GB2281294A - Process for producing half esters of the macrolide FK506 - Google Patents
Process for producing half esters of the macrolide FK506 Download PDFInfo
- Publication number
- GB2281294A GB2281294A GB9317464A GB9317464A GB2281294A GB 2281294 A GB2281294 A GB 2281294A GB 9317464 A GB9317464 A GB 9317464A GB 9317464 A GB9317464 A GB 9317464A GB 2281294 A GB2281294 A GB 2281294A
- Authority
- GB
- United Kingdom
- Prior art keywords
- anhydride
- half esters
- esters
- macrolide
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Half esters of the compound FK506 with dicarboxylic acids are produced bv reacting a mixture comprising FK506 and a dicarboxylic acid or anhydride thereof, such as succinic anhydride, in the presence of a dialkylaminopyridine such as 4-dimethylaminopyridine, in the absence of other bases. The FK506 half esters thus produced are useful as intermediates in the preparation of various conjugates for utilization in diagnostic assays for the compound FK506. The succinate ester has the formula:- <IMAGE>
Description
NEW PROCESS
This invention relates to an improved preparation process for producing a starting materials which can be utilized in the preparation of components for diagnostic assays for determining the presence and/or amount of FK506 in biological fluid such as from patient samples. More particularly, the present invention relates to a preparation process for producing reaction products of
FK506 with dicarboxylic acids or anhydrides thereof.
It is well known that FIX506 of the following formula:
which is produced by fermentation of tomces tsukubaensis No. 9993 (which has been deposited at Fennentation Research Institute, Agency of Industrial
Science and Technology under the deposit No. FERM BP-927), is useful for treatment of rejection by transplantation, autoimmune diseases, etc. ( EP O 184 162-A2). And, techniques for monitoring the blood concentration of FK506 has also been studied in order to control the blood concentration of FK506 most effectively (EP 0 293 892-A2).
During those studies, it was understood that half esters of FKS06 with a dicarboxylic acid or anhydride thereof (hereinafter referred as FK506 half-esters) were very important. Those FK506 half-esters are particularly useful as intermediates in the preparation of various conjugates fcr utilization in diagnostic assays for Pus506.
For example, the Fas06 half-esters can be converted into a covalent conjugates of FK506 with enzyme such as alkaline phosphatase, and further the FK506 half-esters can also be usable in preparation of various conjugates with various poly(amino)acids such as bovine serum albumin (BSA), which are useful as immunogens for raising antibodies (EP o 293 892-A2 and USP 5 164 495).
Accordingly, the production of high yields of FK506 half-esters is economically advantageous when its amounts necessary for commercial scale production are contemplated. For example, the above USP 5 164 495 tells that the yield of the FAS06 half-esters could be improved by using triethylamine compared with the process using pyridine which is described in the prior EP 0 293 892-A2
As a xesult of an extensive study, the inventor of the present invention could found that 6 half-esters could be produced in a quite high yield, even if without using the above triethylamine or pyridine.So, the present inventor has succeeded in providing an further improved preparation process for producing FK506 half-ester which will reliably yields improved amounts of FK506 halfesters, and at the same time, reducing the amount of undesirable side products.
Accordingly, the present invention provides a new preparation process for production of half esters of
FK506, i.e., FK506 half-esters, with dicarboxylic acids or anhydrides thereof, by reacting mixture comprising FK506 and dicarboxylic acids or anhydrides thereof in the presence of dialkylaminopyridine without any other bases such as pyridine or triethylamine.
Dicarboxylic acids and anhydrides usable in the present invention are of relatively low molecular weight, i.e., having a molecular weight in the range of from 90 to 25cur preferably in the range of from 100 to 200. Examples of dicarboxylic acids include oxalic acid, adipic acid, glutaric acid, maleic acid, maleic anhydride, fumaric acid, succinic acid, succinic anhydride, terephthalic acid, terephthalic anhydride, hexahydroterephthalic acid and hexahydrophthalic anhydride. The most preferred one is succinic anhydride.
The reaction of the dicarboxylic acid or their anhydride with FRS06 is carried out in a temperature range of from 5 to 30 degrees Celsius, preferably from 20 to 25 degrees Celsius, for a period of about a few hours.
Preferably the reaction is carried out at atmospheric temperature and pressure.
The reaction is usually conducted in a conventional solvent which does not adversely influence the reaction such as methylene chloride. And the object products can be isolated and purified in a conventional manner.
The suitable alkyl group in "dialkylaminopyridine' may include C1 to C6 alkyl group such as methyl, ethyl, etc. The most preferred "dialkyl2minopyridinel' " is 4- dimethylaminopyridine.
