Method of producing imidazole derivatives

专利摘要:
The invention relates to heterocyclic compounds, in particular to the preparation of imidazole derivatives @, where R - (R) - or (S) - phenylethyl A is a sulfur or oxygen atom that is used in the synthesis of (+) - biotin-vitamin H. The goal is to develop a method for producing new intermediates. The preparation is carried out by the reaction of tetronic acid, f-ly (OH) - C = CH-C (O) -A-CH, where A is indicated above, with a benzenediazonium halide, followed by the interaction of the corresponding 3-aryl azotetronic acid obtained or the tautomeric aryl hydrazone with (R) - or (S) -1-phenylethylamine. In the corresponding 3-arylazo-4- (1-phenylethyl) amino-compound obtained, the azo group is reduced and the diamino compound is subjected to the phosgene compound of the f-ly YCOZ, where Y and Z are the same and mean CL or Y is chlorine, and Z is an aryloxy or alkoxy group.
公开号:SU1549484A3
申请号:SU874203715
申请日:1987-11-25
公开日:1990-03-07
发明作者:Мк Гэррити Джон；Тенуд Леандер；Меул Томас
申请人:Лонца Аг (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing new imidazole derivatives which are intermediate products in the synthesis of (+) - biotin - vitamin H,
The goal of the invention is the synthesis of new imidazole derivatives, which are intermediate products in the synthesis of (+) - biotin and allow forgive the synthesis process of this valuable pharmaceutical preparation.
Example 10 a) Preparation of 3-phenylazotetronic acid (3-phenylazo-4-oxy-furan-2 (5H) -one).
Into a 1.5 liter sulphonation flask equipped with a 250 ml addition funnel, a mechanical stirrer and a thermometer, 330 ml of a 6 N solution of hydrochloric acid are added. To this mixture is added dropwise 57.6 g of distilled aniline (0 , 61 mol) with ice cooling.

