CN101012264A - Method of synthesizing pig ectohormone - Google Patents

Abstract

The invention relates to a method for synthesizing porcine pheromone. The synthesis of porcine pheromones androst-16-en-3-one and androst-16-en-3α-ol was completed using gragnatriol, a degradation product of sisal sapogenin that exists widely in nature, as raw materials. The method of the invention has the advantages of simple operation, low reagent price and high product yield, and is suitable for industrial production. The method realizes the further effective utilization of the degradation product of steroidal sapogenin—pregnanol.

Description

A kind of method of synthesizing pig ectohormone

Technical field

The present invention relates to a kind of method of synthesizing pig ectohormone.The sisalagenin that extensively exists with nature is a basic raw material, has finished synthesizing of pig ectohormone rost-16-en-3-one and androstane-16-alkene-3 α-alcohol by 5 step reactions and the reaction of 6 steps respectively, and is shorter, easy and simple to handle than existing literature method step, yield is high.

Technical background

Contain rost-16-en-3-one (1) and androstane-16-alkene-3 α-alcohol (2) in the urine of boar, they are known two kinds of pig ectohormones, can induce the sexual behaviour of sow, shorten the oestrus cycle, and can when artificial insemination, be used to detect the breeding reaction of pig, improve conception rate, had in the pig industry abroad and used (China Medicine University's journal more widely, 1991,22,367).What is interesting is, in the sweat of man oxter, also found compound 1 (Proc.Int.Symp.Olfaction Taste, 7th, 1980,397-400; CA, 1981,94:115047), and also influential to people's behavior.

These two compounds are the synthetic key intermediate androstane of raw material-16-alkene-3 β-alcohol (4) with epiandrosterone (3) generally, and then obtain through peroxidation or counter-rotating 3-position hydroxyl.Synthetic route (TetrahedronLett., 1962,26,1261 as follows relatively more commonly used at present; Acta Pharmaceutica Sinica, 1982,17,696):

Epiandrosterone 3 industrial be to be raw material with the cheap diosgenin diosgenin that gets bumper crops, obtain through degraded and hydrogenation, i.e. sapogenin and Ac in autoclave ₂O is heated to 200 ℃ and is cracked into false steroid sapogenines, again through chromic anhydride oxidation, elimination reaction and rearrangement reaction preparation (J.Am.Chem.Soc., 1940,62,3350; J.Org.Chem., 1956,21,520), severe reaction conditions, complex operation, particularly chromic anhydride oxidation pollute very serious in process of production:

a，Ac ₂O，200℃；b，CrO ₃；c，NaOAc；d，NH ₂OH；e，POCl ₃；f，K ₂CO ₃，MeOH；g，H ₂，cat.。

Tian Weisheng group has developed method (Chinese patent, the ZL96116304.6 that becomes pregnen alcohol, steroidal lactone, Progesterone and Androstanediol with hydrogen peroxide degradation of steroid sapogenin; Chinese patent, ZL00127974.2; Chinese patent, ZL01113196.9; Chinese patent, ZL03141641.1), new degradation method has not only been eliminated the problem of environmental pollution of the heavy metal chromium that exists in the classical degradation method, has also improved the availability of steroid sapogenines and the yield of degraded product simultaneously.On this basis, developed pregnant steroid-3,16, the regioselectivity acetylize bromo-reaction of 20-triol (Chinese patent ZL200610024097.5), obtains 20-glycolic acid esters-16 alpha-bromo-sterides 5:

Bibliographical information, steroidal-20-hydroxyl-16-sulphonate can chipping rearrangement obtain androstane-16-alkene-3 β-alcohol, but the product complexity, the yield of androstane-16-alkene-3 β-alcohol lower (J.Org.Chem., 1970,35,561):

Ts is a p-toluenesulfonyl, and Ms is a methylsulfonyl.

The contriver wishes that the sisalagenin to obtain in the industrial pollutent of China system fiber crops is a raw material, use the patented technology of the conversion sisalagenin that we have developed, synthetic key intermediate androstane-16-alkene-3 β-alcohol (4) and pig ectohormone compound 1 and compound 2.

Summary of the invention

The novel method that the purpose of this invention is to provide a kind of synthesizing pig ectohormone.

Synthetic route of the present invention is as follows:

The method of starting compound 5 reference synthetic (Chinese patent, ZL200610024097.5).

The concrete operations step is as follows:

1) in polar solvent, 20-glycolic acid esters-16 alpha-bromo-sterides 5 reacted 0.5-50 hour under reflux temperature in room temperature with alkali, obtained 20-hydroxy-16 alpha--bromo steroidal compounds 6; Compound 5 is 1: 0.01～20 with the mol ratio of alkali; Described alkali is LiOH, NaOH, KOH, MeONa, EtONa, Li ₂CO ₃, Na ₂CO ₃, K ₂CO ₃, Cs ₂CO ₃, NaHCO ₃Or KHCO ₃Be recommended as in methyl alcohol and K ₂CO ₃Reaction; Reaction times is recommended as 5-15 hour; Compound 5 is recommended as 1: 0.5 with the mol ratio of alkali～and 5;

2) 20-hydroxy-16 alpha--bromo steroidal compounds 6 or its are dissolved in the solution in the polar solvent, join in polar solvent and the alkaline mixture under reflux temperature at-78 ℃, react 0.2-24 hour, obtain androstane-16-alkene-3 β-alcohol 4; Compound 6 is 1: 0.5～50 with the alkaline mol ratio; Described highly basic is NaOH, KOH, KH, NaH, NaNH ₂, LiNH ₂, hexamethyl two silica-based potassium amides (KHMDS), hexamethyl two silica-based sodium amides (NaHMDS), hexamethyl two silica-based Lithamides (LiHMDS), lithium diisopropylamine (LDA), MeLi, n-BuLi, s-BuLi, t-BuLi, MeONa, EtONa or potassium tert.-butoxide (t-BuOK), be recommended as potassium tert.-butoxide; Reaction times is recommended as 5-15 hour; Compound 6 is recommended as 1: 1 with the alkaline mol ratio～and 5;

3) compound 4 is dissolved in the solvent, adds oxygenant and assistant agent, at-78～60 ℃ of reaction 0.1～24h, obtains compound 1, and compound 4 is 1: 1～10: 0～15 with the mol ratio of oxygenant and assistant agent; Described oxygenant is Na ₂Cr ₂O ₇, CrO ₃, pyridinium chloro-chromate (PCC), pyridinium dichromate (PDC), MnO ₂, KMnO ₄, dimethyl sulfoxide (DMSO) (DMSO) or Dai Si-Martin (Dess-Martin) oxygenant; Described assistant agent is NaOAc, KOAc, Na ₂CO ₃, NaHCO ₃, H ₂SO ₄, acetate, oxalyl chloride, triethylamine, pyridine sulphur trioxide (SO ₃Py), pyridine or their mixture; Be recommended as in acetone with Jones reagent (CrO ₃-H ₂SO ₄-H ₂O) carry out oxidation; Reaction times is recommended as 0.1-5 hour; When not having assistant agent, compound 4 is recommended as 1: 1 with the mol ratio of oxygenant～and 5; When assistant agent, compound 4 is recommended as 1: 1 with the mol ratio of oxygenant and assistant agent～and 5: 1～5;

4) in organic solvent, compound 1 reacted 0.5～15 hour at-78～50 ℃ with reductive agent, got compound 2; Compound 1 is 1: 0.5～15 with the mol ratio of reductive agent; Described reductive agent is NaBH ₄, sodium cyanoborohydride (NaBH ₃CN), KBH ₄, LiBH ₄, ZnBH ₄, aluminum isopropylate, diisobutyl aluminium hydride (DIBALH), lithium triethylborohydride (LiBHEt ₃), 3-sec-butyl lithium borohydride (L-Selectride), three sec-butyl POTASSIUM BOROHYDRIDE (K-Selectride), triisopentyl lithium borohydride (Ls-Selectride) or triisopentyl POTASSIUM BOROHYDRIDE (Ks-Selectride), be recommended as L-Selectride, K-Selectride, Ls-Selectride or Ks-Selectride; When reductive agent is triisopentyl lithium borohydride and solvent when being tetrahydrofuran (THF), the reaction times can not be 3 hours; Reaction times is recommended as 0.5-5 hour; Compound 1 is recommended as 1: 1 with the mol ratio of reductive agent～and 5.

Polar solvent described in the above-mentioned reaction is alcoholic solvent, acetone, water, tetrahydrofuran (THF) (THF), 1,4-diox (dioxane), acetonitrile, dimethyl sulfoxide (DMSO) (DMSO), N, the mixed solvent of dinethylformamide (DMF), N,N-dimethylacetamide (DME) or their compositions; Described solvent is H ₂O, acetate, the trimethyl carbinol (t-BuOH), non-protonic solvent or their mixture; Described organic solvent is non-protonic solvent, alcoholic solvent or their mixture; Described non-protonic solvent is CH ₂Cl ₂, CHCl ₃, CCl ₄, 1,2-ethylene dichloride, tetrahydrofuran (THF) (THF), ether, 1,4-diox, acetonitrile, acetone, sherwood oil (PE), normal hexane, benzene, toluene, methyl-sulphoxide (DMSO), N, dinethylformamide (DMF), pyridine or their mixture; Described alcoholic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, sec-butyl alcohol, the trimethyl carbinol or their mixture.

The present invention has following advantage:

1. with the steroid sapogenines basic raw material, by degraded, bromo, remove key intermediate androstane-16-alkene-3 β-alcohol that ethanoyl and fragmentation reaction have obtained synthesizing pig ectohormone.This synthesis strategy has utilized the new degradation method of steroid sapogenines, has avoided the with serious pollution problem of chromic anhydride degraded.

2. the method for the synthetic rost-16-en-3-one of the present invention and androstane-16-alkene-3 α-alcohol is easy and simple to handle, reagent is cheap, product yield is high.

Specific implementation method

To help to understand the present invention by following specific implementation method, but not limit content of the present invention.

The method of compound 5 reference literatures of the present invention synthetic (Chinese patent, ZL200610024097.5).

Synthesizing of embodiment 1 compound 6

Take by weighing 500mg compound 5 and be dissolved in an amount of MeOH, add 429mg (3eq.) K ₂CO ₃The reaction that is hydrolyzed, 43 ℃ of reactions 10 hours.Concentrate near doing, ethyl acetate is collected residue, and organic phase is washed with saturated common salt, and anhydrous magnesium sulfate drying leaves standstill 30min, filters, and revolves the steaming ethyl acetate, and column chromatography is got 178mg compound 6 (89.2%).

Compound 6, mp168 ℃, [α] ²⁵ _D+ 9.2 (c 0.765, CHCl ₃); ¹H-NMR (CDCl ₃, 400MHz) δ: 0.63 (s, 3H, 18-H), 0.85 (s, 3H, 19-H), 3.33 (m, 1H, 3-H) 3.74 (m, 1H, 20-H), 4.42 (m, 1H, 16-H); IRv:3415,2921,2847,1442,1372,1041cm ^-1Ultimate analysis calculated value C ₂₅H ₃₉O ₄Br:C63.15, H 8.83; Measured value C 63.36, H 8.47.

Synthesizing of embodiment 2 compounds 4

200mg compound 6 and 281mg (5eq.) the t-BuOK 7h that refluxes in t-BuOH, raw material disappears.Add shrend and go out, ethyl acetate extraction, saturated common salt water washing 2 times of the organic phase of merging, anhydrous magnesium sulfate drying.Filter, concentrate, the resistates column chromatography for separation gets product 4 65mg (47.2%).

Compound 4, mp127 ℃; [α] ²⁵ _D+ 13.3 (c 1.30, CHCl ₃); ¹H-NMR (CDCl ₃, 300MHz) δ: 5.83 (d, J=3.9Hz, 1H, 16-H), 5.69 (br s, 1H, 17-H), 3.66-3.54 (m, 1H, 3-H), 0.84 (s, 3H, 18-H), 0.75 (s, 3H, 19-H); ¹³C-NMR (CDCl ₃, 80 MHz) and δ: 144.19; 129.51; 71.52; 56.33; 55.42; 45.80; 45.31; 38.44; 37.08; 36.17; 36.00; 34.34; 32.36; 32.248; 31.74; 28.93; 21.45; 17.31; 12.57; IRv:3346,3040,2938,2844cm ^-1.

Synthesizing of embodiment 3 compounds 1

Method one (Jones reagent oxidation):

1.7g (6.2mmol) compound 4 is dissolved among the acetone 100mL, splashes into Jones reagent (CrO ₃-H ₂SO ₄-H ₂O) do not disappear (about 1.0eq.) until redness, use the methyl alcohol cancellation after 5 minutes, inclining liquid, the residue washing with acetone, and the liquid concentration of merging, ethyl acetate is collected resistates, and organic phase is water and saturated NaHCO respectively ₃Wash, dried over sodium sulfate is filtered, and concentrates, and column chromatography gets 1.477g compound 1 (88%).

Method two (Dess-Martin) oxidation):

1.0mmol compound 4 is dissolved in CH ₂Cl ₂Among the 10mL, add the Dess-Martin oxygenant of 1.5eq., be stirred to raw material and disappear, use saturated NaHCO ₃And Na ₂S ₂O ₃Cancellation, ethyl acetate extraction, the saturated common salt water washing of the organic phase of merging, dried over sodium sulfate is filtered, and concentrates, and column chromatography gets compound 1 (91%).

Compound 1, C ₁₉H ₂₈O; FW 272; HPLC 99.80%; Mp142-143 ℃; [α] ^24.7 _D+ 38.9 (c 1.14, CHCl ₃); 1H-NMR (CDCl ₃, 300MHz) δ: 5.85 and 5.70 (each br s, 2H, 16-and 17-H), 1.06 (s, 3H, 19-H), 0.80 (s, 3H, 18-H); IR v:2952,1712,1443,719cm ^-1.

Synthesizing of embodiment 4 compounds 2

Method one (synthetic by compound 1 reduction, the method for fractional steps):

0.224g (0.82mmol) compound 1 is dissolved among the tetrahydrofuran (THF) 5mL,-60 ℃ splash into L-Selectride 1.12mL 1M (2.5mol 1.36eq.), rise to room temperature, reacted 1 hour, be cooled to-60 ℃ again, add 0.5mL water and 1.5mL ethanol successively, add 0.5mL 50% aqueous sodium hydroxide solution and 1.5mL 30% hydrogen peroxide then successively, rise to room temperature, stirred 3 hours, and added the 100mL ethyl acetate, organic phase washes with water successively, saturated NaHSO ₃With saturated common salt water washing, dried over sodium sulfate, filter, concentrate, column chromatography gets 0.168g compound 2 (74.5%).

Method two (synthetic by one pot of compound 4 oxidation-reduction, one kettle way):

3.58g (13.1mmol) compound 4 is dissolved among the acetone 150mL, splashes into Jones reagent and does not disappear (about 1.0eq.) until redness, uses the methyl alcohol cancellation after 5 minutes, inclining liquid, residue washing with acetone, the liquid concentration of merging, ethyl acetate is collected resistates, and organic phase is water and saturated NaHCO respectively ₃Wash, dried over sodium sulfate, filter, concentrate, the crude product of vacuum suction gained compound 1 is dissolved in the 40mL tetrahydrofuran (THF),-60 ℃ splash into L-Selectride 17mL 1M (1.36eq.), rise to room temperature, reacted 1 hour, be cooled to 0 ℃ again, add 5mL water and 5mL ethanol successively, add 5mL 50% aqueous sodium hydroxide solution and 21mL 30%H then successively ₂O ₂, rise to room temperature, stirred 3 hours, add the 200mL ethyl acetate, organic phase washes with water successively, saturated NaHSO ₃With saturated common salt water washing, dried over sodium sulfate, filter, concentrate, column chromatography gets 2.632g compound 2 (73.5%for two steps), receives 0.525g compound 4 (14.7%) and 0.023g compound 1 (0.7%) in addition.

Compound 2, C ₁₉H ₃₀O; FW 274; HPLC 99.99%; Mp144-145 ℃; [α] ^24.6 _D+ 14.3 (c 1.24, CHCl ₃); ¹H-NMR (CDCl ₃, 300MHz) δ: 5.85 (m, 1H, 16-H), 5.69 (m, 1H, 17-H), 4.05 (br s, 1H, 3-H), 0.82 (s, 3H, 18-H), 0.75 (s, 3H, 19-H); IR v:3294,2932,1451,1001,715cm ^-1.

Claims (6)

1. A method for synthesizing porcine pheromone, characterized in that it is obtained through the steps of 1) to 6): 1) In a polar solvent, react 20-hydroxyacetate-16α-bromosteroid compound 5 with a base at room temperature to reflux temperature for 0.5-50 hours to obtain 20-hydroxyl-16α-bromosteroid compound 6 ; The molar ratio of compound 5 to base is 1:0.01～20; the base is LiOH, NaOH, KOH, MeONa, EtONa, Li ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , _NaHCO3 or _KHCO3 ; 2) 20-hydroxyl-16α-bromo steroidal compound 6 or its solution dissolved in polar solvent is added to the mixture of polar solvent and strong base at -78°C to reflux temperature, and reacted for 0.2-24 hours , to obtain androst-16-ene-3β-ol 4; the molar ratio of compound 6 to strong base is 1:0.5～50; the strong base is NaOH, KOH, KH, NaH, NaNH ₂ , LiNH ₂ , six Potassium methyldisilazide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, lithium diisopropylamide, MeLi, n-BuLi, s-BuLi, t-BuLi, MeONa, EtONa or potassium tert-butoxide; 3) Dissolve compound 4 in a solvent, add oxidizing agent and auxiliary agent, and react at -78-60°C for 0.1-24 hours to obtain compound 1. The molar ratio of compound 4 to oxidizing agent and auxiliary agent is 1:1-10:0-15 ; The oxidant is Na ₂ Cr ₂ O ₇ , CrO ₃ , pyridinium chlorochromate, pyridinium dichromate, MnO ₂ , KMnO ₄ , dimethyl sulfoxide or Dess-Martin oxidant; the auxiliary The agent is NaOAc, KOAc, Na ₂ CO ₃ , NaHCO ₃ , H ₂ SO ₄ , acetic acid, oxalyl chloride, triethylamine, pyridine sulfur trioxide, pyridine or their mixtures; 4) In an organic solvent, react Compound 1 with a reducing agent at -78 to 50° C. for 0.5 to 15 hours to obtain Compound 2; the molar ratio of Compound 1 to the reducing agent is 1: 0.5 to 15; the reducing agent is NaBH _4. Sodium cyanoborohydride, KBH ₄ , LiBH ₄ , ZnBH ₄ , aluminum isopropoxide, diisobutylaluminum hydride, lithium triethylborohydride, lithium tri-sec-butyl borohydride, tri-sec-butyl borohydride Potassium, lithium triisopentyl borohydride or potassium triisopentyl borohydride; when the reducing agent is lithium triisopentyl borohydride and the solvent is tetrahydrofuran, the reaction time cannot be 3 hours; The structural formulas of the compounds 1, 2, 4-6 are as follows:

2, the synthetic method of porcine pheromone as claimed in claim 1 is characterized in that described polar solvent is alcoholic solvent, acetone, water, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethylmethylene Sulfone, N,N-dimethylformamide, N,N-dimethylacetamide or their mixed solvents. 3. A method for synthesizing porcine pheromone as claimed in claim 1, characterized in that said solvent is H ₂ O, acetic acid, tert-butanol, aprotic solvent or their mixture. 4. A method for synthesizing porcine pheromone as claimed in claim 1, characterized in that said organic solvent is an aprotic solvent, an alcoholic solvent or a mixture thereof. 5. A method for synthesizing porcine pheromone as claimed in claim 1, characterized in that said aprotic solvent is CH ₂ Cl ₂ , CHCl ₃ , CCl ₄ , 1,2-dichloroethane, tetrahydrofuran , ether, 1,4-dioxane, acetonitrile, acetone, petroleum ether, n-hexane, benzene, toluene, dimethylsulfoxide, N,N-dimethylformamide, pyridine or their mixtures. 6, a kind of synthetic method of porcine pheromone as claimed in claim 1 is characterized in that described alcoholic solvent is methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, diethylene glycol, glycerol or mixtures thereof.