CN105237606A - Intermediate used for synthesis of desogestrel, and preparation method and application thereof - Google Patents
Intermediate used for synthesis of desogestrel, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an intermediate used for synthesis of desogestrel, and a preparation method and application thereof. The intermediate has a general chemical structural formula as described in the specification, wherein a substituting group R is selected from the group consisting of hydrogen, methyl or ethyl. The intermediate is prepared by subjecting a compound as shown in a formula 2 to selective protection reaction for a 3-carbonyl group by using dihydric alcohol, wherein the dihydric alcohol has a chemical structural formula as described in the specification, wherein R is selected from the group consisting of hydrogen, methyl or ethyl; and a reaction formula of the dihydric alcohol is described in the specification. The method for the synthesis of the desogestrel by employing the intermediate comprises a reaction route as described in the specification.
Description
Technical field
The present invention relates to a kind of intermediate for the synthesis of desogestrel and its preparation method and application, belong to technical field of medicine synthesis.
Background technology
The chemistry of desogestrel is called: 13 β-ethyl-11-methyne-18,19-is two loses the pregnant steroid of carbon-4-alkene-20 alkynyl-17 β-ol, and be a kind of progestin contraceptive medicine, the activity of anti-female hormone is very strong, the secretion of energy ovulation inhibition and gonad-stimulating hormone, for preventing gestation.
The synthetic route of desogestrel is more, as:
1, the following synthetic route of US3927046 report:
This route is classical syntheti c route, but this route Problems existing is the dithioglycol needing to use stench, extremely unfriendly to environment.
2, need to use dithioglycol protective material in the synthetic method that CN201210397815.9 reports until finally by reduction reaction removing epoxy thioether, therefore the peculiar smell in finished product can not be eliminated, the more difficult employing this method of actual production.
3, CN200810246594.9 reports following a kind of synthetic route:
But the method needs the dithioglycol using stench equally, leaking outside of strict labour protection and waste gas must be considered, be unfavorable for industrialization production requirements.
4, following a kind of synthetic route is all disclosed in US3927046 and US5831104:
The method with the precursor of Levonorgestrel walsh thing for fermentation raw material; target compound is obtained after the reaction of number step; building-up process need through steps such as selective protection 17-carbonyl, Wittig reaction, hydrolysis and ethynylations; although this method avoid the dithioglycol using stench; but document (US5831104) report is lower to the selectivity of the protective reaction of 17-carbonyl; cause cost higher, therefore be also not suitable for industrialization production requirements.
Summary of the invention
In order to solve the problems referred to above that prior art exists, the object of this invention is to provide a kind of intermediate for the synthesis of desogestrel and its preparation method and application, to meet the industrialization production requirements of desogestrel better.
For achieving the above object, the technical solution used in the present invention is as follows:
For the synthesis of an intermediate for desogestrel, it is characterized in that there is following chemical structure of general formula:
substituent R in general formula is selected from hydrogen, methyl or ethyl.
Prepare a method for above-mentioned intermediate, it is characterized in that: be obtained by reacting the selective protection that compound shown in formula 2 carries out 3 carbonyls by dibasic alcohol, described dibasic alcohol has following chemical structural formula:
r is wherein selected from hydrogen, methyl or ethyl, and its reaction formula is as follows:
Preferably, aforesaid method comprises following operation: make compound dissolution shown in formula 2 in organic solvent, be cooled to-10 ~-20 DEG C, add dibasic alcohol and dioxane/hydrogen chloride solution; Insulated and stirred, after 10 ~ 15 minutes, drips dewatering agent; Drip and finish, control to continue reaction at-10 ~-15 DEG C; React complete, neutralize with alkali; After concentrated removing organic solvent, in concentrated residue, add water, carry out stirring, suction filtration, washing, drying.
As further preferred version, described organic solvent is glycol dimethyl ether or Propylene Glycol Dimethyl Ether.
As further preferred version, described dewatering agent is triethyl orthoformate.
As further preferred version, the alkali carrying out neutralizing is triethylamine.