The following example is given for the purpose of illustrating the present invention.
Example
Preparation of a half ester of FK506 with succinic
anhydride
FK506 (0.2 g; 0.24 mmole), succinic anhydride (28 mg; 0.28 mmole) and 4-dimethylaminopyridine (92 mg; 0.74 mmole) were dissolved in dry methylene chloride (3 ml) and stirred at room temperature for 1 hr, followed by another addition of succinic anhydride (21 mg, 0.21 mmole). The reaction mixture was further stirred at room temperature for 2 hrs. The reaction was followed by SiO2 TLC as described in Fujisawa's EP 0 293 892-A2. The formation of by-products was significantly suppressed. The reaction mixture was extracted into 20 ml of ethyl acetate with the addition of brine (10 ml). The aqueous phase was further extracted with ethyl acetate (10 ml x 2). The ethyl acetate layer was combined, dried over MgS04 and concentrated under reduced pressure to give an oily residue which was subjected to SiO2 column chromatography purification as described in EP 0 293 892-A2. The halfester of FK506 with succinic anhydride, i.e. FK506hemisuccinate, was obtained quantitatively. The obtained product was confirmed as the same compound as the FK506hemisuccinate shown in EP 0 293 892-A2 by the conventional manner.
Claims (4)
- What we claim is 1. A process for production of half-ester of FX506 with a dicarboxylic acid or anhydride thereof by reacting a mixture comprising FK506 and a dicarboxylic acid or anhydride thereof in the presence of dialkylaminopyridine without any other bases.
- 2. The process of claim 1, in which the dialkylaminopyridine is dimethylaminopyridine.
- 3. The process of claim 1 or 2, in which the dicarboxylic acid or anhydride thereof is succinic anhydride.
- 4. The process of claim 3, in which the half-ester of FK506 is the compound having the following formula.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9317464A GB2281294A (en) | 1993-08-23 | 1993-08-23 | Process for producing half esters of the macrolide FK506 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9317464A GB2281294A (en) | 1993-08-23 | 1993-08-23 | Process for producing half esters of the macrolide FK506 |
Publications (2)
Publication Number | Publication Date |
---|---|
GB9317464D0 GB9317464D0 (en) | 1993-10-06 |
GB2281294A true GB2281294A (en) | 1995-03-01 |
Family
ID=10740868
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB9317464A Withdrawn GB2281294A (en) | 1993-08-23 | 1993-08-23 | Process for producing half esters of the macrolide FK506 |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2281294A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005105812A1 (en) * | 2004-04-14 | 2005-11-10 | Wyeth | Process for preparing rapamycin 42-esters and fk-506 32-esters with dicarboxylic acid, precursors for rapamycin conjugates and antibodies |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0184162A2 (en) * | 1984-12-03 | 1986-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
EP0293892A2 (en) * | 1987-06-05 | 1988-12-07 | Fujisawa Pharmaceutical Co., Ltd. | Anti-FR-900506 substance antibodies and highly-sensitive enzyme immunoassay method |
US5164495A (en) * | 1991-09-18 | 1992-11-17 | Abbott Laboratories | Method for preparing a dicarboxylic acid half-acid ester of FK506 |
-
1993
- 1993-08-23 GB GB9317464A patent/GB2281294A/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0184162A2 (en) * | 1984-12-03 | 1986-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
EP0293892A2 (en) * | 1987-06-05 | 1988-12-07 | Fujisawa Pharmaceutical Co., Ltd. | Anti-FR-900506 substance antibodies and highly-sensitive enzyme immunoassay method |
US5164495A (en) * | 1991-09-18 | 1992-11-17 | Abbott Laboratories | Method for preparing a dicarboxylic acid half-acid ester of FK506 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005105812A1 (en) * | 2004-04-14 | 2005-11-10 | Wyeth | Process for preparing rapamycin 42-esters and fk-506 32-esters with dicarboxylic acid, precursors for rapamycin conjugates and antibodies |
US7445916B2 (en) | 2004-04-14 | 2008-11-04 | Wyeth | Process for preparing rapamycin 42-esters and FK-506 32-esters with dicarboxylic acid, precursors for rapamycin conjugates and antibodies |
US7625726B2 (en) | 2004-04-14 | 2009-12-01 | Wyeth | Process for preparing rapamycin 42-esters and FK-506 32-esters with dicarboxylic acid, precursors for rapamycin conjugates and antibodies |
Also Published As
Publication number | Publication date |
---|---|
GB9317464D0 (en) | 1993-10-06 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |