GB1604864A - Methods of iodinating a progesterone derivative - Google Patents
Methods of iodinating a progesterone derivative Download PDFInfo
- Publication number
- GB1604864A GB1604864A GB4160680A GB4160680A GB1604864A GB 1604864 A GB1604864 A GB 1604864A GB 4160680 A GB4160680 A GB 4160680A GB 4160680 A GB4160680 A GB 4160680A GB 1604864 A GB1604864 A GB 1604864A
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- GB
- United Kingdom
- Prior art keywords
- progesterone
- group
- iodinatable
- solution
- iodine
- 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.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
- C07J41/0016—Oximes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
(54) METHOD OF IODINATING A PROGESTERONE
DERIVATIVE
(71) We, HOECHST UK LIMITED, a British body corporate, of Hoechst House,
Salisbury Road, Hounslow, Middlesex, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to a method of iodinating a progesterone derivative.
The conventional chloramine-T/sodium metabisulphite method does not result in good yields when used for the iodination of progesterone - 3 - (0 - carboxymethyl)oximehistamine. We have found by using sodium hypochlorite as oxidant instead of chloramine
T and using no reductant, but instead adding an excess of an iodinatable group to take up any excess iodine, a considerable improvement in yield is obtained. This is important if the method is to be used on a commercial rather than an experimental scale.
The present invention provides a method iodinating a progesterone derivative having an iodinatable group attached to progesterone by means of a bridging group, which comprises reacting the progesterine derivative with an alkali metal iodide, preferably sodium iodide, in the presence or sodium hypochlorite, and subsequently admixing with the reaction mixture a sufficient amount of free iodinatable group to take up unreacted iodine present in the reaction mixture.
The method of the invention may be carried out by admixing the alkali metal iodide, preferably sodium iodide, and a solution of the progesterone derivative bearing an iodinatable group, adding sodium hypochlorite solution and subsequently adding an excess of free iodinatable group (i.e. iodinatable group not attached to the progesterine derivative) to trap any free iodine remaining in solution.
The reaction mixture is preferably extracted with an organic solvent, preferably ethyl acetate. The product, present in the organic extract. is preferably purified by column or thin layer chromatography, or by high pressure liquid chromatography.
The material to be iodinated comprises progesterone attached via a bridging group to an iodinatable group. The iodinatable group is any group that can be iodinated, preferably an iodinatable aromatic or aromatic heterocyclic residue, for example, tyrosine methyl ester, tyramine or especially histamine.
The progesterone derivative generally has one of the following formulae
wherein
n is an integer of from 1 to 6,
A represents progesterone, and
R represents an iodinatable group.
The iodinatable group is preferably attached via the bridging group to the 3position of progesterone.
Of the above groups the (0 - carboxyalkyl)oxime groups are preferred for attachment to the 3-position of progesterone. The
O-carboxymethyloxime group has been found to be particularly useful.
The radioisotope of iodine that is generally used is 125I although 13lI can also be used. A resulting labelled progesterone, preferably progesterone- 3 - (0 - carboxymethyl)oxime [125I]iodohistamine, may be used in a radio immunoassay for progesterone, for example, as described and claimed in our Co-pending
Application No. 42713/77 (Serial No.
1 604 863).
The following Example illustrates the in
vention. In it, ratios of solvents for chromato
graphy are by volume.
EXAMPLE.
The following esolutions were added in tum to a glass tube over a magnetic stirrer: 2 mCi sodium iodide-125, 10 j1 of 0.2so phopshate buffer pH 7.4 and 20 Xal of a 0.3 mg/ml solution of progesterine - 3 - (0carboxymethyl)oxime - histamine in dioxin, and the mixture was then stirred to 10 seconds.
10 yl of a lul/ml solution of sodium hypo
chlorite (B.D.H. approximately 1 N in 0.1 -N NaOH) in phosphate buffer pH 7.4 was
then added and the mixture was stirred for
120 seconds. 10 A of a 0.5 mg/ml solution
of histamine dihydrochloride in 0.25M phos
phate buffer pH 7.4 were added to trap any
free iodine remaining in solution, and the
mixture was stirred for a further 30 seconds.
