KR101123847B1 - Preparation method of oseltamivirtamiflu - Google Patents
Preparation method of oseltamivirtamiflu Download PDFInfo
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Abstract
In the method for preparing oseltamivir according to the present invention, a method for preparing oseltamivir, which is not mentioned in the related art, has been completed, and a precursor for synthesizing oseltamivir has been prepared, and cyclization is performed by an intramolecular aldol reaction therefrom. Not only are the preparations of tamivir possible, but also starting with readily available starting materials, the synthesis step can be reduced and the oseltamivir produced in high yield by eliminating the conventional protection / unprotection process.
Description
The present invention relates to a novel process for producing oseltamivir.
Oseltamivir, also known as Tamiflu, is a compound of Formula 1 that is widely used as a treatment for swine flu or avian influenza (H1N1: bird flu).
[Formula 1]
Globally, fears of swine flu or avian influenza could be a serious pandemic, and governments in each country are moving to stock up on oseltamivir, and enough oseltamivir to meet these demand spikes. It is required to secure.
The manufacture of oseltamivir was first developed by Gilead Science and Hoffman-La Roche, and oseltamivir was recognized by the World Health Organization (WHO) in 2004 as a treatment for avian influenza. It is a compound that is sold around the world. The oseltamivir has three carbons having chirality in chemical structure, and if the part is changed, the medicament is changed, and thus, a manufacturing method for making chelalt is very difficult in the manufacturing process of oseltamivir.
International publication WO96 / 026933 of Gilad Science and Hoffman-La Roche describes a method for preparing oseltamivir, as shown in Scheme A below.
[Reaction Scheme A]
As shown in Scheme A, in order to have the chirality of oseltamivir, (-)-Shikimic acid or (-)-quinic acid is used as the starting material in Scheme A. Can be. That is, to produce oseltamivir using a starting material having a chirality, the starting material is a chiral material extracted from natural products, the production is limited and expensive raw materials.
In order to solve the above problems, various manufacturing methods are reported as follows.
European Patent No. 1127872 to Hoffman-La Roche A-G describes the preparation of oseltamivir, as shown in Scheme B below.
[Scheme B]
Scheme B describes a method for preparing oseltamivir by a Diels-Alder reaction using furan instead of an expensive starting material. However, although the production method uses a cheap raw material as a starting material, it can be seen that expensive special raw materials are used to have chiral orientation of oseltamivir.
In a paper published by Corey and his colleagues (JACS 2006. 128. 6310 ~ 6311), the Diels-Alder reaction was used, similar to Hoffman-La Roche AG, as shown in Scheme C. A method for preparing oseltamivir is described.
Scheme C
However, as can be seen in Scheme C, it can be seen that an expensive special raw material is used in order to have the chiral orientation of oseltamivir also.
In a paper published by Shibasaki and his colleagues (TL 2007.1403), a method for preparing oseltamivir using the Diels-Alder reaction similar to Hoffman-La Roche AG is shown in Scheme D below. This is described.
[Reaction Scheme D]
However, there is still a need for new manufacturing methods that can meet the surge in demand for oseltamivir.
Therefore, the present inventors completed the present invention by suggesting a new preparation method for forming a major skeleton of oseltamivir using an intramolecular aldol condensation reaction while studying a novel preparation method of oseltamivir, which is not known in the art. .
An object of the present invention is to provide a novel method for producing oseltamivir.
In order to achieve the above object, the present invention provides a novel method for preparing oseltamivir using an intramolecular aldol condensation reaction.
The method for preparing oseltamivir according to the present invention starts with an easily obtainable starting material and performs cyclization by an intramolecular aldol condensation reaction from a precursor in the form of acyclic. Rather, it is possible to prepare oseltamivir with a high yield by reducing the synthesis step by omitting conventional protective / unprotected procedures.
EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.
As shown in Scheme 1 below,
Reacting the compound represented by Chemical Formula 9 under basic conditions to obtain a compound represented by Chemical Formula 10 (step 1);
Dissolving the compound represented by Chemical Formula 10 obtained in step 1 in an organic solvent and then adding a base to obtain a compound represented by Chemical Formula 11 (step 2);
Obtaining a compound represented by Chemical Formula 12 by hydrogenating and acetylating an azide group of the compound represented by Chemical Formula 11 obtained in step 2 in the presence of a catalyst (Step 3);
Obtaining a compound represented by Chemical Formula 13 by adding a base represented by Chemical Formula 12 obtained in step 3 in an organic solvent (Step 4);
Performing a reaction of substituting the primary hydroxy group of the compound represented by Formula 13 obtained in step 4 with an azide group to obtain a compound represented by Formula 14 (step 5); And
It provides a method for preparing oseltamivir comprising the step (step 6) of reducing the azide group of the compound represented by Formula 14 obtained in step 5 to an amine in an organic solvent to obtain a compound represented by Formula 1:
Scheme 1
In step 1 according to the present invention, the newly formed ring in the compound represented by Formula 10 may be formed by performing an intramolecular aldol condensation reaction on the compound represented by Formula 9. The aldol condensation reaction may be carried out by reacting the compound of formula 9 in the presence of Lewis acid and Hunig base in an organic solvent.
For example, a compound represented by Formula 10 may be prepared by adding a dinipropylethylamine, which is a human base, to a solution of TBDMSOTf in dichloromethane using Lewis acid, and adding the compound represented by Formula 9 at a low temperature of 0 ° C. .
In step 2 according to the present invention, the compound represented by Formula 11 may be obtained by dissolving the compound represented by Formula 10 obtained in Step 1 in an organic solvent, followed by a ring opening reaction performed by adding a base.
Specifically, the organic solvent may be used ethanol, the ethanol acts as a nucleophile. In addition, the base may be used as, but not limited to, 1,8-diazabicyclo [5.4.0] undec-7-yne (Diubi).
In step 3 according to the present invention, the compound represented by Chemical Formula 12 is dissolved in a compound represented by Chemical Formula 11 obtained in Step 2 in an organic solvent, and simultaneously with a reduction reaction performed by adding a catalyst, a base, and a hydrogen gas. Obtained through an acetylation reaction.
Specifically, the catalyst is preferably Pd / C, and the base is preferably 1,8-diazabicyclo [5.4.0] undec-7- (diubiyu), but is not limited thereto.
In step 4 according to the present invention, the compound represented by Chemical Formula 13 may be formed by dissolving the compound represented by Chemical Formula 12 obtained in Step 3 in an organic solvent, adding a base, and then introducing a double bond.
Specifically, the organic solvent is preferably ethanol, the base is preferably N, N- dibutyl urea, but is not limited thereto.
In step 5 according to the present invention, the compound represented by the formula (14), after dissolving the compound represented by the formula (13) obtained in step 4 in a solvent, a base and a nucleophile is added to add a hydroxyl group It may be prepared by performing a S N 2 reaction to be substituted with a group.
For example, the compound represented by Formula 13 prepared in Step 4 is first mesylated in a dichloromethane solvent, and then azide substituted by further adding nucleophilic lithium azide under dimethylformamide solvent to the mesylated compound obtained. The compound represented by the formula (14) in which the group has the stereoselectivity opposite to the hydroxyl group can be prepared.
In step 6 according to the present invention, the oseltamivir of the formula (1) by dissolving the compound represented by the formula (14) prepared in step 5 in an organic solvent, and then adding a reducing agent to reduce the azide group to a preamine It can manufacture.
For example, the compound represented by Chemical Formula 14 obtained in Step 5 may be prepared by adding triphenylphosphine as a reducing agent under a mixed solvent of tetrahydrofuran and water.
In the preparation method according to the present invention, the compound of Formula 9 is shown in Scheme 2 below,
Performing a dehydroxylation reaction of the compound represented by the formula (5) in a solvent to obtain a compound represented by the formula (6) (step A);
Obtaining a compound represented by Chemical Formula 7 by substituting the free hydroxy group of the compound represented by Chemical Formula 6 obtained in step A with an azide group (Step B);
Obtaining a compound represented by Chemical Formula 8 under acidic conditions from the compound represented by Chemical Formula 7 obtained in step B (step C); And
It may be prepared by a method comprising the step (step D) of obtaining a compound represented by the formula (9) by performing a SwO oxidation (Swern oxidation) reaction to the compound represented by the formula (8) obtained in step C, but is not limited thereto Does:
Scheme 2
In step A according to the present invention, the dehydroxylation reaction is carried out using a sharpless asymmetric dihydroxylation reaction using AD-mix-β or a dehydroxylation reaction using OsO 4 or the like. It can proceed to. From the standpoint of increasing stereoselectivity of the product obtained after the reaction, the chalices asymmetric dehydroxylation reaction is more preferable.
Specifically, the compound represented by Chemical Formula 6 may be prepared by dissolving AD-mix-β in an organic solvent and then adding a base, and then adding the compound represented by Chemical Formula 5. In this case, it is preferable to use a mixed solvent of t-butanol and water as the organic solvent, and it is preferable to use methanesulfonamide as the base, but is not limited thereto.
In step B according to the present invention, the compound represented by the formula (6) is mesyylated compound represented by the formula (5) prepared in step A in an organic solvent and then substituted by the azide group in the organic solvent It can manufacture. At this time, it is preferable to use dichloromethane and diformamide as the organic solvent, but is not limited thereto. In addition, in the substitution reaction, the azide group substituted by the S N 2 reaction has a stereoselectivity opposite to that of the hydroxyl group.
In step C according to the present invention, the dioxorene ring opening reaction is performed by dissolving the compound represented by Chemical Formula 6 prepared in Step B in an organic solvent and performing a position-selective open reaction in the presence of Lewis acid. The primary alcohol compound to be displayed can be manufactured.
Specifically, the organic solvent for increasing position selectivity in the ring opening reaction is preferably tetrahydrofuran, dichloromethane or a mixed solvent of tetrahydrofuran and dichloromethane, and more preferably a mixed solvent of tetrahydrofuran and dichloromethane. May be, but is not limited thereto.
In step D according to the present invention, the reaction of oxidizing the primary alcohol with an aldehyde group is prepared by the sweroxidation reaction carried out in the presence of dimethyl sulfoxide and oxalyl chloride to prepare the aldehyde compound represented by the formula (8). Can be.
In the preparation method according to the present invention, the compound of Formula 5 is shown in Scheme 3 below,
Performing a protection reaction and an oxidation cleavage reaction of D-mannitol represented by Chemical Formula 2 in an organic solvent to obtain an aldehyde compound represented by Chemical Formula 3 (step a);
Dissolving the aldehyde compound represented by Formula 3 obtained in step a in an organic solvent and then performing a Grignard reaction to obtain a compound represented by Formula 4 (step b);
The compound represented by Chemical Formula 4 obtained in step b may be dissolved in an organic solvent, and then the acid may be added to obtain a compound represented by Chemical Formula 5 by a rearrangement reaction (step c). But not limited to:
Scheme 3
In step a according to the present invention, the compound represented by Chemical Formula 3 is prepared by dissolving D-mannitol represented by Chemical Formula 2, which is commercially available, in an organic solvent, and then adding an acid and 3,3-dimethoxypentane to perform a protective reaction. Thereafter, an inorganic oxidizing agent and an inorganic base may be added to prepare a compound represented by Formula 3, which is a single enantiomer aldehyde.
The organic solvent is preferably dimethylformamide, the acid is preferably camphorsulfonic acid, the inorganic oxidizing agent is preferably potassium periodate, and the inorganic base is preferably potassium bicarbonate, but is not limited thereto.
In step b according to the present invention, the Grignard reaction is a reaction for introducing an olefin into a molecule, and after dissolving the aldehyde compound represented by Formula 3 prepared in step a in an organic solvent, Grignard material Vinylmagnesium bromide may be added to prepare an olefin compound represented by the formula (4).
In this case, the organic solvent is preferably tetrahydrofuran, but is not limited thereto.
In step c according to the present invention, the compound of Formula 5 is dissolved in a compound represented by Formula 4 prepared in step b in an organic solvent, and then acid is added to ortho ester claisen rearrangement reaction You can get it.
At this time, the organic solvent is preferably MeC (OEt) 3 and the acid is preferably propionic acid, but is not limited thereto.
The method for preparing oseltamivir according to the present invention is not only possible to prepare oseltamivir as a target compound by performing cyclization by intramolecular aldol condensation reaction from acyclic precursor, but also starting from an easily obtained starting material. In addition, by eliminating the conventional protection / unprotection process, it is possible to reduce the synthesis step and to prepare oseltamivir with high yield.
Hereinafter, the present invention will be described in more detail with reference to production examples and examples. However, the following examples are only for illustrating the present invention, and the contents of the present invention are not limited by the following preparation examples and examples.
< Example 1> Oseltamivir Produce
Step 1: (R) -2,2- Diethyl -1,3- Dioxolane -4- Carbaldehyde ((R) -2,2- Diethyl -1,3-dioxolane-4-carbaldehyde) (3)
D-mannitol (25.00 g, 137.0 mmol) of Formula 2 was dissolved in dimethylformamide (62.5 ml), and camphorsulphonic acid (0.96 g, 4 mmol) was added thereto and heated to 40 ° C. 3,3-dimethoxypentane (38.00 g, 288 mmol) was added over at least 30 minutes and the reaction mixture was stirred for 4 hours. Triethylamine (0.97 ml, 7.0 mmol) was added and the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure and extracted to give 1,2: 5,6-di-O- (3-pentyridine) -D-mannitol (45.613 g) without purification; 1 H NMR (CDCl 3 ) 4.20-4.11 (4H, m), 3.92-3.91 (2H, m), 3.80-3.78 (2H, m), 2.54 (2H, d, J = 6.8 Hz), 1.67-1.58 ( 8H, m), 0.93-0.86 (12H, m).
The crude product (44.50 g) was dissolved in tetrahydrofuran (87 ml), followed by strong stirring and potassium periodate (35.40 g, 154 mmol) and potassium bicarbonate (1.4 g) suspended in water. , 13.98 mmol) was added for 40 minutes. The reaction mixture was stirred for 4 hours, then cooled in an ice bath and the reaction mixture was filtered through a glass funnel. Sufficient amount of sodium chloride was added until the layers were separated and the water layer was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over sodium sulfate and concentrated to give the protected compound (44.821 g) of the general formula (3) without purification.
1 H NMR (CDCl 3 ) δ 9.74 (1H, d, J = 1.9 Hz), 4.34-4.40 (1H, m), 4.19-4.05 (2H, m), 1.73-1.61 (4H, m), 0.98-0.88 (6H, m).
Step 2: (R) -1- (2,2- Diethyl -1,3- Dioxolane -4-yl) prop-2-pin-1-ol ((R) -1- (2,2-diethyl-1,3-dioxolan-4-yl) prop-2-en-1-ol) (4 Manufacturing
The solution of the compound of formula 3 (44.821 g) obtained in step 1 in tetrahydrofuran (90 ml) was cooled in an ice bath. Vinylmagnesium bromide (1M in THF, 425 ml) was slowly added and stirred for 5 hours. The reaction was terminated and extracted using a saturated aqueous ammonium chloride solution, followed by flash silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the compound of formula 4 (21.861 g, 117.4 mmol, 43% from D-mannitol). It was.
1 H NMR (CDCl 3 ) δ 5.89-5.77 (1H, m), 5.39 (1H, dt, J = 17.3, 1.5 HZ), 5.24 (1H, dd, J = 10.6, 1.5 Hz), 4.38-3.66 (4H , m), 2.39 (0.4H, d, J = 3.5 Hz, diastereomer A), 2.13 (0.6H, d, J = 2.9 Hz, diastereomer B), 1.71-1.58 (4H, m), 0.97-0.87 (6H , m).
Step 3: (S, E) -ethyl 5- (2,2- Diethyl -1,3- Dioxolane -4- days) Pent -4- Inno-Eight ((S, E) -ethyl 5- (2,2- diethyl -1,3- dioxolan -4- yl ) pent -4- enoate Manufacture of 5
The compound of formula 4 (21.86 g, 117.37 mmol) obtained in step 2 was dissolved in MeC (OEt) 3 (128 ml, 704 mmol), and then propionic acid (0.53 ml, 7.04 mmol) was added. The reaction mixture was heated at 132 ° C. for 25 hours and then concentrated under reduced pressure. The obtained residue was subjected to flash silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the target compound (25.771 g, 100.53 mmol, 85%) as a compound of formula (5).
[a] D = + 7.94 ( c 3.905, EtOH).
HRMS (EI) calcd for C 14 H 23 O 4 [M − H] − 255.1595, found 255.1598.
1 H NMR (CDCl 3 ) δ 5.85-5.77 (1H, m), 5.50 (1H, dd, J = 15.4, 7.7 HZ), 4.47 (1H, q, J = 6.7 Hz), 4.20-4.05 (3H, m ), 3.53 (1H, t, J = 8.2 Hz), 2.4 (4H, m), 1.72-1.59 (4H, m), 1.27 (3H, t, J = 7.1 Hz), 0.96-0.90 (6H, m) .
13 C NMR (CDCl 3 ) δ 173.1, 133.6, 128.7, 113.4, 77.6, 70.2, 60.6, 33.8, 30.2, 30.1, 27.7, 14.5, 8.4, 8.3.
FT IR 3450, 2976, 2941, 2882, 1736, 1464, 1372, 1173, 1078, 970, 920 cm -1 .
Step 4: (R) -5-((S)-((R) -2,2- Diethyl -1,3- Dioxalan -3 days)( Hydroxy ) ( methyl ) -Dihydrofuran-2 (3H) -one ((R) -5-((S)-((R) -2,2- diethyl -1,3- dioxolan Preparation of -4-yl) (hydroxy) methyl) -dihydrofuran-2 (3H) -one) (6)
After dissolving AD-mix-β (84.6 g) in t-butanol and water (1: 1 v / v, 600 ml), the mixture to which methanesulfonamide (5.75 g, 60.4 mmol) was added was cooled to 0 ° C. The mixture was added to a round bottom flask containing a compound of Formula 5 (15.485 g, 60.4 mmol), cooled to 0 ° C., and stirred for 6 hours. After 6 hours, sodium sulfite was added to terminate the reaction, and further stirred at room temperature for 4 hours. The organic layer extracted with ethyl acetate was washed with brine, dried over sodium sulfate and flash silica gel column chromatography (hexane: ethyl acetate = 1: 4) to obtain the compound of formula 6 (13.69 g, 56.042 mmol, 93%). It was.
[a] D = -38.89 (c 1.62, EtOH).
HRMS (EI) calcd for C 12 H 21 O 5 [M + H] + 245.1390, found 245.1391.
1 H NMR (CDCl 3 ) δ 4.16-4.11 (2H, m), 4.01-3.91 (1H, m), 3.67-3.61 (1H, m), 2.70-2.47 (2H, m), 2.38-2.28 (2H, m), 2.10-2.05 (1H, m), 1.73-1.59 (4H, m), 0.94-0.87 (6H, m).
13 C NMR (CDCl 3 ) δ 177.7, 113.5, 80.1, 76.3, 74.2, 67.5, 29.8, 29.3, 28.8, 24.2, 8.6, 8.3.
FT IR 3441, 2974, 2941, 2883, 2113, 1767, 1463, 1361, 1198, 1083, 973, 917 cm -1 .
Step 5: (R) -5-((R) -Azido ((S) -2,2- Diethyl -1,3- Dioxolane -2-yl) methyl)- Dihydrofuran -2 (3H) -one ((R) -5-((R)- azido ((S) -2,2- diethyl -1,3- dioxolan Preparation of -4-yl) methyl) -dihydrofuran-2 (3H) -one) (7)
The compound of formula 6 (3.123 g, 12.78 mmol) obtained in step 4 was dissolved in dichloromethane (200 ml), and triethylamine (12.8 ml, 91.8 mmol) was added thereto. The reaction mixture was cooled to 0 ° C. and mesyl chloride (2.47 ml, 32 mmol) dissolved in dichloromethane (180 ml) was added dropwise over 45 minutes. The reaction mixture was stirred at room temperature for 4 hours and water was added to terminate the reaction. Flash silica gel column chromatography (hexane: ethyl acetate = 1: 2) afforded a mesylate compound (4.12 g, 12.78 mmol, 100%). 1 H NMR (CDCl 3 ) δ 4.84-4.75 (2H, m), 4.26-4.14 (2H, m), 3.99-3.95 (1H, m), 3.15 (3H, s), 2.70-2.37 (4H, m) , 1.66-1.59 (4H, m), 0.94-0.86 (6H, m). 13 C NMR (CDCl 3 ) δ 176.4, 114.2, 81.2, 78.3, 74.6, 67.0, 39.4, 29.9, 28.8, 28.0, 24.2, 8.6, 8.3.
The mesylate compound (3.682 g, 11.42 mmol) was dissolved in dimethylformamide (115 ml), and sodium azide (1.11 g, 17.1 mmol) was added thereto, and the reaction mixture was stirred at 120 ° C. in an oil bath for 49 hours. The reaction mixture was concentrated under reduced pressure in vacuo, and the obtained residue was partitioned with dichloromethane and water, and then subjected to flash silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain a compound of formula 7 (2.258 g, 8.384 mmol, 73%). Obtained.
[a] D = -16.46 (c 2.065, EtOH).
HRMS (EI) calcd for C 12 H 20 N 3 O 4 [M + H] + 270.1455, found 270.1455.
1 H NMR (CDCl 3 ) δ 4.48 (1H, q, J = 6.6 Hz), 4.29-4.21 (1H, m), 4.16-4.10 (1H, m), 3.86-3.80 (1H, m), 3.52 (1H , t, J = 6.2 Hz), 2.65-2.55 (2H, m), 2.50-2.25 (2H, m), 1.75-1.59 (4H, m), 0.98-0.88 (6H, m).
13 C NMR (CDCl 3 ) δ 176.2, 114.2, 78.5, 76.6, 67.2, 65.8, 29.7, 29.0, 28.2, 24.8, 8.4, 8.3.
FT IR 3539, 3356, 2975, 2942, 2884, 2520, 2112, 1784, 1462, 1420, 1354, 1280, 1173, 1082, 919 cm -1 .
Step 6: (R) -5-((1R, 2S) -1- Azido -3- Hydroxy -2- (pentane-3- Iloxy ) Propyl) -dihydrofuran-2 (3H) -one ((R) -5-((1R, 2S) -1- azido -3- hydroxy -2-( pentan Preparation of -3-yloxy) propyl) -dihydrofuran-2 (3H) -one) (8)
The solution of the compound of formula 7 (1.643 g, 6.10 mmol) prepared in step 5 in dichloromethane (58 ml) was cooled to -50 ° C. The reaction mixture to which BH 3 SMe 2 (2.0M solution in tetrahydrofuran, 15.25 ml, 30.5 mmol) was added was stirred at -50 ° C for 30 minutes and trimethylsilyltriplate (TMSOTf, 2.2 ml, 12.20 mmol) was added. The reaction mixture produced by addition was stirred at -20 ~ -30 ℃ for 22 hours. Saturated aqueous sodium bicarbonate solution (60 ml) was added to terminate the reaction. The resulting mixture was allowed to react overnight at room temperature. Flash silica gel column chromatography (hexane: ethyl acetate = 1: 1.5) gave a compound of formula 8 (1.554 g, 5.73 mmol, 94%).