about
To the resulting suspension, a solution of 43.92 g of sodium nitrite (0-664 mol) in 90 ml of ice-water is added dropwise and stirred for 40 minutes. The solution of the diazonium salt thus obtained is added dropwise to a solution of 60 g tetronic acid (0.6 mol) and 120 g of sodium acetate trihydrate (0.88 mol) in 900 ml of water for 30 minutes. Immediately after the completion of the addition, a yellow-colored solid precipitates. The reaction mixture is stirred for 1 hour, the product is filtered - watered and washed with 500 ml of cold methanol0. The product is dried at 35 ° C in a vacuum me
Yield: 113.2 g (92.4%), m: 90-2000 ° C (decomp.) „
b) Preparation of 3-phenylazo-4- (S) - (1-phenylethylamino) -furan-2 (5H) -one 0
A three-necked flask (500 ml) equipped with a water separator, a thermometer and a magnetic stirrer, 20.0 g of 3-phenylazotetronic acid (98 mmol) are suspended in 190 ml of toluene and heated to 80 ° C under argon atmosphere. Then 1391 g (8) are added. a) phenylethylamine (L08 mmol) and 2.8 g
triethylborate (19 mmol). The solution is boiled under reflux under vacuum (300 mbar). After 7 hours, toluene is evaporated. The black residue is washed with 100 ml of ether until a brown mass precipitates. This mass is crushed in ether, as a result, receive a yellowish product, Z-Phenylazo-4- | (S)
(1-Phenylethylamino) furan-2- (5J) it
filtered and dried in vacuum. The yield is 28.36 g (94.0 / 0), Y “PLO 114P5 ° C.
NMR (CDCli9 300 MHz), d in ppm:
1.69 d, J 7 Hz, ЗН 4.42, d „J
 16 Hz, 1H; 4.54, sh „m ,, 1H; 45815 D
J 16 Hz, 1H; 7.26 - 7.45, m ,, 8H;
7.78, d, J 8 Hz, 2H; 10.55, ws,
1H.
M.So (E.1. 70.ev), m / e: 307 (9%)
Mf, 195 (25%), 171 (11%), 126 (10%),
H05 (100%), 93 (,).
IR (KVG): 3064, 3026, 1746
(c), 1621 (s), 1456, 1356B 1288,
1045, 765,
UV MeON), Х „Ккс 366 nm (Ј
 21.050), 260 nm (Ј 11.540),
235 nm (Ј 12,800).
Calculated,%: C 70.3; H 5.6;
N 13.7.
P
five
five
0
0
five
C „H„ N30U (307.35) Found,%: C 70.3 H 5.5; N 13.4. MJ (С 1 СНС13) + 785.
c) Preparation of 3-amino-4-Ј (3) - (1-phenyl ethylamino) J -furan-2 (5H) -one.
In an autoclave (500 ml.7), 13B50 g of 3-phenylazo-4- (S) - (1-phenylethylamino X) -FUR-2 (5H) -one (44 mmol) 133 ml of ethyl acetate and 0.77 g are placed platinum on carbon (57,) The autoclave is closed and washed twice with hydrogen with stirring. The reaction mixture is then hydrogenated with hydrogen at 40 bar for 30 minutes. The catalyst is filtered under argon and 130 ml of octane is added dropwise to the mother liquor with cooling. ice, H-Amino-4- {(S) - (1-phenylethylamino) -furan-2 (5H) - it precipitates as beige crystals. The product is dried at room temperature ur in vacuum.
Yield 8.53 g (89.0%), m.p. 127.5 - 128 ,.
NMR (CDC13, 300 MHz), ppm: 1.55 d., J 7.0 Hz, 3N; 2.35, ga.s. 2H; 4.21, d, j 15 Hz, 1H; 4.51, d, KB, J 7 Hz, 7 Hz, 1H; 4.53, d, J 15 Hz, W; 4.83, etc. J 7 Hz, W; 7.25 - 7.4, m ,, 5H.
M.S. (E.1. 70 ev), t / e; 218 (10%) M, 114 (18%), 105 (100%).
IR (KBG), cm: 3424, 3341 (s), 1737, 1651, 1584, 1428, 700.
UV (MeOH), l „А№: 283 nm (t. 16,610).
Calculated,%: C 66.0; H 6.5; N 12,8
C “1C NeOe (218.26)
Found,%: C 66.2; H 6.4; N 12.8. MG (С 1 СНС1Э) + 20.55
d) Preparation of 1-Ј (8) -1-phenylethyl) -1H-furo (3,4-a) -imidazol-2.4 (3N, bN) dione