A small sample of the reaction mixture was
spotted onto a thin layer chromatography
plate to enable an estimate of the reaction
yield to be made, if desired. The remainder
of the reaction mixture was extracted with
200 A of ethyl acetate, the organic layer being
removed and retained. The extraction was
repeated and the ethyl acetate extracts were
combined.
The product was purified by column
chromatography as follows:
A silica gel column (lOog, Merck 7734)
was prepared using chloroform-methanol
(9:1) as solvent. The column was so arranged
that the eluant passed through an LKB Uvi
cord adapted for monitoring radioactivity and
fractions were collected using an LKD frac
tion collector. ("Uvicord" is a Trade Mark.)
The combined ethyl acetate extracts were added to the top of the column, and the column was eluted slowly with chloroformmethanol (9:1), 3 ml fractions were collected, and those corresponding to the main peak were combined and evaporated to dryness in a stream of nitrogen.The residue was reconstituted in 20 ml of phosphate-citrate buffer pH 3.5 containing 1.25% BSA and the solution was sterile filtered through a Millipore filter apparatus. ("Millipore" is a Trade
Mark.) The sterile filtrate was made up to 25 ml with sterilized phosphate-citrate buffer as above.
The total and specific activities of the final solution were calculated accurately.
WHAT WE CLAIM IS:
1. A method of iodinating a progesterone derivative comprising an iodinatable group attached to progesterone by means of a bridging group, which comprises reacting the progesterone derivative with an alkali metal iodide in the presence of sodium hypochlorite, and subsequently admixing with the reaction mixture a sufficient amount of free iodinatable group to take up unreacted iodine present in the reaction mixture.
2. A method as claimed in claim 1, wherein the iodinatable group is an iodinatable aromatic group or an aromatic heterocyclic group.
3. A method as claimed in claim 2, wherein the iodinatable group is tyrosine methyl ester or a tyramine deriavtive.
4. A method as claimed in claim 2, wherein the iodinatable group is histamine.
5. A method as claimed in any one of claims 1 to 4, wherein the iodine comprises a radioisotope of iodine.
6. A method as claimed in claim 5, wherein the radioisotope of iodine is 125I.
7. A method as claimed in any one of claims 1 to 6, wherein the progesterone derivative has one of the following formulae:
wherein
A represents progesterone,
R represents an iodinatable group, and
n is an integer of from 1 to 6.
8. A method as claimed in any one of claims 1 to 6, wherein the progesterine derivative has the formula
in which n, A and R are as defined in claim 7.
9. A method as claimed in claim 8, wherein n is the integer 1.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (15)
1 604 863).
The following Example illustrates the in
vention. In it, ratios of solvents for chromato
graphy are by volume.
EXAMPLE.
The following esolutions were added in tum to a glass tube over a magnetic stirrer: 2 mCi sodium iodide-125, 10 j1 of 0.2so phopshate buffer pH 7.4 and 20 Xal of a 0.3 mg/ml solution of progesterine - 3 - (0carboxymethyl)oxime - histamine in dioxin, and the mixture was then stirred to 10 seconds.
10 yl of a lul/ml solution of sodium hypo
chlorite (B.D.H. approximately 1 N in 0.1 -N NaOH) in phosphate buffer pH 7.4 was
then added and the mixture was stirred for
120 seconds. 10 A of a 0.5 mg/ml solution
of histamine dihydrochloride in 0.25M phos
phate buffer pH 7.4 were added to trap any
free iodine remaining in solution, and the
mixture was stirred for a further 30 seconds.
A small sample of the reaction mixture was
spotted onto a thin layer chromatography
plate to enable an estimate of the reaction
yield to be made, if desired. The remainder
of the reaction mixture was extracted with
200 A of ethyl acetate, the organic layer being
removed and retained. The extraction was
repeated and the ethyl acetate extracts were
combined.
The product was purified by column
chromatography as follows:
A silica gel column (lOog, Merck 7734)
was prepared using chloroform-methanol
(9:1) as solvent. The column was so arranged
that the eluant passed through an LKB Uvi
cord adapted for monitoring radioactivity and
fractions were collected using an LKD frac
tion collector. ("Uvicord" is a Trade Mark.)
