Method of producing crystalline salt of s-6-fluorine-4-ureidochroman-4-carboxylic acid and d-(+)

专利摘要:
Sorbinil is obtained by cyclization of S-6-fluoro-4-ureidoch- romane-4-carboxylic acid, wich is in turn obtained by resolution of racemic 6-fluoro-4-ureidochroman-4-carboxylic acid via dias- teromeric salts with either D-(+)-(1-phenethyl) amine or L-(-)-ephedrine.
公开号:SU1282816A3
申请号:SU843754142
申请日:1984-06-29
公开日:1987-01-07
发明作者:Венделл Кью Беркели (Младший)；Дитрих Хаммен Филип；Сарджент Массетт Стефен；Милдс Мур Бернард；Джон Сиско Роберт
申请人:Пфайзер Инк (Фирма)；
IPC主号:

专利说明:

Yu
00
go
00
eleven
The invention relates to synthetic organic chemistry, in particular to methods for the preparation of a crystalline salt of Sb-fluoro-A-ureidochroman-4-carboxylic acid and B - (+) - {1-fetenyl) -amine or L - (-) - ephedrine which are an intermediate in the synthesis of 2-6-fluorospiro (chromo-4,4-imidazolidine) -2 -5-dione (sorbinyl) - a strong inhibitor of anti-reductase, used in the treatment of complications of diabetic hyperglycemia,
Example 1. RS-4-Amino-b- -fluorochroman-4-carboxylic acid.
A stirred suspension of 78 g (O, -33 mol) of K5-6-fluorospiro (Chro-MaH-jA-imidazolidine) -2, 5 -dione and 208.3 g (Oj66 mol) of barium hydroxide octahydrate in 585 ml of water slowly heat to boiling point (for 3 hours) and reflux f for 16 hours. Then this suspension is cooled to 80 ° C and 78 g of powdered ammonium carbonate are added in separate portions over 5 minutes. Note moderate foaming. After stirring for 1.5 hours at 80 ° C, the mixture is cooled to 60 ° C and filtered through a diatomaceous earth using washing with two portions of 100 MP each with hot vodb1. The combined filtrate and washings are evaporated. to 200 ml and left to stand overnight. 600 ml of 2-propanol are then added and the mixture is kept at 70 ° C to dissolve the precipitated solids. The hot solution is treated with activated carbon, filtered through diatomaceous earth and washed with a hot mixture of water with 2-propanol in a 1: 1 ratio. The combined filtrate and washings were evaporated to a residual volume of 200 ml and water was displaced by 3 portions of 300 ml of fresh 2-propanol. The prepared thick suspension is diluted with 200 ml of additional 2-propanol, cooled to, granulated for 0.5 hours, filtered and dried in air to obtain the desired product of the example in the amount of 63.6 g (yield 91.2%) , t. pl, which 252-253 ° C (with decomp.)
Example 2. KZ-6-Fluoro-4- ureidochroman-4-carboxylic acid
828162
Method A,
21.1 g (0.1 mol) of the desired product, xa of the previous example, are suspended in 250 M. L of water. In the form of individual portions, 16.2 g (0.2 mol) of KOCN are added over 2.5 minutes. After almost complete dissolution, the mixture is stirred at 23 ° C for 22 hours, during which the pH of the mixture increases from 6 to 9.1 and the dissolution process is completed. Within 1 hour, 19.0 ml of concentrated hydrochloric acid is added, maintaining the temperature of the solution at 25-29 C. Obraf5
20
the called suspension is granulated for 1 hour at a pH of 3.2-3.5, filtered using 150 ml of water for washing, isolating the desired product of the example, which is then partially dried in air, after which
for 18 h at 50-55 ° C, it is dried in vacuum to obtain 20.0 g of material (79% yield). Method B.
 The same starting imidazoline used in the experiment of the previous example is 47.2 g (0.2 mol). and 0.28 g (0.7 mol) of a tableted sodium hydroxide solution is dissolved in
30 to 600 ml of water and maintained at reflux for 40 hours. The reaction mixture is cooled to 24 ° C and the pH is lowered from 11.8 to 5.0 by adding 6 n,
35 hydrochloric acid. At pH below 8, gas evolution is noted. After stirring the suspension for 20 minutes at pH 5 for 2 minutes, 32.5 g (0, 4 mol) of KOCN was added to it.
The mixture is stirred for 20 hours and a small amount of solid material is isolated by filtration using 50 ml of water for washing. The pH of the combined filtrate and
The 45 washings were adjusted from 5.5 to 4.0 by the addition of 6N. hydrochloric acid. The precipitated target product of the sample is isolated by filtration, washed with warm water and dried in air to obtain 39.7 g (78% yield) of the substance, t, Ø1. which 198-199 with (with,).
Alternatively, the stage of hydrolysis using hydrate
55 sodium oxide is carried out at an excess pressure of 27 psig (1.9 atm) for 18 hours. As a result of the subsequent reaction with KOCN and isolation as described above,
38.8 of the target product of the example (yield 76.4%) with m. Pl. 199-200 ° C (with times.).
In another embodiment, instead of sodium hydroxide, 26.4 g (0.4 mol) of 85% potassium hydroxide is used and refluxing is carried out for 22 hours. As a result of reaction with KOCN and isolation as described above, 36.8 are obtained. g (yield 72.4%) of the desired product of the example with t, pl, 198-199 ° C (with decomp.).
Example 3. D - (+) - (- Phenethyl) ammonium-8-6-fluoro-4-ureidochroman-4-carboxylate,
10.0 g (39.4 mol) of the desired product of the previous example are suspended in 400 ml of methanol at 45 ± 5 С | h. For 4 min, 4.87 g (40.1 mmol) of D - (+) - (1-phenethyl) amine in 45 ml of methanol are added to the liquid suspension that forms, resulting in a solution, then a bath is removed, the mixture is slowly cooled to room temperature, it is granulated for 16 hours and the crude desired product of the example is isolated by filtration, after which it is dried in air at 60 ° C to obtain 6.4 g (yield 86, f 206-210 ° C (0 ) +54.3 methanol), 6 g of the indicated target crude product is suspended in 180 m of methanol at 40-50 C for 1 h, the suspension is cooled to room temperature, granulated for 3 hours, filtered stand out and dried in air, as a result of which 4.4 g of the purified desired product with t. Pieces. 214-216 C (oL) + 69 ° (c 0.3, methanol) are obtained.
substances with tpl - - (with 0.3.
; recovery rate 73, yield 63.5%,
general
The mother liquor of the crude desired product of the example is evaporated to obtain a mixture containing primarily 0 - (+) - (1-phenethyl) ammonium-K-6-fluoro-4-ureidochroman-4-carboxylate together with the target product of the example ( 8.3 g), mp. 198-200 ° C (L) - -85.4 (c 0.5, methanol), acceptable for return to 6-fluoro-4-4-chrononon. In one embodiment, this mixture is partitioned between ethyl acetate and water, first bringing the pH to 10. The ethyl acetate layer is separated, and the optically active amine is recovered by evaporation. Then the pH of the water
the phases are brought to -2 by the addition of hydrochloric acid and are subjected to extraction treatment with a fresh portion. ethyl acetate. The organic phase is washed with additional small portions of water, dried over magnesium sulphate and evaporated to give a mixture of R- and C8-6-fluoro-4-ureidochroman-4-carboxylic acid.
/ Example 4. Sorbinyl. Trust
The product of the previous example, 4.3 g (11 mmol) is suspended in 30 ml of glacial acetic acid at 93 ° C for 2 h, and the solution is formed by is-) for the first 15 minutes. Next, the solution is cooled to 60 ° C and evaporated to a residual volume of 10 ml. To the residue, 21.5 ml of water, heated to 50 ° C, pH of the resulting suspension of 0 3.5, is added. After 5 minutes, the pH is adjusted to 4.5 by adding 4 ml of 4N sodium hydroxide (while the temperature of the mixture is 28 ° C and the mixture is cooled to 30 ° C for 30 minutes). Filtration 5 directly yielded 2.35 g (yield 90.3%) of relatively pure sorbinyl with m.p. 233-24GS; + 52.7 ° (s 1, methanol). This sorbine is purified by dissolving 2.2 g of the product in 27.4 ml of boiling acetone, clarifying by hot filtration and evaporation of the mother liquor to a residual volume of 13 ml. The resulting slurry was slowly diluted with twice twice 17.2 ml of hexane and evaporated to a residual volume of 13 ml. Filtration and air drying gave 1.924 g (87.5% yield) of purified sorbinyl with a m.p. 239.50 242.5 ° С (). + 54.5 ° (s 1, methanol),
56.2 g of relatively pure sorbinil with m. PL, 237-24GS (o). + 52.3 ° (c 1, methanol), obtained in a similar way to achieve a yield of 89.8% from the product of the previous example, is dissolved in 700 ml of boiling acetone, the solution is clarified by filtration and evaporated to a residual volume of 300 ml . 400 ml of hexane is gradually added to this residue, and the mixture is again evaporated to a residual volume of 300 ml. The operations of adding hexane and subsequent evaporation
5 is not repeated, and as a result, after vacuum drying at 40 ° C for 18 hours, 54.9 g (yield, 97.7%) of product with m.p. 236-241 ° С (ot) | +53.4 (with 1, methanol).
Example 5. d .- (-) - Ephedrine-B9Ya salt of 8-6-fluoro-4-ureidochroman-4-carboxylic acid.
Method A,
35.6 g (0.14 mol) of the target compound of example 2 are suspended in 1.07 l of acetone, the suspension is stirred at reflux temperature with a HiiiM condenser for 30 minutes, cooled to 54 ° C, in one portion 24.4 g (0.148 mol) ot () Ephedrine; The slurry becomes thinner and almost a solution forms. After less than 2 minutes at 55 ° C, rapid crystallization begins. Then the suspension is kept under reflux for 2 hours, cooled to 40 ° C and 26.1 g of sugar-like crystals of the desired crude product of the example from st. pl, (oL) f +37,0 From uterine
204 ° C (with decomp.); (with
1, methanol), at room temperature, an atura temperature is obtained a second pore g of solid material with ° D. (from p.
BUT ALSO
-1.3
mp, 180-185 ° C (c,); (Jl)
0 (with 1, methanol)
As a result of the concentration of the mother liquor, 32.9 g of a foam-like solid material are obtained, m, mp, 72-90 ° C (c); (d) -55.7 (c 1, methanol).
The first portion of solid material (25 g) is re-suspended in 250 mp of boiling (with reflux) acetone and after cooling to 40 ° C, 24 g of product are obtained with T i mp. 205 ° C (with decomp.); (oDj + 38.2 ° (c 1, methanol). As a result of evaporation of the mother liquor to dryness, 1.2 g of product are obtained. mp. 90- (c), (s) + 34.4 ° (c 1, methanol).
Once suspended, 13 g of solid material is re-suspended in 260 MP of refluxing acetone, after which the suspension is cooled to and 11.7 g of product are isolated; (ss) + 39.3 ° (c 1, methanol). As a result of evaporation of the mother liquor, an additional 1.1 g of solid material is obtained,.
Method B.
The target product of example 2 (100 g is transferred at reflux temperature () to 374 ml of methanol for 30 minutes, after the mixture is cooled to 59 ° C, then to
7.42 ml of water and 68 - () ephedrine were added, resulting in rapid precipitation. The slurry is refluxed.
() 45 minutes, cooled to 27 ° C, and as a result of filtration, 70.4 g of the high purity target product of the example was directly isolated; () 44.36 ° (c 1.04, in methanol).
The filtrate is evaporated to give
crude diastereomeric salt, ct - (-) -. -ephedrine-K-6-fluoro-4-ureidochroman-4-carboxylate, 116.3 g. Example 6,
SorbiniLo
9.6 g of the suspended desired product of the previous example, prepared according to method A, and 68 ml of glacial acetic acid are maintained (y))
95 ° C 1
h, evaporated
the mixture in vacuo at bU C to obtain 20 g of a mass-like residue, diluted with a grayish 50 ml of water heated to 60 ° C, and then 50 ml of water at, the pH of the resulting suspension was adjusted from 3 to 4.5 by adding 4 and. sodium hydroxide, resulting in a yield of 4.7 g of crude sorbinyl with mp 234-240 ° C; + 50, .5
(with 1, methanol). 4.0 g of this raw sorbinyl is dissolved in 60 ml of boiling absolute ethanol, and the solution is clarified by filtration, resulting in 2.0 g of product with a mp of 240.5-243.0 ° C, (o) + 55.4 (, methanol).
By the same method, high-purity target product of the previous example (10 g, obtained by method B), sub 40
 50
convert conversions to high-frequency sorbinyl (4.93 g with T.Sh1. 240-242 0; (o (-) 54.7 (, methanol),
 Etc
and Ler 7. R- and RS-6-Fluoro-spiro- (chroman-4,4 -im-Dazolidine-) - 45 -2, 5-dion,
In accordance with the procedure of Example 4, the B - (+) - 1- (phenethyl) -amnna salt of R- and C8-6-fluoro-4-ureidochroman-4-carboxylic acid is converted to the desired product.
Example 8, Crude 6-fluoro-4-chromanone from sorbinyl ethantiomer and racemate,
