CN109134578A - A kind of synthetic method of the 5- steroid derivatives containing carboxyl - Google Patents
A kind of synthetic method of the 5- steroid derivatives containing carboxyl Download PDFInfo
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- CN109134578A CN109134578A CN201811180964.3A CN201811180964A CN109134578A CN 109134578 A CN109134578 A CN 109134578A CN 201811180964 A CN201811180964 A CN 201811180964A CN 109134578 A CN109134578 A CN 109134578A
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- containing carboxyl
- steroid derivatives
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- steroid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- 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
- C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
- C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
Abstract
The invention discloses a kind of synthetic methods of 5- steroid derivatives containing carboxyl, include the following steps: the first step, under organic solvent and alkali existence condition, using steroid hormone and diethyl malonate as raw material, nucleophilic addition occurs in anhydrous and oxygen-free environment, obtains the steroid derivatives of 5- ester groups substitution；Second step is added hydrochloric acid solution in the product that the first step obtains and carries out decarboxylation and acidification reaction, isolated and purified after reaction, obtain steroid derivatives of the position 5- containing carboxyl of biological purity >=95%.The present invention has the advantages that raw materials used be easy to get, commercial product is can be used in all raw materials；Entire operation is simple, and synthesis cycle is short, and obtained product yield high, configuration are single.For the final product that will be obtained -- the 5- steroid derivatives for containing carboxyl as the raw material for preparing hypertension diagnosis kit antigen, reaction effect is good, economic value with higher.
Description
Technical field
The present invention relates to the synthesis of steroid hormone derivative, spread out more particularly, to a kind of 5- steroids containing carboxyl
The synthetic method of biology.
Background technique
Steroid hormone, also known as steroid hormone have epochmaking pharmaceutical value.Sustain life, adjusting sexual function, with
And there is specific effect to body development, immunological regulation, treating skin disease and birth control aspect.Wherein aldosterone is kidney
One kind of upper gland cortin, the metabolic mineralocorticoid hormone of representative strong electrolyte, effect are to protect
Sodium arranges potassium and maintains electrolyte balance and body fluid capacity constant.Aldosterone is to be generated by adrenal cortex glomerular zone, and divided by kidney
The adjusting for the renin secreted.Steroid hormone has in very strong as a kind of typical body incretion interferent
Interference effect is secreted, therefore the measurement of steroid hormone is particularly important.
In human body in the measurement of a variety of hormones, the measurement of steroids has always been considered as being a problem, tradition
Immunization method cannot accurately measure the content of steroid hormone in human body.In general, antigen or antibody in vitro testing principle are
Combined according to antigen-antibody and form the character and activation characteristics of immune complex, in sample antigen or antibody carry out it is qualitative,
Positioning or quantitative detection.The adaptation feature of antigen-antibody can change with the difference of antigen or antibody structure.For antigen
For, the functional group of the idiosyncrasy of free state is The more the better.The Main way of current research is to synthesize efficient aldehyde to consolidate
Ketone derivatives replace aldosterone as haptens, are detected by label and antibody progress specific reaction,
JK Mckenzie and JA Clements are in " J Clin Endocrinol Metab ", 1974,38 (4): 622-
Steroid hormone derivative (3- carbonyls and half hydrochloride of the carboxymethyl azanol condensation de- one of 3- CMO substitution are referred in 627
One's share of expenses for a joint undertaking water formed oxime derivatives) synthetic method (synthetic route is as shown in Figure 1).However, these derivatives and antibody are special
The opposite sex combine functional group can covered a part, cause with the suitability of antibody and specifically bind efficiency can become to pay no attention to
Think.
It refers in the patent document that the Masao Kono of Japan was delivered in 1987 at aldosterone 4- and 6-
The synthetic method (synthetic route is as shown in Figure 2) of substituted derivative, advantage is can be fine by the reaction site of aldosterone
Ground is exposed, and 4- and 6- can be labeled, and exposed functional group can be efficiently in conjunction with antibody specificity；Disadvantage exists
Longer in synthetic route, the reaction time is long, and yield is low, and what is obtained is the mixing of the aldosterone derivative of 4- and 6- substitutions
Object.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation process is simple, carboxyl is contained in the 5- position good as antigen-reactive effect
Steroid derivatives synthetic method.
To achieve the above object, the present invention can take following technical proposals:
The synthetic method of the 5- steroid derivatives containing carboxyl of the present invention includes the following steps:
The first step, under organic solvent and alkali existence condition, using steroid hormone and diethyl malonate as raw material, in anhydrous nothing
Nucleophilic addition occurs in oxygen environment, obtains the steroid derivatives of 5- ester groups substitution；
Second step is added hydrochloric acid solution in the product that the first step obtains and carries out decarboxylation and acidification reaction, after reaction through dividing
From purifying, steroid derivatives of the position 5- containing carboxyl of biological purity >=95% are obtained.
Organic solvent used in the first step can be used including dimethyl sulfoxide, tetrahydrofuran, methanol or ethyl alcohol etc. pair
Reaction substrate has preferable deliquescent solvent.
Alkali used in the first step is sodium ethoxide or sodium methoxide, and the temperature of the nucleophilic addition is -5 ~ 5 DEG C,
Reaction time is 5 ~ 7h.
To improve the conversion ratios such as steroid hormone, steroid hormone used in the first step, diethyl malonate and
Molar ratio between alkali is 1:(1.1~1.5): (1.2 ~ 1.6).
Concentration of hydrochloric acid used in the second step is 6N.
In the second step temperature of decarboxylation and acidification reaction be 70 ~ 90 DEG C, the reaction time be 16 ~ for 24 hours；Reaction time mistake
Length will increase reaction cost, and the reaction time is too short, is difficult to ensure the complete of reaction.During real reaction, thin layer color can be passed through
Whether spectrum carries out real-time monitoring reaction complete.
The present invention has the advantages that raw materials used be easy to get, commercial product is can be used in all raw materials；Entire operation letter
Single, synthesis cycle is short, and obtained product yield high, configuration are single.The final product that will be obtained -- the 5- class containing carboxyl is solid
For 01 derivatives as the raw material for preparing hypertension diagnosis kit antigen, reaction effect is good, economic value with higher.
Detailed description of the invention
Fig. 1, Fig. 2 are the synthetic route charts of existing steroid hormone derivative.
Fig. 3 a, Fig. 3 b, Fig. 3 c, Fig. 3 d are that four kinds of the steroid derivatives of the position 5- containing carboxyl of the invention synthesized are specific
Compound.
Fig. 4 is synthetic route chart of the present invention.
Specific embodiment
The synthetic method of the 5- steroid derivatives containing carboxyl of the present invention includes the following steps:
The first step, in organic solvent (such as dimethyl sulfoxide, tetrahydrofuran, methanol or ethyl alcohol) and alkali (sodium ethoxide, sodium methoxide etc.)
Under existence condition, using steroid hormone and diethyl malonate as raw material, nucleophilic addition occurs in anhydrous and oxygen-free environment,
Reaction temperature is -5 ~ 5 DEG C, and the reaction time is 5 ~ 7h, obtains the steroid derivatives of 5- ester groups substitution；Swash to improve steroids
The conversion ratio of element, the molar ratio between steroid hormone, diethyl malonate and alkali are limited to 1:(1.1~1.5): (1.2 ~
1.6)；
The hydrochloric acid solution that concentration is 6N is added in the product that the first step obtains and carries out decarboxylation and acidification reaction, reaction for second step
Temperature be 70 ~ 90 DEG C, the reaction time be 16 ~ for 24 hours, isolated and purified after reaction, the position 5- for obtaining biological purity >=95% contains
There are the steroid derivatives of carboxyl, structural formula is shown in Fig. 3 a, 3b, 3c, 3d.
It, can be by thin when real reaction (decarboxylation of nucleophilic addition and second step including the first step and acidification reaction)
Whether the reaction of layer chromatography real-time monitoring is complete: when the first step is reacted to terminal, thin layer silica gel platelet panel polarity is PE:EA:
MeOH=1:1:0.2；When second step is reacted to terminal, thin layer silica gel platelet panel polarity is CH2Cl2:MeOH=4:1。
The process that isolates and purifies after reaction includes: that water quenching is added to go out, and extracts liquid separation, silica gel mixed sample, finally using column
Chromatographic purifying.The process is conventional method, is repeated no more.
The route map of synthetic method of the present invention is as shown in figure 4, wherein R1For hydroxyl or hydrogen atom (preferably hydroxyl)；The R2
For hydrogen atom or-CHO(preferably-CHO)；The R3For hydroxyl or hydrogen atom (preferably hydrogen atom)；The R4For-COCH3, hydrogen it is former
Son or-COCH2OH(preferably-COCH2OH).
More detailed explanation is done to the present invention below by specific embodiment, wherein the raw material used is existingization
Object is closed, can directly buy, can also voluntarily be prepared by existing method.
Embodiment 1 prepares the aldosterone derivative of 5- carboxyl
In the Schlenk pipe of 50mL be added 50mg aldosterone (11 β, 21- dihydroxy -3.20- dioxy -4- pregnene -18- aldehyde (11 →
18) lactic aldehyde), vacuum and exchange nitrogen three times, is cooled to 0 DEG C, instills tetrahydrofuran 10mL and is added dropwise third after aldosterone dissolution completely
The mixed solution of diethyl adipate (30ul) and sodium ethoxide (15mg) is transferred to room temperature after being added dropwise completely, is stirred to react 6 hours.
After contact plate monitors fully reacting, add water quenching reaction, ethyl acetate extracts liquid separation, silica gel mixed sample, and (eluant, eluent is by column chromatography
Methylene chloride: ethyl acetate=3:1) purifying obtain 5- esterification aldosterone derivative, yield 57%；
The aldosterone derivative of esterification is added in the aqueous hydrochloric acid solution of 6mol/L, is warming up to 80 DEG C, temperature control reacts 20 hours,
Ethyl acetate extract liquid separation, silica gel mixed sample, by column chromatography (eluant, eluent is methylene chloride: ethyl acetate=1:1, be added thousand/
One acetic acid) purifying obtain the aldosterone derivative of 5- carboxyl, yield 73%；
The aldosterone derivative of the 5- carboxyl of preparation nuclear magnetic resonance (1H NMR and13C NMR) detection data are as follows:
1H NMR(400MHz, CDCl3): 12.14(s, 1H),9.43(s, 1H),4.83(t, 1H),4.62(d, 2H),
4.13(t, 1H),3.32(m, 1H),2.53(m, 5H),2.13(m,7H),1.93(m,6H),1.54(m,4H),1.43(s,
3H);
13C NMR (100MHz, CDCl3): 213.78,207.13,203.64,180.23,81.35,73.85,71.43,
69.97,65.32,62.13,58.85,57.32,54.19,51.45,48.23,43.15,39.15,38.46,35.23,
34.85,32.12,30.84,25.13。
Embodiment 2 prepares the aldosterone derivative of 5- carboxyl
Cortisol (hydrocortisone) is added in the Schlenk pipe of 50mL, vacuum and exchange nitrogen three times, is cooled to 0 DEG C, instills
The mixed solution of diethyl malonate (31ul) and sodium ethoxide (15mg) is added dropwise after cortisol dissolution completely in tetrahydrofuran 10mL,
It is transferred to room temperature after being added dropwise completely, is stirred to react 7 hours.After contact plate monitors fully reacting, add water quenching reaction, ethyl acetate extraction
Liquid separation is taken, silica gel mixed sample is consolidated by the aldehyde that column chromatography (eluant, eluent is methylene chloride: ethyl acetate=5:1) purifying obtains 5- esterification
Ketone derivatives, yield 48%；
The aldosterone derivative of esterification is added in the aqueous hydrochloric acid solution of 6mol/L, is warming up to 80 DEG C, temperature control reacts 20 hours,
Ethyl acetate extract liquid separation, silica gel mixed sample, by column chromatography (eluant, eluent is methylene chloride: ethyl acetate=2:1, be added thousand/
One acetic acid) purifying obtain the aldosterone derivative of 5- carboxyl, yield 69%；
The aldosterone derivative of the 5- carboxyl of preparation nuclear magnetic resonance (1H NMR and13C NMR) detection data are as follows:
1H NMR (400MHz, CDCl3): 12.38(s, 1H), 4.95 (t, 1H), 4.54 (m, 3H), 4.18 (d, 1H),
3.43(m, 1H),2.78(m, 6H), 2.09(m,6H), 1.73(m, 6H),1.66(m,6H),1.25(s,3H);
13C NMR (100MHz, CDCl3): 215.63,209.79,85.47,79.69,78.14,76.63,
72.53, 66.78, 65.12, 63.76, 59.98, 57.62, 55.17, 50.34, 49.88, 43.76, 39.87,
36.87, 34.97, 34.66, 32.25, 31.76, 25.65。
Embodiment 3 prepares the aldosterone derivative of 5- carboxyl
Progesterone (pregn-4-ene-3,20-dione) is added in the Schlenk pipe of 50mL, vacuum and exchange nitrogen three times, is cooled to 0
DEG C, it instills tetrahydrofuran 10mL and the mixing of diethyl malonate (25ul) and sodium ethoxide (12mg) is added dropwise after pregnant alcohol dissolution completely
Solution is transferred to room temperature after being added dropwise completely, is stirred to react 6 hours.After contact plate monitors fully reacting, add water quenching reaction, acetic acid
Ethyl ester extracts liquid separation, and silica gel mixed sample obtains 5- esterification by column chromatography (eluant, eluent is methylene chloride: ethyl acetate=5:1) purifying
Derivatives of progesterone, yield 48%；
The derivatives of progesterone of esterification is added in the aqueous hydrochloric acid solution of 6mol/L, is warming up to 80 DEG C, temperature control reacts 20 hours, second
Acetoacetic ester extracts liquid separation, and silica gel mixed sample, by column chromatography, (eluant, eluent is methylene chloride: ethyl acetate=2:1, and one thousandth is added
Acetic acid) purifying obtain the derivatives of progesterone of 5- carboxyl, yield 64%；
The derivatives of progesterone of the 5- carboxyl of preparation nuclear magnetic resonance (1H NMR and13C NMR) detection data are as follows:
1H NMR (400MHz, CDCl3): 12.06 (s, 1H), 2.1 (m, 7H), 1.98 (s, 3H), 1.74 (m, 6H),
1.47(m, 8H), 1.14(m, 1H), 1.12(s,3H), 1.04(m, 2H), 0.89(s, 1H)
13C NMR (100MHz, CDCl3): 210.8,209.5,177.3,63.6,55.6,51.7,46.4,
44.1, 42.1, 39.0, 38.4, 38.1, 35.6, 33.2, 32.0, 28.2, 26.6, 24.3, 23.4, 21.4,
17.9, 13.3。
Claims (6)
1. a kind of synthetic method of the 5- steroid derivatives containing carboxyl, it is characterised in that: include the following steps:
The first step, under organic solvent and alkali existence condition, using steroid hormone and diethyl malonate as raw material, in anhydrous nothing
Nucleophilic addition occurs in oxygen environment, obtains the steroid derivatives of 5- ester groups substitution；
Second step is added hydrochloric acid solution in the product that the first step obtains and carries out decarboxylation and acidification reaction, after reaction through dividing
From purifying, the 5- steroid derivatives containing carboxyl are obtained.
2. the synthetic method of the 5- steroid derivatives containing carboxyl according to claim 1, it is characterised in that: described
Organic solvent used in the first step is dimethyl sulfoxide, tetrahydrofuran, methanol or ethyl alcohol.
3. the synthetic method of the 5- steroid derivatives containing carboxyl according to claim 1, it is characterised in that: described
Alkali used in the first step is sodium ethoxide or sodium methoxide, and the temperature of the nucleophilic addition is -5 ~ 5 DEG C, the reaction time is 5 ~
7h。
4. the synthetic method of the 5- steroid derivatives containing carboxyl according to claim 1, it is characterised in that: described
Molar ratio between steroid hormone used in the first step, diethyl malonate and alkali is 1:(1.1~1.5): (1.2 ~
1.6).
5. the synthetic method of the 5- steroid derivatives containing carboxyl according to claim 1, it is characterised in that: described
Concentration of hydrochloric acid used in second step is 6N.
6. the synthetic method of the 5- steroid derivatives containing carboxyl according to claim 1, it is characterised in that: described
In second step the temperature of decarboxylation and acidification reaction be 70 ~ 90 DEG C, the reaction time be 16 ~ for 24 hours.
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| CN102557851A (en) * | 2011-12-13 | 2012-07-11 | 安徽省新星药物开发有限责任公司 | New method for synthesizing tapentadol hydrochloride and analogue of tapentadol hydrochloride |
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| CN102557851A (en) * | 2011-12-13 | 2012-07-11 | 安徽省新星药物开发有限责任公司 | New method for synthesizing tapentadol hydrochloride and analogue of tapentadol hydrochloride |
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