CN106946962A - One kind 16 α, 16 β, the synthetic method of the androstenedione of 17 β, tri- deuteriums 1,4 - Google Patents

One kind 16 α, 16 β, the synthetic method of the androstenedione of 17 β, tri- deuteriums 1,4 Download PDF

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Publication number
CN106946962A
CN106946962A CN201710159039.1A CN201710159039A CN106946962A CN 106946962 A CN106946962 A CN 106946962A CN 201710159039 A CN201710159039 A CN 201710159039A CN 106946962 A CN106946962 A CN 106946962A
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China
Prior art keywords
synthetic method
androstenedione
isosorbide
nitrae
solvent
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CN201710159039.1A
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Inventor
赵鹏
陈武炼
张驰中
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Shanghai Anpu Experimental Technology Co Ltd
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Shanghai Anpu Experimental Technology Co Ltd
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Priority to CN201710159039.1A priority Critical patent/CN106946962A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07B59/007—Steroids
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present invention relates to a kind of 16 α, 16 β, the synthetic method of the deuterium Isosorbide-5-Nitrae androstenedione of 17 β tri-, the synthetic method comprises the following steps：(A1) Isosorbide-5-Nitrae androstenedione is mixed with deuterated water in the first solvent, and is heated to reflux under the catalytic action of alkalescent salt；(A2) α of intermediate product 16,16 β-two deuterium Isosorbide-5-Nitrae androstenedione are obtained after extract return method reaction solution, the organic phase for concentrating extraction；(A3) intermediate product is mixed with boron deuterate sodium in the second solvent, and carries out under condition of ice bath selective reduction；(A4) acidifying reduction reaction liquid makes its pH≤2；(A5) the reduction reaction liquid after extraction acidifying, organic phase is separated using column chromatography, obtains the deuterium Isosorbide-5-Nitrae androstenedione of target product 16 α, 16 β, 17 β tri-.The present invention is with reaction scheme is simple, product purity is high, low cost and other advantages.