[a] D = -49.07 (c 1.08, EtOH).
HRMS (EI) calcd for C 12 H 22 N 3 O 4 [M + H] + 272.1612, found 272.1607.
1 H NMR (CDCl 3 ) δ 4.76 (1H, q, J = 7.1 Hz), 3.81-3.64 (4H, m), 3.34 (1H, quint, J = 5.5 Hz), 2.72-2.56 (2H, m), 2.39-2.19 (2H, m), 1.80 (1H, t, J = 5.4 Hz), 1.64-1.49 (4H, m), 0.95-0.87 (6H, m).
13 C NMR (CDCl 3 ) δ 176.8, 81.9, 77,7, 76.7, 65.2, 61.5, 28.4, 26.3, 25.7, 24.3, 9.7, 9.6.
FT IR 3463, 2966, 2938, 2879, 2108, 1780, 1461, 1347, 1276, 1185, 1056, 921 cm -1 .
Step 7: (2S, 3R) -3- Azido -3-((R) -5-oxo- Tetrahydrofuran -2-yl) -2- (pentane-3- Iloxy ) Propanal ((2S, 3R) -3- azido -3-((R) -5- oxo - tetrahydrofuran -2- yl ) -2- (pentan-3-yloxy) propanal) (9)
The solution of oxalyl chloride (0.8 ml, 9.442 mmol) in dichloromethane (85 ml) was cooled to -68 ° C. Dichloromethane (10 ml) solution to which dimethyl sulfoxide (1.22 ml, 17.13 mmol) was added was added dropwise for 10 minutes, and 5 minutes later, the compound of formula 8 obtained in step 6 (2.324 g) was dissolved in dichloromethane (10 ml). , 8.565 mmol) was added dropwise over 10 minutes. After stirring for 30 minutes, triethylamine (6.0 ml, 42.8 ml) was added and the reaction mixture was further stirred at -68 ° C for 30 minutes, the temperature was raised to room temperature, and water (100 ml) was added to terminate the reaction. . Flash silica gel column chromatography (hexane: ethyl acetate = 1: 1) gave a compound of formula 9 (2.113 g, 7.85 mmol, 92%).
[a] D = -40.26 (c 1.565, EtOH).
HRMS (EI) calcd for C 12 H 20 N 3 O 4 [M + H] + 270.1455, found 270.1451.
1 H NMR (CDCl 3 ) δ 9.83 (1H, s), 4.72 (1H, q, J = 1.1 Hz), 4.08 (1H, dd, J = 3.6, J = 1.4 Hz), 3.59 (1H, dd, J = 8.3, J = 3.5 Hz), 3.41 (1H, quint, J = 5.8 Hz), 2.66-2.43 (3H, m), 2.24-2.19 (1H, m), 1.66-1.49 (4H, m), 1.02- 0.90 (6 H, m).
13 C NMR (CDCl 3 ) δ 203.5, 175.9, 84.0, 81.6, 76.2, 64.4, 28.2, 26.3, 25.2, 25.1, 9.7, 9.5.
FT IR 3444, 2968, 2939, 2880, 2512, 1779, 1732, 1461, 1178, 1160 cm -1 .
Step 8: (1S, 2S, 3S, 4R, 5R) -4- Azido -2- (t- Butyldimethylsilyloxy ) -3- (pentane-3- Iloxy ) -6-oxa- Bicyclo [3.2.1] octane -7-on ((1S, 2S, 3S, 4R, 5R) -4- azido -2-( tert Preparation of -butyldimethylsilyloxy) -3- (pentan-3-yloxy) -6-oxa-bicyclo [3.2.1] octan-7-one) (10)
The solution of diisopropylethylamine (1.80 ml, 10.29 mmol) in dichloromethane (20 ml) was cooled to 0 ° C. To the solution was added TBDMSOTf (2.36 ml, 10.29 mmol), stirred for 10 minutes and dissolved in dichloromethane (15 ml) to the compound of formula 9 (0.924 g, 3.43 mmol) obtained in step 7 above. The reaction mixture was stirred at 0 ° C. for 25 minutes and further stirred for 2 hours before warming to room temperature. The reaction was terminated by addition of saturated ammonium chloride solution and flash silica gel column chromatography (hexane: ethyl acetate = 2: 1) yielded the compound of formula 10 (1.005 g, 2.62 mmol, 76%).
mp 75-76 ° C.
[a] D = + 2.22 ( c 1.805, EtOH).
HRMS (EI) calcd for C 18 H 33 N 3 O 4 Si [M] + 383.2240, found 383.2258.
1 H NMR (CDCl 3 ) δ 4.75 (1H, d, J = 6.2 Hz), 3.83 (1H, dd, J = 7.6, 3.3 Hz), 3.76-3.66 (1H, m), 3.58 (1H, t, J = 8.1 Hz), 3.34 (1H, dd, J = 8.4, 1.1 Hz), 2.69 (1H, dd, J = 5.6, 3.4 Hz), 2.49-2.39 (1H, m), 1.79 (1H, d, J = 12.6 Hz), 1.72-1.39 (4H, m), 0.96-0.84 (15H, m), 0.17 (3H, s), 0.14 (3H, s).
13 C NMR (CDCl 3 ) δ 173.9, 82.5, 80.4, 78.9, 74.6, 66.9, 44.6, 32.4, 26.1, 26.0, 24.7, 18.2, 9.5, 9.3, -4.0, -4.2.
FT IR 3433, 2964, 2361, 2103, 1786, 1466, 1260, 1129, 839 cm -1 .