In a three-neck flask with a capacity of 50 ml, equipped with a dropping funnel (50 ml) and a magnetic stirrer, 8.06 g of 3- (amino-4- f (S) - (1 phenylethylaminoX1-furan-2 (5H) -one) (36 mmol) and 65 ml of tetrahydrofuran and the mixture is cooled to 0 ° C. Then a solution of 5.78 g of phenyl ester of chloroformic acid (36 mmol) in 10 ml of tetrahydrofuran and simultaneously a solution of 3.78 g of triethylamine (36 mmol; in 10 ml of tetrahydrofuran, for 40 minutes, the white suspension is filtered and the slightly brown mother liquor is evaporated. The residue, the brown foam, is dissolved in 60 ml of acetone onitrile, and this solution was added dropwise to a solution of 3.78 g of triethylamine (36 mmol) in 40 ml of acetonitrile, which was previously heated under reflux, the reaction mixture was evaporated and the residue was washed with 50 ml of ether. Beige product (s) - (l-Phenylethyl) J-1 H-furo (3,4-d) -imidazol-2.4 (3N, 6N-dione is filtered and dried in vacuo.
After recrystallization in methanol, the yield is 5.75 g (66.0%), so pl. 159.5-160 ° C.
NMR (SL13.300 MHz), tf in ppm: 1.77, d, J 7 Hz, 3N; 4.07 d., J 16 Hz, W; 4.72, d, J 16 Hz, W; 5.57, q, J, 7 Hz, 1H; 7.35 - 7.58, m., 5H; 9.75, i.e. 1H.
M.S. (E.1. 70 ev), ha / e: 244 (16%), 105 (100%), 77 (37%).
IR (KBG), 3250, 2981, 1761, 1700, 1482, 1450, 1340, 1268, 1000, 739, 705.
UV (Meon), JIMQW. : 266 nm (Ј- 12,900).
Calculated,%: C 63.9; H 4.9; N 11.5.
 OjNa (244.25)
Found,%: C 63.3, H 4.9; N 11.3. Wf (01 CHC13) -69.56.
Example. A) Preparation of 3-phenylazothiotetronic acid (3-phenyl-azo-4-oxythiophen-2 (5H) -one or 2,3,4-trioxotetrahydrothiophen-3-phenyl hydrazone).
A 100 ml chemical beaker equipped with a dropping funnel (100 ml), a thermometer and a mechanical stirrer is injected with 28 ml of 6 N hydrochloric acid solution. To this mixture is added dropwise 5.02 g of aniline (53.9 mmol) and the mixture is cooled, washed with 30 ml of water and dried in vacuo.
After recrystallization in toluene, yield 10.5 g (95.0%), so pl. 195-196.5 ° C.
NMR (CDC1X, 300 MHz), & ppm: 3.89, s, 2H; 3.95, s., W; 7.32, t. 7.46, t.,
ten
J 7 Hz,
J 7 Hz, 2H; 3.89, s.
Ш; 7.32, t., 7 Hz
Hz, 2H; 7.57 d.
J 7
15
20
J 7 Hz, 2H; 2H; 7.58, d, 2H; 6.67, s., IHj 7.45, t., J = 7 Hz, 2H.
The tautomeric ratio of 3-phenyl-azothiotetronic acid and 2,3,4-tri oxotetrahydrothiophene 3-phenylhydrazone is 3: 1.
M.S. (E.1. 70 ev), ha / e: 220 (70%) M, 143 (13%), 105 (31%), 92 (30%), 77 (100%).
IR (KBG), cm: 3450, 1688, 1673 (s), 1532 (s), 1465, 1424, 1397 (s), 1129 (s), 912 (s), 764 (s)
UV (Meon), And
Max
408 nm (Ј
25
thirty
35
40
 14.100), 372 nm (Ј. 16,700), 235 nm (6.670).
Calculated,%: C 54.5, H 3.7J N 12.7; S 14.6.
С „0На О, .8 (220,25).
Found,%: C 54.3J H 3.5; N 2.7; S 14,8.
b) Preparation of 3-Lenizo-4-E (S) - (1-phenylethylamino) -thien-2 (5H) -one.
In a three-necked flask with a capacity of 250 ml, equipped with a water divider, a cooler, intensive action and a magnetic stirrer, 6.56 g of 3-phenyl ethometronic acid (29.8 mmol) are dissolved in 165 ml of toluene under reflux in a nitrogen atmosphere. Then, 14.53 g of S-1-phenylethylamine (119.9 mmol) and then a solution of 2.19 g of boron trifluorideethylethyrate boron in 40
by ice. Then to the received tbene-45 5 toluene. The reaction mixture give
cool to room temperature. Then this reaction mixture is extracted with 100 ml of 0, q n. hydrochloric acid, then 50 ml of saturated sodium bicarbonate solution, and finally 50 ml of saturated sodium sulfate solution.
A solution of 3.81 g of sodium nitrite (55.2 mmol) in 21 ml of ice is added dropwise with vigorous stirring. water for 30 min. The solution of the diazonium salt thus obtained is added dropwise, with vigorous stirring, to a solution of 5.78 g of thiotetraonic acid (50 mmol) in 49 ml of 1N sodium hydroxide at 5 ° C for 30 minutes. At the same time, 55 ml of 1N sodium bicarbonate solution is added dropwise in order to keep the pH value constant at 7.0. The resulting product mustard color
-