Description

The synthetic method of one kind β-three deuterium -1,4- androstenedione of 16 α, 16 β, 17
Technical field
The present invention relates to organic synthesis field, the more particularly to a kind of β-three of the α of internal standard compound 16,16 β, 17 deuteriums-Isosorbide-5-Nitrae-androstene two The synthetic method of ketone.
Background technology
The popularization detected with chromatogram, the standard items of cold labeling have turned into optimal quantitative internal standard compound, with Stable isotope is (such as2H、13C、15N、18O) as internal standard, the reliability of experimental data is not only increased, and also improves survey Try sensitivity.The β-three of 16 α, 16 β, 17 deuteriums-Isosorbide-5-Nitrae-androstenedione, are commonly called as 17 β-boldenone-D3, use2H is stable isotope, is A kind of extremely stable, signal is strong will not to produce the internal standard compound of interference again, be usually used in the detection of residue of veterinary drug, in sample to be analysed Add 17 β-boldenone-D3Detected as internal standard compound.At present, 17 β-boldenone-D3Complex synthetic route, it is deuterated Rate is low, and synthetic product is complicated, and last handling process is cumbersome, causes production cost very high, and China substantially can only be according to such standard items By external import.
The content of the invention
In order to solve the deficiency in above-mentioned prior art, the invention provides a kind of reaction scheme is simple, reaction bar Part is gentle, product purity is high, deuterated rate high, the synthetic method of the β-three deuterium -1,4- androstenedione of 16 α of low cost, 16 β, 17.
The purpose of the present invention is achieved through the following technical solutions：
The synthetic method of one kind β-three of 16 α, 16 β, 17 deuteriums-Isosorbide-5-Nitrae-androstenedione, the synthetic method comprises the following steps：
(A1) Isosorbide-5-Nitrae-androstenedione is mixed with deuterated water in the first solvent, and is heated under the catalytic action of alkalescent salt Backflow, Isosorbide-5-Nitrae-androstenedione occurs hydrogen deuterium with deuterated water and exchanged；
(A2) α of intermediate product 16,16 β-two deuteriums-Isosorbide-5-Nitrae-hero are obtained after extract return method reaction solution, the organic phase for concentrating extraction Alkene diketone；
(A3) intermediate product is mixed with boron deuterate sodium in the second solvent, and carries out selectivity also under condition of ice bath It is former；
(A4) acidifying reduction reaction liquid makes its pH≤2；
(A5) the reduction reaction liquid after extraction acidifying, separates organic phase using column chromatography, obtains target product 16 α, 16 β, 17 β-three deuterium -1,4- androstenedione.
According to above-mentioned synthetic method, alternatively, Isosorbide-5-Nitrae-androstenedione is 1 with the amount ratio of the material of deuterated water:100~1: 500。
According to above-mentioned synthetic method, alternatively, first solvent is 1 with the volume ratio of deuterated water:2~1:4.
According to above-mentioned synthetic method, it is preferable that in (A1) step, the time is heated to reflux for 24~30 hours.
According to above-mentioned synthetic method, it is preferable that first solvent is organic solvent miscible with water.
According to above-mentioned synthetic method, it is preferable that first solvent is tetrahydrofuran.
According to above-mentioned synthetic method, it is preferable that the alkalescent salt is potassium carbonate.
According to above-mentioned synthetic method, alternatively, the ratio between amount of material of the intermediate product and boron deuterate sodium is 1:1~ 1:1.2。
According to above-mentioned synthetic method, alternatively, ice bath temperature is -10 DEG C~0 DEG C, and the ice bath reaction time is 20-60 points Clock.
According to above-mentioned synthetic method, it is preferable that second solvent is deuterated methanol.
According to above-mentioned synthetic method, it is preferable that in (A2), (A5) step, extracted using ethyl acetate.
Compared with prior art, the device have the advantages that being：
1st, the present invention creatively proposes a kind of synthetic method of the β-three of 16 α, 16 β, 17 deuteriums-Isosorbide-5-Nitrae-androstenedione, i.e., Isosorbide-5-Nitrae-androstenedione is used for raw material, first carrying out hydrogen deuterium with deuterated water exchanges, then selective reduction is carried out by boron deuterate sodium and obtained To target product, simply, reaction raw materials are cheap and easy to get, low cost for synthetic route.
2nd, the present invention is simple to operate, and reaction condition is gentle, yield stable.
3rd, the product purity that synthetic method of the invention is obtained is more than 99%, and deuterated rate is more than 98.5%.
Brief description of the drawings
Fig. 1 is the β-three deuterium -1,4- androstenedione of 16 α, 16 β, 171H NMR spectras；
Fig. 2 is the β-three deuterium -1,4- androstenedione of 16 α, 16 β, 1713C NMR spectras.
Embodiment
Fig. 1-2 and the optional embodiment of the present invention is following description described to instruct how those skilled in the art implement It is of the invention with reproducing.In order to instruct technical solution of the present invention, simplify or eliminate some conventional aspects.Those skilled in the art It should be appreciated that modification or replacement from these embodiments will within the scope of the invention.Those skilled in the art should understand that Following characteristics can combine to form multiple modifications of the present invention in a variety of ways.Thus, the invention is not limited in it is following can Embodiment, and only limited by claim and their equivalent.
Embodiment 1
The present embodiment provides a kind of synthetic method of the β-three of 16 α, 16 β, 17 deuteriums-Isosorbide-5-Nitrae-androstenedione, the synthetic method Comprise the following steps：
(A1) Isosorbide-5-Nitrae-androstenedione is mixed with deuterated water in tetrahydrofuran, catalytic amount alkalescent salt (such as potassium carbonate, Sodium carbonate) catalytic action under be heated to reflux 24-30 hours；The 1,4- androstenedione is 1 with the amount ratio of the material of deuterated water: 100~1:500 (such as 1:300), the volume of the tetrahydrofuran is 1/2~1/4 (such as 1/3) of deuterated water volume；
(A2) stop backflow, be cooled to room temperature, using ethyl acetate extract return method reaction solution, the organic phase after extraction is entered Row concentration obtains the α of intermediate product 16,16 β-two deuterium -1,4- androstenedione；
(A3) intermediate product is mixed with boron deuterate sodium in deuterated methanol, anti-under -10 DEG C~0 DEG C of condition of ice bath Answer 20-60 minutes；The intermediate product is 1 with the amount ratio of the material of boron deuterate sodium:1~1:1.2 (such as 1:1.1)；
(A4) its pH≤2 is made with hydrochloric acid or sulfuric acid acidifying reduction reaction liquid, it is to avoid-the OH after reduction on 17 becomes- ONa；
(A5) the reduction reaction liquid being extracted with ethyl acetate after acidifying is adopted, and organic phase is separated with column chromatography, mesh is obtained Mark product.
Fig. 1 gives target product1H NMR spectras, as can be seen from the figure obvious 3 double bond hydrogen, and hydrogen Quantity is just corresponded to completely with the hydrogen quantity of the β-three deuterium -1,4- androstenedione of 16 α, 16 β, 17；Fig. 2 gives target product13C NMR spectra, an obvious carbonyl carbon and four double key carbons, can also be seen that two are connected with D-atom as we can see from the figure Carbon is split point, and carbon number amount of the quantity just with the β-three of 16 α, 16 β, 17 deuteriums-Isosorbide-5-Nitrae-androstenedione of carbon is corresponded to completely.Cause This, can confirm that target product is the β-three of 16 α, 16 β, 17 deuteriums-Isosorbide-5-Nitrae-androstenedione.
Advantage of this embodiment is that：Synthetic route is simple, and reaction condition is gentle, and raw material is cheap and easy to get, low cost.
Embodiment 2
The concrete application example of the embodiment of the present invention 1.
(1) weigh 1.42g Isosorbide-5-Nitraes-androstenedione to be put into there-necked flask, add catalytic amount potassium carbonate 50mg, measure 30mL Purity is added in reaction solution jointly for 99.9% deuterated water and 10mL tetrahydrofuran, is heated to reflux after 24 hours stopping reaction, It is cooled to room temperature；
(2) reaction solution is extracted three times with 40ml ethyl acetate, and organic phase is collected into one and reinstates Rotary Evaporators revolving, obtains White solid powder 1.28g, reaction yield is 90%；
(3) the 1.28g white solid powders are added in there-necked flask, weighs boron deuterate sodium 207mg and be put into there-necked flask, plus Enter 18mL deuterated methanols as reaction dissolvent, the there-necked flask is placed under condition of ice bath (0 DEG C) and reacted 30 minutes；
(4) stop reaction, 1mol/L hydrochloric acid is added dropwise into reduction reaction liquid until pH≤2；
(5) extracted three times with 20mL ethyl acetate, leave organic phase, use n-hexane：Ethyl acetate=1:1 solvent is carried out Post separation is crossed, with white product 0.75g is obtained after Rotary Evaporators organics removal, yield is 59%.