Annl. Calcd for C 18 H 33 N 3 O 4 Si: C, 56.37; H, 8.67; N, 10.96. Found: C, 56.43; H, 8. 76; N, 10.87.
Step 9: (1S, 2S, 3S, 4R, 5R) -Ethyl-4- Azido -2- (t- Butyldimethylsiloxy ) -5- Hydroxy -3- (pentane-3- Iloxy ) Cyclohexanecarboxylate ((1S, 2S, 3S, 4R, 5R)- ethyl 4- azido Preparation of -2- (tert-butyldimethylsilyloxy) -5-hydroxy-3- (pentan-3-yloxy) cyclohexanecarboxylate)
The compound of formula 10 (2.252 g, 5.871 mmol) obtained in step 8 was dissolved in ethanol (88 ml), and lithium bromide (3.06 g, 35.213 mmol) was added thereto and cooled to 0 ° C. 1,8-diazabicyclo [5.4.0] undec-7-phosphorus (DBU, 2.63 ml, 17.61 mmol) was added and stirred at 0 ° C. for 1 hour and then reacted with saturated ammonium chloride solution (100 ml) Terminated. Flash silica gel column chromatography (hexane: ethyl acetate = 3: 1) yielded compound of formula 11 (2.441 g, 5.61 mmol, 96%).
[a] D = -29.1 ( C 0.825, EtOH).
HRMS (EI) calcd for C 20 H 39 N 3 O 5 Si [M + H] + 430.2737, found 430.2719.
1 H NMR (CDCl 3 ) δ 4.25-4.12 (2H, m), 4.10-4.00 (1H, m), 3.97-3.87 (1H, m), 3.78 (1H, br s), 3.67 (1H, t, J = 3.2 Hz), 3.26 (1H, quint, J = 5.7 Hz), 2.76 (1H, dt, J = 12.0, 3.0 Hz), 2.28-2.01 (2H, m), 1.84 (1H, dt, J = 13.0, 4.9 Hz), 1.56-1.42 (4H, m), 1.26 (3H, t, J = 7.15 Hz), 0.94-0.88 (15H, m), 0.12 (3H, s), 0.02 (3H, s).
13 C NMR (CDCl 3 ) δ 172.8, 82.9, 69.8, 68.0, 64.0, 60.9, 43.9, 26.5, 26.4, 26.1, 25.7, 18.1, 14.3, 10.0, 9.7, -3.7, -5.4.
FT IR 3454, 2963, 2930, 2858, 2103, 1729, 1463, 1371, 1257, 1192, 1140, 1080 cm -1 .
Step 10: (1S, 2S, 3S, 4R, 5R) -Ethyl-4- Acetami Midido -2- (t- Butyldimethylsilyloxy ) -5- Hydroxy -3- (pentane-3- Iloxy ) Cyclohexanecarboxylate ((1S, 2S, 3S, 4R, 5R) -ethyl 4- acetamido -2-( tert - butyldimethylsilyloxy ) -5- hydroxy -3- ( pentan Preparation of -3-yloxy) cyclohexanecarboxylate) (12)
In a round bottom flask, the compound of formula 11 (0.762 g, 1.774 mmol) obtained in step 9 was dissolved in ethyl acetate (20 ml), followed by Pd / C (10%, 0.38 g) and acetic anhydride (0.18 ml, 1.95 mmol). And triethylamine (1.24 ml, 8.87 mmol) were added to fill the flask with hydrogen gas. After the reaction mixture was stirred at room temperature for 22 hours, the remaining catalyst was washed with ethyl acetate and filtered using a celite bed. The obtained residue was subjected to flash silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain a compound of formula 12 (0.756 g, 1.696 mmol, 96%).
[a] D = + 5.4 ( c 3.15, EtOH).
HRMS (EI) calcd for C 22 H 43 NO 6 Si [M + H] + 446.2938, found 446.2927.
1 H NMR (CDCl 3 ) δ 6.87 (1H, d, J = 8.6 Hz), 4.45-4.42 (1H, m), 4.26-4.02 (4H, m), 3.50 (1H, t, J = 3.0 Hz), 3.28 (1H, quint, J = 6.7 Hz), 2.89-2.80 (2H, m), 2.02 (3H, s), 1.96-1.88 (2H, m), 1.55-1.43 (4H, m), 1.27 (3H, t, J = 7.15 Hz), 0.94-0.87 (15H, m), 0.13 (3H, s), 0.10 (3H, s).
13 C NMR (CDCl 3 ) δ 172.6, 172.1, 82.1, 76.9, 71.3, 68.5, 60.9, 51.8, 43.1, 26.6, 26.1, 25.9, 24.7, 23.5, 18.1, 14.3, 10.1, 9.6, -3.7, -5.5.
FT IR 3473, 3337, 2963, 1716, 1654, 1558, 1465, 1374, 1245, 1128, 1062 cm -1 .
Step 11: (3R, 4R, 5R) -ethyl-4- Acetamido -5- Hydroxy -3- (pentane-3- Iloxy Cyclohex-1- Shincarboxylate ((3R, 4R, 5R)- ethyl 4- acetamido -5- hydroxy -3- ( pentan Preparation of -3-yloxy) cyclohex-1-enecarboxylate) (13)
The compound of formula 12 (0.152 g, 0.340 mmol) prepared in step 10 was dissolved in ethanol (6 ml), and then 1,8-diazabicyclo [5.4.0] undec-7-yne (DBU, 0.50 ml, 3.40 mmol) and lithium perchlorate (0.18 g, 1.70 mmol) were added, and the resulting reaction mixture was heated to reflux for 2 hours 30 minutes. The reaction was cooled in an ice bath and saturated aqueous ammonium chloride solution (10 ml) was added and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and then subjected to flash silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the compound of formula 13 (0.069 g, 0.210 mmol, 62%).
mp 129-130 ° C.
[a] D = -85.36 ( c 1.64, EtOH).
HRMS (EI) calcd for C 16 H 27 NO 5 [M] + 313.1889, found 313.1893.
1 H NMR (CDCl 3 ) δ 6.86 (1H s), 5.74 (1H, d, J = 6.2 Hz), 4.35 (1H, s), 4.27-4.13 (3H, m), 3.88 (1H, t, J = 6.7 Hz), 3.62 (1H, s), 3.42 (1H, quint, J = 6.1 Hz), 2.71 (1H, d, J = 17.0 Hz), 2.46 (1H, dd, J = 18.7, 4.9 Hz), 2.06 (3H, s), 1.59-1.49 (4H, m), 1.32 (3H, t, J = 7.1 Hz), 0.94 (6H, t, J = 7.3 Hz).
13 C NMR (CDCl 3 ) δ 171.8, 166.7, 136.4, 129.5, 82.1, 72.8, 67.3, 61.1, 55.1, 31.8, 26.5, 26.2, 23.7, 14.4, 9.8, 9.7.
FT IR 3486, 3318, 2968, 1702, 1643, 1545, 1465, 1373, 1306, 1251, 1214, 1103, 1085 cm -1 .
Annl. Calcd for C 16 H 27 NO 5 : C, 61.32; H, 8.68; N, 4.47. Found: C, 61.45; H, 8.75; N, 4.40.
Step 12: (3R, 4R, 5S ) - ethyl-4-acetamido-5-azido-3-(pentane-3-yl-phenoxy) -1-cycle rohek Shin-carboxylate ((3R, 4R, 5S) Preparation of ethyl 4- acetamido -5- azido -3- (pentan -3-yloxy) cyclohex-1-enecarboxylate) (14)
The compound of formula 13 (0.525 g, 1.661 mmol) obtained in step 11 was dissolved in dichloromethane (20 ml), and triethylamine (1.16 ml, 8.30 mmol) was added. The solution was cooled in an ice bath, a mesyl chloride solution (0.32 ml, 4.152 mmol) dissolved in dichloromethane (5 ml) was added dropwise, and the reaction mixture was stirred at 0 ° C. for 1 hour 30 minutes. The reaction was terminated by addition of water and flash silica gel column chromatography (hexane: ethyl acetate = 1: 9) afforded mesylate compound (0.634 g, 1.62 mmol, 97%).
The reaction mixture was dissolved in the mesylate compound (0.108 g, 0.276 mmol) in dimethylformamide (DMF, 5 ml) and an aqueous solution of lithium azide (LiN 3 , 20%, 0.25 ml, 1.104 mmol) was added at 90 ° C. for 7 hours. Heated to. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and flash silica gel column chromatography (hexane: ethyl acetate = 1: 4) to obtain a compound of formula 14 (0.073 g, 0.217 mmol, 78%).
mp 135-136 ℃
[a] D = -93.6 ( c 0.235, EtOH), -42.6 ( c 0.61, CHCl 3 ).
HRMS (EI) calcd for C 16 H 26 N 4 O 4 [M] + 338.1954, found 338.1958.
1 H NMR (CDCl 3 ) δ 6.80 (1H, s), 5.86 (1H, d, J = 7.2 Hz), 4.60 (1H, d, J = 8.7 Hz), 4.38-4.18 (3H, m), 3.37- 3.25 (2H, m), 2.87 (1H, dd, J = 17.6, 5.7 Hz), 2.31-2.18 (1H, m), 2.05 (3H, s), 1.55-1.49 (4H, m), 1.31 (3H, t, J = 7.1 Hz), 0.95-0.88 (6H, m).
13 C NMR (CDCl 3 ) δ 171.3, 166.0, 138.1, 128.4, 82.2, 73.5, 61.3, 58.6, 57.2, 30.8, 26.5, 25.8, 23.8, 14.4, 9.8, 9.6. FT IR 3217, 2972, 2105, 1716, 1660, 1560, 1375, 1332, 1253, 1081 cm-1.
Annl. Calcd for C 16 H 26 N 4 O 4 : C, 56.79; H, 7. 74; N, 16.56. Found: C, 57.09; H, 7.79; N, 16.39.
Step 13: Oseltami Beer ( Oseltamivir Manufacture of (1)
A compound of formula 14 (0.222 g, 0.656 mmol) obtained in step 12 was dissolved in tetrahydrofuran: water (5: 1 v / v, 9 ml) and triphenylphosphine (0.34 g, 1.313 mmol) was added thereto. It heated at 50 degreeC and made it react for 19 hours. The reaction mixture was cooled to room temperature and dried using sodium sulfate, followed by flash silica gel column chromatography (ethyl acetate: methanol = 1: 1) to oseltamivir (0.202 g, 0.647 mmol, 98%) as a target compound. Obtained.
[a] D = -49.2 ( c 9.33, EtOH), -54.2 ( c 0.48, CHCl 3 )).
HRMS (EI) calcd for C 16 H 28 N 2 O 4 [M] + 312.2049, found 312.2043.
1 H NMR (CDCl 3 ) δ 6.79 (1H, t, J = 1.8 Hz), 5.68 (1H, d, J = 7.9 Hz), 4.30-4.17 (3H, m), 3.57-3.46 (1H, m), 3.37 -3.30 (2H, m), 2.76 (1H, dd, J = 17.7, 5.0 Hz), 2.20-2.13 (1H, m), 2.05 (3H, s), 1.57-1.45 (6H, m), 1.30 ( 3H, t, J = 7.1 Hz), 0.94-0.83 (6H, m).
13 C NMR (CDCl 3 ) δ 171.1, 166.6, 137.8, 129.8, 81.8, 75.0, 61.1, 59.4, 49.4, 33.9, 26.5, 25.9, 23.9, 14.4, 9.8, 9.6.
FT IR (KBr) 3282, 2967, 1716, 1654, 1558, 1465, 1374, 1245, 1128, 1062 cm -1 .
