was added. Linoleic acid (850 mg; 3.04 mmol; 2.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 19 h, at which point a sample was removed and analyzed by HPLC, indicating 58.5% conversion to retinyl linoleate with 40.0% retinyl acetate and 1.6% retinol.
	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); Amberlyst A-21; In limonene.; at 20℃; for 23h;Enzymatic reaction;Product distribution / selectivity;	Example 14; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid in Limonene with Amberlyst A-21; Retinyl acetate (500 mg; 1.52 mmol) and linoleic acid (850 mg; 3.04 mmol; 2.0 equiv) were dissolved in 3.5 mL of limonene. Dried Amberlyst A-21 (0.25 g) and Novozyme 435 (120 mg) were added and the reaction mixture was stirred at RT for 23 h, at which point a sample was removed and analyzed by HPLC, indicating 90.3% conversion to retinyl linoleate with 8.5% retinyl acetate and 1.2% retinol.
	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); In vegetable oil; toluene; at 50℃; for 1h;Enzymatic reaction;Product distribution / selectivity;	Example 7; Preparation of Retinyl Linoleate in Vegetable Oil with 2 Equiv of Linoleic Acid; Retinyl acetate (52% in vegetable oil, 63 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (56 mg; 2.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred and heated at 50 C. for 1 h, at which point a sample was removed and analyzed by HPLC, indicating 71.7% conversion to retinyl linoleate with 18.0% retinyl acetate and 10.2% retinol.; Example 10; Preparation of Retinyl Linoleate in Vegetable Oil with 5 Equiv of Linoleic Acid; Retinyl acetate (52% in vegetable oil, 63 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (140 mg; 5.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred and heated at 50 C. for 1 h, at which point a sample was removed and analyzed by HPLC, indicating 83.0% conversion to retinyl linoleate with 10.9% retinyl acetate and 6.2% retinol.
	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); In toluene; at 50℃; for 1 - 49h;Enzymatic reaction; Molecular sieve;Product distribution / selectivity;	Example 2; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid in the Presence of Organophilic Molecular Sieves; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 100 mg of organophilic molecular sieves. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred and heated at 50 C. for 1 h, at which point a sample was removed and analyzed by HPLC, indicating 53.2% conversion to retinyl linoleate with 14.4% retinyl acetate and 32.4% retinol.
	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); In acetonitrile; at 20℃; for 19h;Enzymatic reaction; Sonication;Product distribution / selectivity;	Example 11; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid in Acetonitrile; Retinyl acetate (500 mg; 1.52 mmol) was dissolved in 3.5 mL of acetonitrile with sonication. Linoleic acid (850 mg; 3.04 mmol; 2.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred at RT for 19 h, at which point a sample was removed and analyzed by HPLC, indicating 28.7% conversion to retinyl linoleate with 70.8% retinyl acetate and 0.5% retinol.
	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin); In limonene.; at 20℃; for 23h;Enzymatic reaction;Product distribution / selectivity;	Example 13; Preparation of Retinyl Linoleate with 2 Equiv of Linoleic Acid in Limonene; Retinyl acetate (500 mg; 1.52 mmol) and linoleic acid (850 mg; 3.04 mmol; 2.0 equiv) were dissolved in 3.5 mL of limonene. Novozyme 435 (120 mg) was added and the reaction mixture was stirred at RT for 23 h, at which point a sample was removed and analyzed by HPLC, indicating 65.8% conversion to retinyl linoleate with 32.3% retinyl acetate and 1.9% retinol.
	With lipase PS-C (from Psuedomonas sp immobilized on ceramic); Amberlyst A-21; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity;	Example 20; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipase PS-C in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0. 10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS-C (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 68.8% conversion to retinyl linoleate with 23.6% retinyl acetate and 7.6% retinol.
	With lipase PS-C (from Psuedomonas sp immobilized on ceramic); In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity;	Example 19; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic acid Using Lipase PS-C; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS-C (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 46.1% conversion to retinyl linoleate with 48.7% retinyl acetate and 5.2% retinol.
	With lipase PS-D (from Pseudomonas sp immobilized on diatomaceous earth); Amberlyst A-21; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity;	Example 22; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipase PS in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0. 10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS-D (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 69.2% conversion to retinyl linoleate with 25.8% retinyl acetate and 5.0% retinol.
	With lipase PS-D (from Pseudomonas sp immobilized on diatomaceous earth); In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity;	Example 21; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipase PS-D; Retinyl acetate (33 mg; 0. 10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS-D (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 35.4% conversion to retinyl linoleate with 63.4% retinyl acetate and 1.2% retinol.
	With Lipase PS; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity;	Example 18; Preparation of Retinyl Linoleate with 1Equiv of Linoleic Acid Using Lipase PS in the Presence of Amberlyst A-21; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene and added to 50 mg of dried Amberlyst A-21. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 10.0% conversion to retinyl linoleate with 87.3% retinyl acetate and 2.7% retinol.
	With Lipase PS; In toluene; at 20℃; for 45h;Enzymatic reaction;Product distribution / selectivity;	Example 17; Preparation of Retinyl Linoleate with 1 Equiv of Linoleic Acid Using Lipase PS; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Linoleic acid (28 mg; 1.0 equiv) was added followed by 120 mg of Lipase PS (Amano). The reaction mixture was stirred at ambient temperature for 45 h, at which point a sample was removed and analyzed by HPLC, indicating 1.4% conversion to retinyl linoleate with 97.5% retinyl acetate and 1.1% retinol.

Reference： [1]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 5-8
[2]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 4-6
[3]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 9-10
[4]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 9
[5]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 5
[6]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 7
[7]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 7
[8]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 6
[9]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 5
[10]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 6-7
[11]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 7
[12]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 9
[13]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 8-9
[14]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 9
[15]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 9
[16]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 8
[17]Patent: US7566795,2009,B2 .Location in patent: Page/Page column 8

24
[ 112-63-0 ]
[ 127-47-9 ]
retinyl linoleate [ No CAS ]
[ 68-26-8 ]

Yield	Reaction Conditions	Operation in experiment
	With Novozyme 435 (from Candida antarctica immobilized on acrylic resin) In toluene at 20℃; Enzymatic reaction;	16 Example 16; Preparation of Retinyl Linoleate with 1 Equiv of Methyl Linoleate; Retinyl acetate (33 mg; 0.10 mmol) was dissolved in 5 mL of toluene. Methyl linoleate (30 mg; 1.0 equiv) was added followed by 120 mg of Novozyme 435. The reaction mixture was stirred overnight at RT, at which point a sample was removed and analyzed by HPLC, indicating 49.3% conversion to retinyl linoleate with 36.9% retinyl acetate and 13.8% retinol.

Reference： [1]Current Patent Assignee: EASTMAN CHEMICAL CO - US7566795, 2009, B2 Location in patent: Page/Page column 8

25
[ 127-47-9 ]
[ 24951-77-7 ]
[ 1332483-34-7 ]
[ 1332483-20-1 ]

Yield	Reaction Conditions	Operation in experiment
	With Hoveyda-Grubbs catalyst second generation; In toluene; at 20℃; for 96h;Inert atmosphere;	General procedure: To the solution of a polyene (c=9.7×10-2 or 4.9×10-2 M) and of Hoveyda (Grubbs) second generation catalyst (15 mol %) in dry toluene (or dichloromethane or methanol) olefin (1-4 equiv) was added dropwise. The reaction mixture was stirred at rt under argon atmosphere. Then the mixture was analyzed by HPLC and purified by semipreparative HPLC or column chromatography.