Claims (10)

1. a kind of synthetic method of the β-three of 16 α, 16 β, 17 deuteriums-Isosorbide-5-Nitrae-androstenedione, it is characterised in that：The synthetic method includes Following steps：
(A1) Isosorbide-5-Nitrae-androstenedione is mixed with deuterated water in the first solvent, and is heated back under the catalytic action of alkalescent salt Stream, Isosorbide-5-Nitrae-androstenedione occurs hydrogen deuterium with deuterated water and exchanged；
(A2) α of intermediate product 16,16 β-two deuteriums-Isosorbide-5-Nitrae-androstene two are obtained after extract return method reaction solution, the organic phase for concentrating extraction Ketone；
(A3) intermediate product is mixed with boron deuterate sodium in the second solvent, and carries out under condition of ice bath selective reduction；
(A4) acidifying reduction reaction liquid makes its pH≤2；
(A5) the reduction reaction liquid after extraction acidifying, separates organic phase using column chromatography, obtains target product 16 α, 16 β, 17 β-three deuterium -1,4- androstenedione.
2. synthetic method according to claim 1, it is characterised in that：The amount ratio of 1,4- androstenedione and the material of deuterated water For 1:100~1:500.
3. synthetic method according to claim 2, it is characterised in that：First solvent is 1 with the volume ratio of deuterated water: 2~1:4.
4. synthetic method according to claim 1, it is characterised in that：(A1) in step, the time that is heated to reflux is 24~30 Hour.
5. synthetic method according to claim 1, it is characterised in that：First solvent is miscible with water organic molten Agent.
6. synthetic method according to claim 1, it is characterised in that：The alkalescent salt is potassium carbonate.
7. synthetic method according to claim 1, it is characterised in that：The amount of the intermediate product and the material of boron deuterate sodium The ratio between be 1:1~1:1.2.
8. synthetic method according to claim 7, it is characterised in that：Ice bath temperature is -10 DEG C~0 DEG C, when ice bath reacts Between be 20-60 minutes.
9. synthetic method according to claim 1, it is characterised in that：Second solvent is deuterated methanol.
10. synthetic method according to claim 1, it is characterised in that：(A2), in (A5) step, entered using ethyl acetate Row extraction.
CN201710159039.1A 2017-03-17 2017-03-17 One kind 16 α, 16 β, the synthetic method of the androstenedione of 17 β, tri- deuteriums 1,4 Pending CN106946962A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014122480A1 (en) * 2013-02-11 2014-08-14 University Of Bath 16- and 17- deuterated estrogen-3-sulfamates as estrogenic agents
CN104558081A (en) * 2015-01-26 2015-04-29 中国科学院上海有机化学研究所 Synthesis method of 17-alpha-hydroxy steroid compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014122480A1 (en) * 2013-02-11 2014-08-14 University Of Bath 16- and 17- deuterated estrogen-3-sulfamates as estrogenic agents
CN104558081A (en) * 2015-01-26 2015-04-29 中国科学院上海有机化学研究所 Synthesis method of 17-alpha-hydroxy steroid compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JAMES SCARTH ET AL.: "Validation of a Quantitative Multi-Residue Urinary Assay for the Detection of Androgen, Oestrogen and Progestagen Abuse in the Bovine", 《CHROMATOGRAPHIA》 *
M. FIDANI ET AL.: "Evaluation of equine urine reactivity towards phase II metabolites of 17-hydroxy steroids by liquid chromatography/tandem mass spectrometry", 《RAPID COMMUNICATIONS IN MASS SPECTROMETRY》 *

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