5494846
filtered off, washed with 30 ml of water and dried in vacuum.
After recrystallization in toluene, yield 10.5 g (95.0%), so pl. 195-196.5 ° C.
NMR (CDC1X, 300 MHz), & ppm: 3.89, s, 2H; 3.95, s., W; 7.32, t., 7.46, t.,
ten
J 7 Hz,
J 7 Hz, 2H; 3.89, s.,
Ш; 7.32, t., 7 Hz,
Hz, 2H; 7.57 d.
J 7
15
20
J 7 Hz, 2H; 2H; 7.58, d, 2H; 6.67, s., IHj 7.45, t., J = 7 Hz, 2H.
The tautomeric ratio of 3-phenyl-azothiotetronic acid and 2,3,4-tri-oxotetrahydrothiophene 3-phenylhydrazone is 3: 1.
M.S. (E.1. 70 ev), ha / e: 220 (70%) M, 143 (13%), 105 (31%), 92 (30%), 77 (100%).
IR (KBG), cm: 3450, 1688, 1673 (s), 1532 (s), 1465, 1424, 1397 (s), 1129 (s), 912 (s), 764 (s).
UV (Meon), And
Max
408 nm (Ј
25
thirty
35
40
 14.100), 372 nm (Ј. 16,700), 235 nm (6.670).
Calculated,%: C 54.5, H 3.7J N 12.7; S 14.6.
С „0На О, .8 (220,25).
Found,%: C 54.3J H 3.5; N 2.7; S 14,8.
b) Preparation of 3-Lenizo-4-E (S) - (1-phenylethylamino) -thien-2 (5H) -one.
In a three-necked flask with a capacity of 250 ml, equipped with a water divider, a cooler, intensive action and a magnetic stirrer, 6.56 g of 3-phenyl ethometronic acid (29.8 mmol) are dissolved in 165 ml of toluene under reflux in a nitrogen atmosphere. Then, 14.53 g of S-1-phenylethylamine (119.9 mmol) and then a solution of 2.19 g of boron trifluorideethylethyrate boron in 40
5 toluene. The reaction mixture give
cool to room temperature. Then this reaction mixture is extracted with 100 ml of 0, q n. hydrochloric acid, then 50 ml of saturated sodium bicarbonate solution, and finally 50 ml of saturated sodium sulfate solution.
The dark brown solution is dried over 20 g of magnesium sulfate and evaporated. 50 ml of ether are added to the brown, viscous residue, and the mixture is rotated under a gentle vacuum. The solid thus obtained is dissolved in 6 ml of dichloromethane under reflux, and after the addition of 14 ml of ether, the crystal is recrystallized at OC.
After additional recrystallization, the yield of 3-phenylazo-4- (S) - (l-phenylethylamino) -thien-2 (5H) -one is 5.59 g (58%), mp. .
NMR (CDC13, 300 MHz), Ј in pjm: 1.71, d ,, J 7 Hz, 3N; 3.64, d, J 17 Hz, 1H; 3.98, d, J 17 Hz, 1H; 4.77, d, apt., J 7 Hz, 7 Hz, 1H; 7.25-7.5, m., 8H; 7.76, d., J
8 Hz, 2H; 12.34, i.e. 1H. M.S.
, 415
20
25
35
(E.1. 70 ev), m / ej 323 (10%) Nr, 195 (22%), 105 (100%), 93 (30%), 77 (25%).
IR (KBG): 3500 (w), 1720, 1600 (s), 1580 (s), 1450, 1280.
UV (MeOH), MQN: 410 nm (Ј.. 9.600), 375 nm (Ј- 21.910); 290 nm (Ј. 11.880), 231 nm (Ј 13.823);
Calculated,%: C, 66.8; H, 5.3; N 13.0; S 9.9.
C18HnN3OS (323.41); Found,%: C, 66.7; H 5.2; N 13.2; S 9,5. “About Y (CHClj) + 889.
c) Preparation of 3-amino-4-Ј (8) - (1-phenylethylamino) -thien-2 (5H) -one.
In an autoclave with a capacity of 1QO ml, a solution of 5.0 g of 3-phenylazo-4- (S) - (1-phenylethylamino) -thien 2 (5H) - it (15.5 mmol in 30 ml of tetrahydrofuran) is placed. There are 0.49 g of platinum on carbon 5%, the autoclave is washed twice and the solution is hydrogenated under a hydrogen pressure of 30 bar for 45 minutes, the catalyst is filtered under argon and 90 ml of hexane is added dropwise with ice-cooling to the mother liquor. -Amino-4- Ј (S) - (I-phenylethylamino) -thien-2 (5H) -it precipitates as a beige, thick-flowing oil. Output 2.4 g (65.0%), NMR (, 300 MHz) , d in ppm: 1.54, d., J 7 Hz, ZN; 3.30, i.e. 3-4 H; 3.37, d., J 16.5 Hz, W; 3.72, d., J 7 Hz, 1H; 7.22-7.37, m., 5H.