The combined ethyl acetate extracts were added to the top of the column, and the column was eluted slowly with chloroformmethanol (9:1), 3 ml fractions were collected, and those corresponding to the main peak were combined and evaporated to dryness in a stream of nitrogen.The residue was reconstituted in 20 ml of phosphate-citrate buffer pH 3.5 containing 1.25% BSA and the solution was sterile filtered through a Millipore filter apparatus. ("Millipore" is a Trade
Mark.) The sterile filtrate was made up to 25 ml with sterilized phosphate-citrate buffer as above.
The total and specific activities of the final solution were calculated accurately.
WHAT WE CLAIM IS:
1. A method of iodinating a progesterone derivative comprising an iodinatable group attached to progesterone by means of a bridging group, which comprises reacting the progesterone derivative with an alkali metal iodide in the presence of sodium hypochlorite, and subsequently admixing with the reaction mixture a sufficient amount of free iodinatable group to take up unreacted iodine present in the reaction mixture.
2. A method as claimed in claim 1, wherein the iodinatable group is an iodinatable aromatic group or an aromatic heterocyclic group.
3. A method as claimed in claim 2, wherein the iodinatable group is tyrosine methyl ester or a tyramine deriavtive.
4. A method as claimed in claim 2, wherein the iodinatable group is histamine.
5. A method as claimed in any one of claims 1 to 4, wherein the iodine comprises a radioisotope of iodine.
6. A method as claimed in claim 5, wherein the radioisotope of iodine is 125I.
7. A method as claimed in any one of claims 1 to 6, wherein the progesterone derivative has one of the following formulae:
wherein
A represents progesterone,
R represents an iodinatable group, and
n is an integer of from 1 to 6.
8. A method as claimed in any one of claims 1 to 6, wherein the progesterine derivative has the formula
in which n, A and R are as defined in claim 7.
9. A method as claimed in claim 8, wherein n is the integer 1.
10. A method as claimed in any one of
claims 1 to 9, wherein the iodinatable group is attached via the bridging group to the 3position of progesterone.
11. A method as claimed in claim 1, claim 5 or claim 6, wherein the progesterone deriva
tive is progesterone - 3 - (0 - carboxy methyl ) oxime-histamine.
12. A method as claimed in claim 1, carried
out substantially as described in the Example herein.
13. Progesterone having an iodinated group
attached thereto by means of a bridging group,
whenever prepared by a method as claimed in any one of claims 1 to 12.
14. Progesterone as claimed in claim 13, wherein the iodinated group is iodinated with 125I
15. Progesterone - 3 - (O - carboxymethyl)- oxime - [us1] iodohistamine whenever prepared by a method as claimed in claim 1 or claim 12.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4160680A GB1604864A (en) | 1978-05-31 | 1978-05-31 | Methods of iodinating a progesterone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4160680A GB1604864A (en) | 1978-05-31 | 1978-05-31 | Methods of iodinating a progesterone derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1604864A true GB1604864A (en) | 1981-12-16 |
Family
ID=10420475
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB4160680A Expired GB1604864A (en) | 1978-05-31 | 1978-05-31 | Methods of iodinating a progesterone derivative |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB1604864A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2537586A1 (en) * | 1982-12-13 | 1984-06-15 | Roussel Uclaf | IODE BRANCHED RADIOACTIVE ESTRATRIENE DERIVATIVES, PROCESS FOR PREPARING THEM AND THEIR APPLICATION TO RADIOIMMUNOLOGICAL ASSAYS |
-
1978
- 1978-05-31 GB GB4160680A patent/GB1604864A/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2537586A1 (en) * | 1982-12-13 | 1984-06-15 | Roussel Uclaf | IODE BRANCHED RADIOACTIVE ESTRATRIENE DERIVATIVES, PROCESS FOR PREPARING THEM AND THEIR APPLICATION TO RADIOIMMUNOLOGICAL ASSAYS |
| EP0114011A1 (en) * | 1982-12-13 | 1984-07-25 | Roussel-Uclaf | Iodine-labelled radioactive estratriene derivatives, process and intermediates for their preparation, their use in radioimmuno assays and in the preparation of antigens, and antigens so obtained |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |