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WO2004069774A2 - Synthese d'analogues d'oestrogenes marques par 13c - Google Patents

Synthese d'analogues d'oestrogenes marques par 13c Download PDF

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WO2004069774A2
WO2004069774A2 PCT/GB2004/000419 GB2004000419W WO2004069774A2 WO 2004069774 A2 WO2004069774 A2 WO 2004069774A2 GB 2004000419 W GB2004000419 W GB 2004000419W WO 2004069774 A2 WO2004069774 A2 WO 2004069774A2
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mmol
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Nigel Botting
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The University Court Of The University Of St Andrews
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/06—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation
    • C07C37/07—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation with simultaneous reduction of C=O group in that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/08—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to 13 C-labelled estrogen analogues and a method of producing them.
  • phytoestrogens There is currently considerable interest in phytoestrogens with respect to their impact on human health.
  • the isoflavonoid phytoestrogens, daidzein (1) and genistein (2) are present at significant levels in soya beans and soy products.
  • an estrogen analogue comprising at least one 13 C atom at one or more pre-determined positions .
  • the estrogen analogue may be a lignan, flavone, isoflavone, prenylated isolflavone, daidzein, genistein, formononetin, biochanin A, equol, 0- desmethylangolensin (O-DMA) , angolensin, enterolactone, enterodiol, enterofuran matairesinol, secoisolariciresinol, shonanin, glyciten, 8- prenylgenistein, 8-prenylnaringenin, 8- prenylapigenin, coumestrol, or a mixture thereof.
  • the estrogen analogue is [3, 4, 8- 13 C 3 ]- daidzein, [3, 4, 1' - 13 C 3 ] -genisten, [3, 4, 8- 13 C 3 ] formononetin [3, 4, 1' - 13 C 3 ] -biochanin A, [3, 4, 8- 13 C 3 ]-equol, [1 , 7, 8 13 C 3 ] -genistein deoxybenzion, [6, 7, 8- 13 C 3 ] daidzein deoxybenzoin or a mixture thereof.
  • the estrogen analogue • suitably comprises at least one 13 C atom at more than one pre-determined position, and may comprise at least one 13 C atom at two or three pre-determined positions, advantageously at three pre-determined positions.
  • the 13 C-labelled compounds have two very important, and major advantages over deuterium labelled compounds. Firstly the level of 13 C incorporation depends entirely on the level of incorporation in the synthetic starting materials. The reactants used in this work are generally commercially available and have a 99% incorporation of 13 C, thus there will be 99% 13 C at the corresponding position in the estrogen analogue molecule. This is in contrast to the variable levels of deuterium incorporation obtained through exchange procedures. Also the method of synthesising the 13 C-labelled estrogen analogues is specific for incorporation of 13 C into a particular position in the estrogen analogue molecule. The second important advantage the present invention provides is that the 13 C will not exchange back out from the molecule during the analysis procedures which is a big problem with deuterium labelled compounds. Thus compounds of the present invention are far superior as internal standards to the deuterium labelled compounds currently available.
  • an estrogen analogue comprising at least one 13 C atom at one or more pre-determined positions, said method comprising the steps of; i) contacting reactants able to form an estrogen analogue wherein x amount of at least one reactant comprises at least one 13 C atom at a pre-determined position; and ii) forming an estrogen analogue wherein at least 0.9x amount of the estrogen analogue comprises at least one 13 C atom.
  • the reactant comprising at least one 13 C atom at a pre-determined position is an alkane, alkene, alkyne or aryl group, especially a phenyl or benzene group.
  • These groups may be unsubstituted, or substituted by one or more nitro, halogen, amino, hydroxyl, ketone or aldehyde groups.
  • aryl group is a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached in a pendant manner or may be fused.
  • aryl incorporates aromatic systems containing one or more non-carbon atoms as ring atoms.
  • aryl as used herein therefore includes heteroaryl compounds .
  • the reactant is hydroxymethoxybenzonitrile, benzyloxymethoxy- benzonic acid, benzyloxymethoxybenzonitrile, iodobenzyloxymethoxybenzene, benzyloxymethoxybenzyl alcohol, benzyloxymethoxybenzyl bromide, benzyloxymethoxybenzylpropane, or methoxybenzyliodide .
  • the reactant comprising at least one 13 C atom is Na 13 CN, K 13 CN, Na 2 13 C0 3 , NaH 13 C0 3 , K 2 13 C0 3 KH 13 C0 3 , [2- 13 C] Diethyl malonate, [1, 2- 13 C 2 [-Diethyl malonate, [1, 2- 13 c 2 ] -Acetyl chloride, [1, 2- 13 C 2 ]- Acetic acid or a halogen'alkane such as H 3 13 CBr, H 3 13 CI' or H 13 CN.
  • the method of producing the estrogen analogue comprises the step of forming an intermediate wherein the intermediate has the structure A or B or C;
  • Y is CI, Br, I, CN or COORi
  • Ri is H, Me, Et or Bn;
  • R is hydrogen or an optionally substituted alkane, alkene, alkyne or aryl group. These groups may be substituted with one or more nitro, halogen, amino, hydroxyl, ketone or aldehyde groups;
  • n 1 or 2;
  • X is I, Br, CN, COORi, CH 2 OR ⁇ , CH 2 Y, CH(C0 2 R ⁇ ) 2 , CH(CH 2 OR ⁇ ) 2 , CH(CH 2 OR ⁇ )CH 2 Y, CHCH 3 Y or CHCHsCOORx.
  • substituents Y, R., R or X represent a group having a carbon atom
  • the carbon atom may be a 13 C isotope, for example 13 CN, 13 COOH, CH 13 CH 3 Br, etc.
  • the intermediate has the structure A or B as listed above.
  • R is -CH 2 Ph, Me, Et or Bn.
  • One preferred intermediate is 13 C-resorcinol.
  • the present invention further comprises a method of forming 13 C-resorcinol, said method comprising the following reaction:
  • 13 C-resorcinol may be used as an intermediate in forming a 13 C-labelled estrogen analogue according to the invention.
  • At least 0.99x amount of the estrogen analogue comprises at least one 13 C atom at one or more pre-determined positions.
  • a method of screening the amount and/or location of an estrogen analogue in a human or animal body comprising the steps of; i) administering an estrogen analogue comprising a at least one 13 C atom at one or more pre-determined positions, to the human or animal body; and ii) detecting the amount and/or location of the
  • a deoxybenzoin was reacted with BF 3 .Et 2 0 and DMF and a short burst of microwave irradiation was used as the heat source.
  • Mesyl chloride was then added and the microwave treatment repeated. Addition of water resulted in precipitation of the product. Longer periods of microwave heating provides larger yields and a more reliable procedure especially when working on a larger scale.
  • the nitrile was reacted with phloroglucinol under Hoesch conditions to give the deoxybenzoin (23) .
  • Formylation and cyclisation were then achieved under microwave conditions using DMF and mesyl chloride to give 13 C-biochanin A (24) .
  • Spectral data confirmed the presence of the 13 C atom at the 4-position. 1 Modification of the synthesis then allowed the
  • the final 13 C atom was incorporated into the phenol fragment, i.e. resorcinol for daidzein or phloroglucinol for genistein.
  • a methylcuprate was reacted with methyl 4- (chloroformyl) butyrate (32) which gives the required methyl ketone (33) in 90% yield.
  • Cyclisation of the ketone was carried out using sodium ethoxide, followed by acid treatment to give the cyclic diketone (34) . This was aromatised by dehydrogenation using a palladium on charcoal catalyst at 190°C in triglyme to give the resorcinol.
  • the synthetic strategy for the production of [3,4,8- 13 C 3 ]-daidzein (36) has now been fully optimised (Scheme 7) .
  • the [2- 13 C]resorcinol (35) is prepared in 4 steps from methyl 4- (chloroformyl)butyrate in 26% overall yield, using [ 13 C]methyl iodide to provide the source of the labelled carbon.
  • the 4'- benzyloxy-[l,2- 13 C]-2-phenylacetic acid (31) was produced in 7 steps from 4-iodophenol and both of the 13 C atoms were derived from 13 C-labelled potassium cyanide.
  • This alternative method offers a route to the triply 13 C-labelled genistein and produces material suitable for use as an internal standard.
  • the synthetic targets with respect to the lignans are enterolactone (3), enterodiol (4), matairesinol (5) and secoisolariciresinol (6), which are all of biological interest.
  • the aim is to prepare these compounds in a form containing three 13 C atoms for use as internal standards in GC-MS analysis.
  • the synthetic route to enterolactone and enterodiol is given in Scheme 10.
  • the required 13 C-labelled bromide (54) can be prepared using a similar procedure to that employed above, starting from the commercially available iodide (57) via the nitrile (58), as shown in Scheme 12.
  • Analogous procedures can be employed for the synthesis of the matairesinol (5) and secoisolariciresinol (6) using suitably substituted starting materials.
  • Example 5a Synthesis of 13 C-Labelled Secoisolariciresinol and Matairesinol lodo 4-acetoxy-3-methoxybenzene.
  • Acetic anhydride 28 ml was added to a solution of iodo 4-hydroxy-3-methoxybenzene (5.22 g, 20.9 mmol) in pyridine (70 ml) and the mixture was stirred for 48 h at room temperature. Water (75 ml) and ethyl acetate (75 ml) were added and the organic layer was separated. The organic phase was washed with hydrochloric acid (1M; 2x 50 ml), dried (MgS0 4 ) and was concentrated in vacuo.
  • Trimethylsilyl bromide (0.6 ml, 7.4 mmol) was added to a solution of 4-benzyloxy-3-methoxy- [ 13 C] -benzyl alcohol (1.2 g, 4.9 mmol) in dry ether (30 ml) and the mixture was stirred at room temperature for 2.5 h. The reaction was quenched with water (10 ml) and was extracted with ether (2x 15 ml) .
  • Triethylamine (0.4 ml, 2.98 mmol) was added to a solution of 2- (4' -Benzyloxy-3' -methoxy- [ 13 C] - benzyl) propane-1, 3-diol (1.3 g, 4.3 mmol) and p- toluenesulfonyl chloride (0.57 g, 2.98 mmol) in dry dichloromethane (40 ml) and the mixture was stirred for 24 h at room temperature. The mixture was washed with hydrochloric acid (1M; 2x 30 ml) . The organic phase was dried (MgS0 4 ) and concentrated in vacuo.
  • the product was purified by semi prep HPLC, reverse phase, MeCN/ H 2 0 1:1, ⁇ 3 mg/ml.
  • the crude product was purified by column chromatography (ethyl acetate/ dichloromethane (55 : 45) elution) to give the ti tle compound as a white solid (0.11 g, 32 %) , 55.2 (OMe), 63.4 (CH 2 OH) , 112 . 0 (C-4 ' ) , 114 . 8 (C-2 ' ) , 118 .
  • Example 5b Synthesis of 13 C-Labelled Enterodiol and Enterolactone 3-Methoxybenzo- [ 13 C] -nitrile .
  • Triethylamine (4.2 ml, 31.3 mmol) was added to a solution of 2- (3' -methoxy- [ 13 C] -benzyl) propane-1, 3- diol (8.83 g, 44.8 mmol) and p-toluenesulfonyl chloride (5.97 g, 31.3 mmol) in dry dichloromethane (200 ml) and the mixture was stirred at room temperature overnight. The mixture was washed with hydrochloric acid (IM; 2x 120 ml), dried (MgS0 4 ) and concentrated in vacuo.
  • IM hydrochloric acid
  • MgS0 4 dried
  • Phosphorus triiodide (8.88 g, 21.5 mmol) was added to a solution of 3-methoxy- [ 13 C] -benzyl alcohol (1.76 g, 12.7 mmol) in dry ether (40 ml) at 0 °C and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water and the mixture was extracted with ether (3x 75 ml) .
  • the crude product was purified by column chromatography (light petroleum/ ether (gradient) elution) to give the ti tle compound as a yellow oil (0.85 g, 55%), (Found M + , 329.1625.
  • the desired product was obtained as a white solid (1.819 g, 80%) m.p. 66 - 69°C.
  • Phenol was added to a solution of sodium hydroxide (635 mg, 15.9 mmol) in methanol (10 ml). The solution was then cooled to -5°C, and iodine (2.015g, 7.94 mmol) in methanol (15 ml) was added dropwise. After 1 hour stirring at -5°C, the resulting mixture was acidified with hydrochloric acid (0.5 N) to pH 2 and extracted with diethyl ether (5 x 25 ml) . The combined organic layer was washed with sodium thiosulfate (3 x 20 ml), then brine (2 x 20 ml) and dried over MgS0 .
  • the desired product was obtained as white crystals (264 mg, 88%) m.p. 67 - 70°C.
  • Solution B was introduced into solution A slowly, the temperature was kept below 27 °C during addition.
  • the resulting mixture was stirred at room temperature for 20 minutes, then poured into aqueous sodium acetate (12.5%, 30 ml), stirred for 2 hours, and left overnight.
  • the solid formed was collected by filtration and washed with water (3 x 5 ml) . Further purification was carried out by HPLC. After removal of the solvent, the desired product was obtained as a white solid (47 mg, 52%) m.p. > 280°C (dec. ) .
  • O-Desmethylangolensin is a metabolite of daidzein where the B-ring has been cleaved.
  • the doubly R elabelled benzyl nitrile (134) precursor for the [3, 4, 8- 13 C] daidzein was alkylated using 13 C-labelled methyl iodide to give the nitrile (135) containing three 13 C-atoms in good yield (Scheme 38). Hydrolysis under basic conditions gave the acid (136) in 88% yield.
  • Coupling to resorcinol was accompanied by loss of the benzyl protecting group to give the 13 C-labelled O-desmethylangolensin (137) by prior removal of the protecting group.
  • Flavanones having prenyl substituents have increased biological activity.
  • 8-prenylnaringenin (143) is a potent estrogen found in hops and beer.
  • a large number of prenylated isoflavones are also known and recent work has begun to demonstrate interesting biological effects including anti-cancer activity.

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Abstract

L'invention concerne un procédé de synthèse d'analogues d'oestrogènes marqués par 13C. Ledit procédé consiste de préférence à se munir d'un intermédiaire A ou B ou d'un mélange de A et B. Selon l'invention, un atome de 13C est situé dans une ou plusieurs des positions 1, 2, 3 ou 4, et R est un groupe alcane, alcène, alcyne ou aryl éventuellement substitué, R étant de préférence -CH2Ph. Dans un autre mode de réalisation, un composé intermédiaire préféré est 13C-résorcinol.
PCT/GB2004/000419 2003-02-04 2004-02-04 Synthese d'analogues d'oestrogenes marques par 13c WO2004069774A2 (fr)

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WO2006057323A1 (fr) * 2004-11-26 2006-06-01 Nagasaki University Composition pour le diagnostic de maladies associées aux amyloïdes
JP2007084526A (ja) * 2004-11-26 2007-04-05 Nagasaki Univ アミロイド関連疾患診断用組成物
CN103288605A (zh) * 2013-06-06 2013-09-11 陕西师范大学 考布他丁的合成方法
WO2013144857A1 (fr) 2012-03-28 2013-10-03 Dr. Reddy's Laboratories Limited Procédé amélioré pour la production de (s)-équol
CN103936706A (zh) * 2014-03-19 2014-07-23 常州大学 一种黄羽扇豆怀特酮的合成方法
CN105693496A (zh) * 2016-03-18 2016-06-22 上海化工研究院 一种稳定同位素13c或d标记对羟基苯甲酸的合成方法
CN114349605A (zh) * 2022-02-15 2022-04-15 营口兴福化工有限公司 对碘苯酚合成方法
WO2023212130A1 (fr) * 2022-04-28 2023-11-02 GreenStone Biosciences, Inc. Traitement des effets cardiovasculaires indésirables de cannabinoïdes

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WO2006057323A1 (fr) * 2004-11-26 2006-06-01 Nagasaki University Composition pour le diagnostic de maladies associées aux amyloïdes
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