100 g (0.423 mmol) of levorotatory 55 Shego (R-) and / or testic (RS) -6-fluoro-spiro- (chroman-4,4-imidazolidine) -2.5-dione are suspended in 750 ml of water. Then, 267.0 g (0.846 mol) of barium octahydrate and barium oxide are added to the suspension and the resulting liquid suspension is heated to reflux for 48 hours. The thick suspension formed is cooled to 60-65 0 and 100 g (0.876 mol) is added to it. ammonium carbonate. The slag is then stirred for 30 minutes and then (diluted at 50-55 ° C using 300 ml of warm water to wash the collected inorganic salts. The combined filtrate and washing liquid are sprinkled with hydrochloric acid, the pH is adjusted to 8.5 to 4.5 -5.0, 57.0 (0.427 mol) of N-chloro-succinium 1 is added to the acidified solution in 30-45 minute intervals in 5- to 30-minute intervals. The resulting suspension is stirred for 17 hours at room temperature, and then in for 1 h at room temperature, and then for 1 h at 15 ° C, a solid formed The product is separated by sintering, dissolved in dichloromethane, the solution is treated with activated carbon and dichloromethane is replaced with hexane to a boiling point of 68-69 ° C and a final volume of 400-500 mp, and crystallization occurs after this replacement. cooling and leaching for 1 hour at 20-25 ° C. The purified desired product of the example is isolated by filtration, 50.2 g, the physical properties of the product being identical to the physical properties of the known material.
The target product obtained in this way contains 6-fluoro-4-chloroiminochroman as an impurity, the latter affecting the further use of the target product of the example in the synthesis of additional sorbinyl. Said impurity is removed (after conversion to the desired 6-fluoro-2-chromanone) according to the procedure described in the following example.
Example 9, Purification of raw 6-fluoro-4-chromanone by hydrogenation.
Crude 6-fluoro-4-chromanone, containing as impurity 5.0 g 6-fluoro-4-chloroiminochroman, 0.25 g 5% palladium on coal (50% moisture) and 100 mp of water mixture 1: 1 ethanol is mixed and the mixture is hydrogenated under an overpressure of 45 psi
o
five
0
five
(3.16 kg / cm 2) of hydrogen (4 atm) for 2 h. After this time, a thin-layer chromatographic analysis on silica gel (using a mixture of toluene-methyl ethyl ketone: acetic acid in a ratio of 5: 2: 1 as eluent) shows the absence of more highly mobile chloramine (R.-0.8) in 6-fluoro-4-chromanone (Rr-0.7). The reaction mixture is diluted with 100 ml of methanol (which causes the complete dissolution of the solid material, except the catalyst), the catalyst removed by vacuum filtration on a bed of diatomaceous earth and the filtrate is evaporated in vacuo to about tatochnogo volume of 50 ml (in a water bath at 45 C), cooled to 5 ° C, granulated for 15 min and filtered to yield 2.65 g of purified title product of Example t, mp, 108-, thin layer analysis data are shown vsh1e.
Example 10, R- and RS-6-fluoro-4-ureidochroman-4-carboxylic acid.
Method A,
Recovered D - (+) - (1-phenethyl) ammonium-I-6-fluoro-4-ureidochroman-4-carboxylate (32.3 g), also containing a small amount of the corresponding B-ammonium-5- carboxylate salt, combined with 215 mp 1 n hydrochloric acid and stirred 5 at 16-23 0 21 h. The target header of the product of the sample is isolated by filtration to obtain 20.6 g (94% yield) of the substance with , pl, 195-198 ° C (with,), Method B, Column containing 50 ml of the ion exchange resin previously used (Amberlit IRA 900), slowly successively pour 250 ml of demineralized water, 250 mp 1 n, sodium hydroxide and, 250 ml of nitrogen-flushed water and 250 ml of nitrogen-flushed metalone, 10 g of the crude enantiomer-salt are then placed in 50 ml of methanol in the column, and an additional 100 mp of methanol is added and the eluate is evaporated in vacuo to yield 0 , 0199 mole of isolated ephedrine, as established by titrimetric testing using O, 1 N, solution of hydrogen chloride in methanol. Then the contents of the column are eluted with 150 ml of methanol, containing
4.4 g of dry hydrogen chloride, and finally 150 ml of fresh methanol. The last eluents in methanol containing hydrogen chloride and simply in methanol are combined and evaporated in vacuo to give 5.86 g of enantiomeric (R) and racemic (RS) -6-fluoro-4-ureidochroman-4-carboxylic acid .
Example 11. Crude 6-fluoro-4-chromanone from R- and K8-6-fluoro-4- -ureidochroman-4-carboxylic acid. 100 g of the product of the previous example are suspended in 475 ml of water. 32 g are added to the suspension. 50% sodium hydroxide, resulting in incomplete dissolution. This mixture is kept for 40 minutes at the boiling point (reflux), whereby complete dissolution is achieved. The reflux was continued for 18 hours and then the mixture was cooled. pH 9.6; thin layer chromatography shows incomplete reaction. The pH is raised to 1 2.0 by the addition of 13.8 g of a 50% sodium hydroxide solution, and the mixture is again maintained at a temperature of 4.5 by simultaneously adding 7 ml of condenser; after this time, a thin-layer chromatographic analysis on silica gel (a mixture of toluene with methyl ethyl ketone and acetic acid in a ratio of 5: 2: 1 as eluent) shows the presence of only the following starting material Rf- 0.5 with a high concentration of intermediate product, R- and RS-6-fluorop-4-aminoxoman-4-carboxylic acid (R, -0,0). The reaction mixture is cooled to .20 ° C and, keeping the temperature below 30 ° C, the pH is adjusted to 4.5 by adding concentrated hydrochloric acid to precipitate out. Within 15 minutes, 53 g of N-chlorosuccinimide is added, maintaining the temperature below 30 ° C and pH in the range of 4.0–4.5 simultaneously fc by adding 7 ml of 50% sodium hydroxide solution. The reaction mixture is stirred for 1 h at 25 ° C, and during this time the pH is 5.2 and a thin-layer chromatographic analysis (in the described system) shows the complete conversion of the intermediate amino acid into products. The pH is then adjusted to 9.6 by adding approximately 27 ml of a 50% sodium hydroxide solution. The slurry slurry was granulated for 2 hours at and the desired product was isolated by filtration (50.0 g); his t. pl. 55-58 ° C (partial melting) and 65-75 ° C (complete melting, but the melt is not transparent); thin layer chromatography (| nnichesky analysis
(indicated system) indicates the presence of the target product (R, -0.7) containing 6-fluoro-4-chloroimochroman (R-0.8).
Alternatively, D - (+) - (- phenethyl) -ammonium-R-6-fluorop-4-yreidoxproman-4-carboxylate containing a small amount of the corresponding B-ammonium-8- is used for drying the proposed method. carboxyl At the initial stage of the process, salt is distributed between 50%
sodium hydroxide solution and an equal volume of dichloromethane. The aqueous phase is washed with 2 portions of 1/3
volume of dichloromethane. The organic layers are combined and evaporated to give D - (+) - (- phenethyl) amine, acceptable for recycling. The aqueous phase is passed through the rest.
stages of the proposed method to obtain the target product of the example. Example 12. 6-Fluoro-4-chloro-iminochroman from R- and RS-6-fluoro-4-ype-idochroman.
The experiment of the previous example is repeated using the tenth fraction of the quantities of the previous example, resulting in an intermediate R- and RS-6-fluor-4-amino-opoman-4-carboxylic acid in solution of sodium hydroxide, B This solution is added dropwise 48.2 ml of a 15% solution of sodium hypochlorite, the temperature of which is
support 20-30 C. This mixture is stirred for 3.5 hours at 20-25 C | moreover, during this time, a thin layer chromatographic analysis (the system is similar to that described in the previous example) shows the conversion of the tatty acid into a practically pure target product with inconspicuous traces of 6-fluoro-4-chromanone. The desired product is isolated by filtration (3.8 g). For
specified Rp is 0.8.
Example 13. 6-Fluoro-4-chroman from chloro. 3.6 g of the target product of the example and 0.18 g (in terms of Sa is the dry weight) of 5% platinum on coal
at 50% moisture content between 72 mA of a mixture of methanol and water in a ratio of 9: 1, the pH is adjusted to 2.0 by the addition of concentrated hydrochloric acid, and the mixture is subjected to hydrogenation under an overpressure of 40-45 psi 2.8-3.2 kg / cm (3.7-4 atm) of hydrogen for 2 hours. The catalyst is isolated by filtration through a bed of diatomaceous earth. Thin-layer chromatographic analysis of the filtrate (R f- 0.7 in the system described only in the previous examples) shows that it contains only the target product of the example, easily separated by evaporation in a vacuum. Thin-layer chromatographic analysis shows that a certain amount of products are retained on the filter cake from the catalyst, and this amount is easily released by suspending the catalytic filter cake in methanol.
Thus, the proposed method can be used for semi

权利要求:
Claims (1)
[1]
intermediate for the synthesis of valuable biologically active compounds. Invention Formula
The method of obtaining the crystalline salt of 8-6-fluoro-4-ureidochroman-4-carboxylic acid and 1) - (+) - (1-phenethyl) -amine or "and - (-) -shedrine, characterized in that interaction of the racemic compound of the formula
HN COOH
 hy
about
with an equimolar amount of D - (+) - - (1-phenethyl) -amine or 1 .- (-) -Sefedrine in a reaction-inert solvent with isolation of the desired product.

类似技术:

---

公开号 | 公开日 | 专利标题

---

PL83152B1|1975-12-31|Process for preparing pentacyclic alkaloids[us3770724a]

---

JP2691442B2|1997-12-17|Novel proline derivative

---

US4606854A|1986-08-19|Method of preparing α-L-aspartyl-L-phenylalanine methyl ester and its hydrochloride

---

SU1282816A3|1987-01-07|Method of producing crystalline salt of s-6-fluorine-4-ureidochroman-4-carboxylic acid and d-|-|amine or l-|-ephedrine

---

US5057615A|1991-10-15|Process for purifying tryptophan

---

SU1240358A3|1986-06-23|Method of regenerating purified 6-fluorine-4-chromanon

---

SU843749A3|1981-06-30|Method of preparing 4a,9b-trans-hexahydro-gamma-carboline

---

FR2571366A1|1986-04-11|PROCESS FOR THE PREPARATION OF L-CARNITINE AND ITS SALTS

---

US4222970A|1980-09-16|Process for producing phosphonomycin

---

JP3209041B2|2001-09-17|Optical resolving agent and process for producing optically active tetrahydrofurancarboxylic acids using the same

---

JP4057088B2|2008-03-05|Method for producing pyrrolidine derivative

---

EP0109231B1|1986-10-22|Sorbinil by optical resolution with aminopinane derivatives

---

HU193127B|1987-08-28|Process for preparing spiro/chroman-4,4'-imidazoline/ derivatives

---

SU629883A3|1978-10-25|Method of obtaining vincamone and/or vincanole, their racemates or optically active antipodes

---

JP2578797B2|1997-02-05|Method for producing N- | formamides

---

JPH11228512A|1999-08-24|Production of d-alloisoleucine and intermediate therefor

---

JP4199318B2|2008-12-17|Process for the preparation of chiral, non-racemic | acetic acid

---

KR870000909B1|1987-05-06|Process for preparing a salt of crystalline s'-6-fluoro-4-ureidochroman-4-carboxylic acid

---

US4528387A|1985-07-09|Sorbinil by optical resolution of precursor 6-fluoro-4-ureidochroman-4-carboxylic acid

---

SU1209030A3|1986-01-30|Method of producing sorbinyl |

---

KR870000910B1|1987-05-06|A process for the regeneration of 6-fluoro-4-chromanone

---

JP3699769B2|2005-09-28|Peptide type compound

---

RU2063968C1|1996-07-20|Method of dihydroergocristine synthesis

---

SU1340586A3|1987-09-23|Method of regenerating 6-fluorchroman-4-on from |-6-fluor-4-ureidochroman-4-carboxylic acid or from mixture of |- and |-6-fluor-4-ureidochroman-4-carboxylic acids

---

SU294339A1|LIBRARY I

同族专利:

---

公开号 | 公开日

---

JPH0248555B2|1990-10-25|

---

IE832619L|1984-05-10|

---

JPS63211281A|1988-09-02|

---

DE3367099D1|1986-11-27|

---

EP0109232B1|1986-10-22|

---

JPH032866B2|1991-01-17|

---

JPS63211278A|1988-09-02|

---

PL143960B1|1988-03-31|

---

IE56256B1|1991-06-05|

---

HUT36124A|1985-08-28|

---

JPS6344755B2|1988-09-06|

---

JPH0244832B2|1990-10-05|

---

EP0109232A1|1984-05-23|

---

GT198303963A|1985-04-30|

---

ZA838336B|1985-06-26|

---

PH18843A|1985-10-10|

---

CA1202034A|1986-03-18|

---

JPS59101491A|1984-06-12|

---

BG45388A3|1989-05-15|

---

US4435578A|1984-03-06|

---

HU191708B|1987-03-30|

---

PL250369A1|1985-09-24|

---

AT23044T|1986-11-15|

---

JPS63211282A|1988-09-02|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US4286098A|1980-03-28|1981-08-25|Pfizer Inc.|Process for the preparation of chiral hydantoins|DE3565105D1|1984-08-20|1988-10-27|Pfizer|Process for the production as asymmetric hydantoins|

---

US4620019A|1984-08-23|1986-10-28|Pfizer Inc.|S-6-fluoro-4-aminochroman-4-carboxylic acid derivatives useful as intermediates for sorbinil|

---

US4551542A|1984-09-26|1985-11-05|Pfizer Inc.|Regeneration of 6-fluoro-4-chromanone from 6-fluoro-4-ureidochroman-4-carboxylic acid|

---

WO1986007353A1|1985-06-14|1986-12-18|Pfizer Inc.|Intermediate in the production of an asymmetric hydantoin|

---

US4841079A|1987-08-07|1989-06-20|Pfizer, Inc.|Process for the production of asymmetric hydantoins|

---

US5206367A|1992-02-18|1993-04-27|Pfizer Inc.|Preparation of optically active spiro-hydantoins|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

US06/440,641|US4435578A|1982-11-10|1982-11-10|Sorbinil by optical resolution of precursor 6-fluoro-4-ureidochroman-4-carboxylic acid|

---