M.S. (E.1. 70 ev), t / e: 234 (4%) M, 130 (18%), 105 (100%).
d) Preparation of (8) - (1-phenylethyl) -1H-thieno- (3,) - imidazol-2.4 (3H, 6H) - 5 dione.
In a three-necked flask with a capacity of 250 ml, equipped with two drip
Using a 50 ml funnel, each with a thermometer and magnetic stirrer, add 22 ml of tetrahydrofuran. The mixture is cooled to 0 ° C and 11.1 ml of a solution of phosgene (1.25 M) in toluene (13.87 mmol) are added under argon. A solution of 3.24 g of 3-amino-4- (S) - (1-phenylethylamino) -thien-2 (5H) -one (13.82 mmol) in 10 ml of tetrahydrofuran and a solution of 2.18 are added dropwise at the same time. g of triethylamine (27.75 mmol) in 10 ml of tetrahydrofuran for 3 hours. To this mixture was added 10 ml of 5% aqueous ammonia solution, the tetrahydrofuran was evaporated and the aqueous residue was extracted three times with 10 ml of dichloromethane. The solution is concentrated and chromatographed; it is passed through 100 g of silica gel with 700 ml of ethyl ester of acetic acid.
Yield (8) - (1-phenylethyl) thieno- (3, 4-d) -imidazole-2,4- (3N, 6H) -dione (beige crystals) 2.16 g (60%)} mp , 218-220 ° C.
NMR (CDClI, 300 MHz), & in ppin; 1.83, d, J 7 Hz, 3N; 3.23, d, J 16.5 Hz, W; 3.86, d., J -. 30 16.5 Hz, 1H; 5.73, apt., J = 7 Hz, 1H; 7.40, m., 511; 8.78, i.e. 1H. t M.S. (E.1. 70 ev), t / e: 260 (4%)
40
45
156 (4%), 105 (100%), 79 (10%),
M
77 (12%).
.J
IR (KBg) 8 cm: 3225, 2945, 2918, 1702 (s), 1619, 1451, 1351, 1268.
UV (MeOH), ox: 297 nm (Ј 9.805), 248 nm (Ј 5.960).
Calculated,%: C 60.0) H, 4.7; N 10.7; S 12.3.
.S (260.31).
Found,%: C 59.6, H 4.7; N 10.8; S 12,0. (СНС13) - 63.2 °.
e) Preparation of 1- (S) - (1-phenylethyl)} - 3-acetyl-1H-thieno- (3,4-e) -imidazol-2.4 (3N, bH) -dione.
In a 25 ml flask, heat
 6 EVH ° 5 g) - (-phenylethyl) -Sh-thieno (3,4-d) -imidazol-2,4 (3H, 6H) -dione (1.94 mmol) in 20 ml of acetic anhydride to 50 ° С for 3 hours. Then the solvent is evaporated and the residue is washed with 3 ml of ether. Thereafter . beige product is dried.
The yield of 1- (J) - (1-phenylethyl) -3-acetyl-1H-thieno- (3,4-d) -imidazol-2.4 (3N,
0
five
Using a 50 ml funnel, each with a thermometer and magnetic stirrer, add 22 ml of tetrahydrofuran. The mixture is cooled to 0 ° C and 11.1 ml of a solution of phosgene (1.25 M) in toluene (13.87 mmol) are added under argon. A solution of 3.24 g of 3-amino-4- (S) - (1-phenylethylamino) -thien-2 (5H) -one (13.82 mmol) in 10 ml of tetrahydrofuran and a solution of 2.18 are added dropwise at the same time. g of triethylamine (27.75 mmol) in 10 ml of tetrahydrofuran for 3 hours. To this mixture was added 10 ml of 5% aqueous ammonia solution, the tetrahydrofuran was evaporated and the aqueous residue was extracted three times with 10 ml of dichloromethane. The solution is concentrated and chromatographed; it is passed through 100 g of silica gel with 700 ml of ethyl ester of acetic acid.
Yield (8) - (1-phenylethyl) thieno- (3, 4-d) -imidazole-2,4- (3N, 6H) -dione (beige crystals) 2.16 g (60%)} mp , 218-220 ° C.
NMR (CDClI, 300 MHz), & in ppin; 1.83, d, J 7 Hz, 3N; 3.23, d, J 16.5 Hz, W; 3.86, d., J -. 0 16.5 Hz, 1H; 5.73, apt., J = 7 Hz, 1H; 7.40, m., 511; 8.78, i.e. 1H. t M.S. (E.1. 70 ev), t / e: 260 (4%)
156 (4%), 105 (100%), 79 (10%),
M
77 (12%).
.J
IR (KBg) 8 cm: 3225, 2945, 2918, 1702 (s), 1619, 1451, 1351, 1268.
UV (MeOH), ox: 297 nm (Ј 9.805), 248 nm (Ј 5.960).
Calculated,%: C 60.0) H, 4.7; N 10.7; S 12.3.
.S (260.31).
Found,%: C 59.6, H 4.7; N 10.8; S 12,0. (СНС13) - 63.2 °.
e) Preparation of 1- (S) - (1-phenylethyl)} - 3-acetyl-1H-thieno- (3,4-e) -imidazol-2.4 (3N, bH) -dione.
In a 25 ml flask, heat
° 5 g) - (-phenylethyl) -Sh-thieno ° 5 g) - (-phenylethyl) -Sh-thieno (3,4-d) -imidazol-2.4 (3H, 6H) -dione (1.94 mmol) in 20 ml of acetic anhydride to 50 ° C for 3 hours. Then the solvent is evaporated and the residue is washed with 3 ml of ether. Thereafter . beige product is dried.
The yield of 1- (J) - (1-phenylethyl) -3-acetyl-1H-thieno- (3,4-d) -imidazol-2.4 (3N,
6H) -dione 0.43 g (73.0%), so pl. 187-189 ,.
NMR (CDCl, 300 MHz), 5 per ppm; 1.85, d, J = 7 Hz, RR; 2.71, p., ZN; 3.18, d, J 17.5 Hz, 1H; 3.83, d, J 17.5 Hz, 1H; 5.71, q, J = 7 Hz; 1H; 7.35-7.45 / m., 5H.
M.S. (E.1. 70 ev), t / e: 302 (1%)
MT 260 (10%) (-CHUCO), 165 (5%), 105 (100%), 43 (20%).
IR (KBG), 2920, 1736 (s), 1447, 1376, 1354, 1298.
UV (MeOH); iMavu. : 297 nm (Ј 11.480), 248 nm (Ј 6.930).
Calculated,%: C 59.6; H 4.7; N 9.3; S 10.6.
St HW0, N2S (302.35).
Found,%: C 58.9; H 4.7; N 9.2; S 10.3, G ° 0 (СНС13) - 63.3.
Litter 3. Production of 1- (S) - (1-phenylethyl) -3-benzyl-1H-thieno- (3,4) -imidazole-2.4 (3N, bN) -dione.
To a suspension of 75 mg of sodium hydride (3.1 mmol) in 15 ml of tetrahydrofuran is added 0.73 g of 1- (S) - (1-phenyl-ethyl) -1H-thieno- (3,4-d) - imidazole-2,4 (3N, 6H) -dione (2.8 mmol), 0.54 g of benzyl bromide (3.2 mmol) and 10 ml of diethylene glycol diethyl ether. The reaction mixture is heated under reflux for 12 hours. The solvents are evaporated in vacuo and the residue is separated in phases with 10 ml of dichloromethane and 10 ml of water. The aqueous phase is washed twice with 10 ml of dichloromethane. The organic phases are combined, dried with 10 g of magnesium sulfate and evaporated. The solid residue is washed with 1 ml of ether, filtered and dried.
Yield of 1- (S) - (1-phenylethyl) J-3-benzyl-1H-thienol- (3,4-d) -chmidazol-2.4 (ZN.bN) -dione 57.0 mg (60 %), so pl. 143-145 ° C.
NMR (CDCij, 300 MHz), Ј in ppin; 1.79, d, J - 7 Hz, 3N; 3.18, d, 17 Hz, 1H; 3.78, d, J 17 Hz, 1H; 5.03, s., 2H; 5.21, J 7 Hz, W; 7.27 - 7.4, m., 8H; 7.49 d, 8 and 1.5 Hz, 2H.
M.S. (E.1. 70 ev), m / e: 350 (4%), 246 (12%), 105 (100%), 91 40%).
IR (KBG), 2982, 1707 (s), 672 (s), 1456, 1346, 846, 700.
UV (MeOH), L „lks: 285; 8 nm (Ј– 10,200).
Example 4. Preparation of I-Ј (S) -I-phenylethyl -1H-furo (3,4-y) -imidazol-2.4 (3H, 6H) -dione.
Proceed analogously to the example of 1 g, with the exception that instead of phenyl chloroformic acid, 3.9 g (36 mmol) of ethyl chloroformic acid are used. 0 Get the product yield 5.85 g (67%), so pl. 160 ° C.
The obtained technically readily available intermediate products make it possible to optically split the products by a simple operation even at an early stage in relation to the overall synthesis.
(+) - Biotin is obtained from the proposed compounds according to the following scheme 0 IU.
B
, "G with
 VIVI1-N
lRlNH2 HN NN-R2
V /
(80SSGAIJ,
(0 V
IYCOZ about
about
A
I when necessary
ZAZITN Yu
 the group
R
I ng, to /
IA-O
about
-AH
°
i
CATALYST
H
if necessary, 1 PROTECTIVE group
about
H-W-H
 Ksh about
RiNrSwi
Ht # o
V ® | ph3P (
about
H-W-H
(SN (CIS) 3Sooi
w
| N2,1CHALIZER
ABOUT
H7) - (
Xsah
splitting off (PROTECTIVE GROUP
NIS% N
H V- CCH1 COOH H5Ln Ybiotin
154948412

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of im-Dazol formula
ten
20
25
thirty
35
ABOUT
AO
where R is (R) - or (W) -phenylethyl;
A is sulfur or oxygen, 15 characterized in that the tetronic acid of the formula
BUT
about
where A has the indicated value, is reacted with a benzoldiazonium halide to obtain the corresponding 3-arylazotetronic acid or tautomeric aryl hydrazone, which is reacted with (R) - or (8) -1-phenylethylamine with the preparation of the corresponding 3-arylazo-4- (1-Phenylethyl) -amino compounds, restore the azo group, and the resulting diamino compound is reacted with a phosgene compound of the formula
YCOZ
where Y and Z are the same and mean chlorine or Y - chlorine;
Z is aryloxy or alkoxy.
ten
ABOUT
AO
where R is (R) - or (W) -phenylethyl;
A is sulfur or oxygen, 15 characterized in that the tetronic acid of the formula
20
BUT
about
five
0
five
where A has the indicated value, is reacted with a benzoldiazonium halide to obtain the corresponding 3-arylazotetronic acid or tautomeric aryl hydrazone, which is reacted with (R) - or (8) -1-phenylethylamine to obtain the corresponding 3-arylazo-4- ( 1-phenylethyl) -amino compounds, restore the azo group and the resulting diamino compound is subjected to interaction with the compound of the phosgene of the formula
YCOZ
where Y and Z are the same and mean chlorine or Y - chlorine;
Z is aryloxy or alkoxy.

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同族专利:

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公开号 | 公开日

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DE3773625D1|1991-11-14|

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IE61145B1|1994-10-05|

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DD264696A5|1989-02-08|

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DK630187D0|1987-12-01|

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FI90425B|1993-10-29|

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IL84590A|1992-07-15|

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PT86258A|1988-01-01|

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HU198721B|1989-11-28|

---

PT86258B|1990-11-07|

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YU215487A|1989-04-30|

---

IE873229L|1988-06-02|

---

IL84590D0|1988-04-29|

---

ES2039227T3|1993-09-16|

---

FI90425C|1994-02-10|

---

EP0270076B1|1991-10-09|

---

CH671227A5|1989-08-15|

---

EP0270076A1|1988-06-08|

---

CA1322756C|1993-10-05|

---

AT68187T|1991-10-15|

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NO875002L|1988-06-03|

---

US4873339A|1989-10-10|

---

TR24505A|1991-11-12|

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NO875002D0|1987-12-01|

---

HUT47285A|1989-02-28|

---

NO167922C|1991-12-27|

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DK630187A|1988-06-03|

---

JP2560358B2|1996-12-04|

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FI875290A|1988-06-03|

---

JPS63145284A|1988-06-17|

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YU46091B|1992-12-21|

---

FI875290A0|1987-12-01|

---

US4851540A|1989-07-25|

---

NO167922B|1991-09-16|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US2489232A|1949-11-22|Synthesis of biotin |

---

US2489235A|1947-07-24|1949-11-22|Hoffmann La Roche|Synthesis of biotin|

---

JPS463580Y1|1967-06-13|1971-02-06|

---

BE759512A|1969-11-29|1971-05-27|Hoffmann La Roche|LACTONE|

---

US4054740A|1974-12-24|1977-10-18|Hoffmann-La Roche Inc.|Hydroxybiotin|

---

EP0092194B1|1982-04-16|1987-07-08|Sumitomo Chemical Company, Limited|Method of obtaining optically active half esters|

---

EP0161580B1|1984-05-18|1990-11-07|F. Hoffmann-La Roche Ag|Process for the preparation of a lacton|

---

DE3575717D1|1984-08-25|1990-03-08|Merck Patent Gmbh|METHOD FOR PRODUCING -AND / OR -1,3-DIBENZYL-HEXAHYDRO-1H-FURO IMIDAZOLE-2,4-DION.|CH670644A5|1986-12-18|1989-06-30|Lonza Ag|

---

FI95034C|1989-03-15|1995-12-11|Lonza Ag|Process for the preparation of 1,3-substituted tetrahydro-1H-thieno [3,4-d] imidazol-2-one-4-ylidenepentanoic acid ester|

---

FI935609A|1992-12-18|1994-06-19|Lonza Ag|Asymmetric hydrogenation of dihydrofuroimidazole derivatives|

---

HUT71109A|1993-04-20|1995-11-28|Lonza Ag|Process for preparing optical active furoimidazole derivatives by asymmetric hydrogenation|

---

CA2122511A1|1993-05-14|1994-11-15|John Mcgarrity|Asymmetric hydrogenation of furoimidazole derivatives|

---

CA2210821A1|1996-09-04|1998-03-04|Lonza Ag|Process for the preparation of an arylazotetronic acid derivative|

---

DE19843931A1|1997-09-29|1999-04-01|Sumitomo Chemical Co|Production of hexa:hydro-thienoÝ3,4-d¨imidazole-2,4-dione derivatives useful as biotin intermediates|

---

DE10033284A1|2000-07-07|2002-01-17|Merck Patent Gmbh|Process for the production of- biotin|

---

US20030082235A1|2001-08-13|2003-05-01|Yissum Research Development Company Of The Hebrew University Of Jerusalem|Novel reverse thermo-sensitive block copolymers|

---

US20080063620A1|2001-08-13|2008-03-13|Yissum Research Development Company Of The Hebrew University Of Jerusalem|Novel reverse thermo-sensitive block copolymers|

---

CN105418634B|2015-12-10|2018-07-10|蚌埠丰原医药科技发展有限公司|The preparation method of biotin intermediate impurity|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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CH4790/86A|CH671227A5|1986-12-02|1986-12-02|LV930151A| LV5267A3|1986-12-02|1993-02-26|Attempt to obtain imidazole derivatives|

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LTRP361A| LT2104B|1986-12-02|1993-02-26|THE IMIDAZOL'S DAILY RECEIPT|