Claims (5)
Reacting the compound represented by Chemical Formula 9 under basic conditions to obtain a compound represented by Chemical Formula 10 (step 1);
Dissolving the compound represented by Chemical Formula 10 obtained in step 1 in an organic solvent and then adding a base to obtain a compound represented by Chemical Formula 11 (step 2);
Obtaining a compound represented by Chemical Formula 12 by hydrogenating and acetylating an azide group of the compound represented by Chemical Formula 11 obtained in step 2 in the presence of a catalyst (Step 3);
Obtaining a compound represented by Chemical Formula 13 by adding a base represented by Chemical Formula 12 obtained in step 3 in an organic solvent (Step 4);
Performing a reaction of substituting the primary hydroxy group of the compound represented by Formula 13 obtained in step 4 with an azide group to obtain a compound represented by Formula 14 (step 5); And
A method for preparing oseltamivir comprising the step (step 6) of reducing the azide group of the compound represented by Formula 14 obtained in step 5 to an amine in an organic solvent to obtain a compound represented by Formula 1.
[Reaction Scheme 1]
Performing a dehydroxylation reaction of the compound represented by the formula (5) in an organic solvent to obtain a compound represented by the formula (6) (step 1);
Obtaining a compound represented by Chemical Formula 7 by replacing the free hydroxy group of the compound represented by Chemical Formula 6 obtained in step 1 with an azide group (Step 2);
Performing a ring opening reaction on the compound represented by Chemical Formula 7 obtained in step 2 under acid conditions to obtain a compound represented by Chemical Formula 8 (step 3);
Obtaining an aldehyde compound represented by the formula (9) by a primary oxidation of the primary alcohol of the compound represented by the formula (8) obtained in step 3 (Swern oxidation) (step 4);
Reacting the compound represented by Chemical Formula 9 obtained in step 4 under basic conditions to obtain a compound represented by Chemical Formula 10 (step 5);
Dissolving the compound represented by Formula 10 obtained in step 5 in an organic solvent, and then adding a base to obtain a compound represented by Formula 11 (step 6);
Obtaining a compound represented by Chemical Formula 12 by hydrogenating and acetylating an azide group of the compound represented by Chemical Formula 11 obtained in step 6 in the presence of a catalyst (Step 7);
Adding a base represented by Chemical Formula 12 obtained in Step 7 under a organic solvent to obtain a compound represented by Chemical Formula 13 (step 8);
Performing a reaction of substituting the primary hydroxy group of the compound represented by Chemical Formula 13 obtained in step 8 with an azide group to obtain a compound represented by Chemical Formula 14 (step 9); And
A method for preparing oseltamivir comprising the step (step 10) of reducing the azide group of the compound represented by Formula 14 obtained in step 9 to an amine in an organic solvent to obtain a compound represented by Formula 1.
Scheme 2
Performing a protection reaction and an oxidative fission reaction on the D-mannitol represented by the formula (2) in an organic solvent to obtain an aldehyde compound represented by the formula (3) (step 1);
Dissolving the aldehyde compound represented by Formula 3 obtained in step 1 in an organic solvent and then performing a Grignard reaction to obtain a compound represented by Formula 4 (step 2);
Dissolving the compound represented by Chemical Formula 4 obtained in step 2 in an organic solvent and then adding an acid to perform a rearrangement reaction to obtain a compound represented by Chemical Formula 5 (step 3);
Performing a dehydroxylation reaction of the compound represented by Chemical Formula 5 obtained in step 3 in a solvent to obtain a compound represented by Chemical Formula 6 (step 4);
Obtaining a compound represented by Chemical Formula 7 by replacing the free hydroxy group of the compound represented by Chemical Formula 6 obtained in step 4 with an azide group (Step 5);
Performing a ring opening reaction on the compound represented by Chemical Formula 7 obtained in step 5 under acidic conditions to obtain a compound represented by Chemical Formula 8 (step 6);
Obtaining an aldehyde compound represented by the formula (9) by a primary oxidation of the primary alcohol of the compound represented by the formula (8) obtained in step 6 (Swern oxidation) (step 7);
Reacting the compound represented by Chemical Formula 9 obtained in step 7 under basic conditions to obtain a compound represented by Chemical Formula 10 (step 8);
Dissolving the compound represented by Chemical Formula 10 obtained in step 8 in an organic solvent, and then adding a base to obtain a compound represented by Chemical Formula 11 (step 9);
Obtaining a compound represented by Chemical Formula 12 by hydrogenating and acetylating an azide group of the compound represented by Chemical Formula 11 obtained in Step 9 in the presence of a catalyst (Step 10);
Adding a compound represented by Chemical Formula 12 obtained in step 10 under a organic solvent to obtain a compound represented by Chemical Formula 13 (step 11);
Performing a reaction of substituting the primary hydroxy group of the compound represented by Formula 13 obtained in step 11 with an azide group to obtain a compound represented by Formula 14 (step 12); And
A method for preparing oseltamivir, comprising the step (step 13) of reducing the azide of the compound represented by Formula 14 obtained in step 12 to an amine in an organic solvent to obtain a compound represented by Formula 1.
[Reaction Scheme 3]
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| US20080009639A1 (en) | 2006-07-10 | 2008-01-10 | Apotex Pharmachem Inc. | Preparation of oseltamivir phosphate (Tamiflu) and intermediates starting from D-glucose or D-xylose |
| WO2009137916A1 (en) | 2008-05-12 | 2009-11-19 | Brock University | Processes and intermediates for the preparation of oseltamivir and analogs thereof |
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| US20080009639A1 (en) | 2006-07-10 | 2008-01-10 | Apotex Pharmachem Inc. | Preparation of oseltamivir phosphate (Tamiflu) and intermediates starting from D-glucose or D-xylose |
| WO2009137916A1 (en) | 2008-05-12 | 2009-11-19 | Brock University | Processes and intermediates for the preparation of oseltamivir and analogs thereof |
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