Apply a method for above-mentioned intermediate synthesis desogestrel, comprise following reaction scheme:
Wherein:
Reaction a carries out reduction reaction to compound shown in formula 3, obtains compound shown in formula 4;
Reaction b carries out reduction reaction to compound shown in formula 4, obtains compound shown in formula 5;
Reaction c carries out eliminative reaction to compound shown in formula 5, obtains compound shown in formula 6;
Reaction d carries out ethynylation to compound shown in formula 6, namely obtains the desogestrel shown in formula 1;
Substituent R in above-mentioned reaction formula is selected from hydrogen, methyl or ethyl.
Preferably, react a and comprise following operation: under room temperature, in compound shown in formula 3, add second alcohol and water; Being cooled to interior temperature is 0 ~ 10 DEG C, starts to add reductive agent in batches, and it is 15 ~ 20 DEG C that the adition process of reductive agent need control interior temperature; Finish, be incubated at 15 ~ 20 DEG C of stirring reactions; React complete, neutralize with acid; Concentration of reaction solution, adds acetone and water in concentrated residue, is warming up to 40 ~ 60 DEG C, continues reaction 1 ~ 3 hour; Cooling, carries out aftertreatment, obtains compound shown in formula 4.
As further preferred version, described reductive agent is POTASSIUM BOROHYDRIDE, sodium borohydride or borine, and the acid carrying out neutralizing is acetic acid.
Preferably, the reduction reaction of reaction described in b adopts Claisen reduction method or huang-Minlon reduction.
As further preferred version, described Claisen reduction method comprises following operation: under room temperature, is added in acetic acid and water by compound shown in formula 4, then adds zinc powder, react in stirred at ambient temperature; Reaction terminates, and carries out aftertreatment, obtains compound shown in formula 5.
Preferably, reaction c comprises following operation: in compound shown in formula 5, add tetrahydrofuran (THF) and methylene dichloride, and stirring makes clearly molten; Add the aqueous solution of mineral alkali, in stirred at ambient temperature 5 ~ 15 minutes; Add Losantin and 2,2,6,6-tetramethyl piperidine-1-oxyradical (TEMPO), under room temperature, continue stirring reaction; Question response is complete, leaves standstill, suction filtration, separatory, collects dichloromethane layer, dry, concentrated, obtains compound shown in formula 6.
As further preferred version, described mineral alkali is sodium carbonate or sodium bicarbonate.
Preferably, reaction d comprises following operation: added by quadrol in reaction vessel, stirs, is warming up to 50 ~ 70 DEG C, adds metallic lithium, is after blue clarification until system, Temperature fall to 50 ± 2 DEG C; Insulation, passing into acetylene gas, is after canescence clarified liq until system, and being cooled to temperature in system is 30 ± 2 DEG C, is then added dropwise in system by the tetrahydrofuran solution of compound shown in formula 6, drips and finishes, insulation reaction; React completely, carry out aftertreatment, namely obtain the desogestrel shown in formula 1.
Compound shown in formula 2 described in the present invention can refer to method described in US3927046 and prepares.
Compared with prior art, the present invention has following significance beneficial effect:
1, by intermediate provided by the invention, the starting material source that can realize preparing desogestrel is more extensive, and the desogestrel that purity is greater than 99% can be prepared relatively easily, not only increase the quality of desogestrel, and reduce the production cost of desogestrel.
2, intermediate of the present invention preparation method and apply described intermediate synthesis desogestrel method all evaded the use of dithioglycol; have environmental protection, simple to operate controlled, yield is high, cost is low, be easy to purifying, be easy to the advantages such as suitability for industrialized production; the large-scale production requirement of desogestrel can be met better, there is using value.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail and completely.
Embodiment
1, the preparation of compound 3
In 250mL there-necked flask, add compound 2 (10.2g), glycol dimethyl ether (150mL), be stirred to dissolve; Be cooled to-10 DEG C, add ethylene glycol (2.51mL) and dioxane/hydrogen chloride solution (1.0mL, 3.5N), stir 10 ~ 15 minutes, then start to drip dewatering agent triethyl orthoformate (6.93g), control temperature continues reaction 3 hours at-10 to-15 DEG C, slowly instills triethylamine (1.8mL), stirs 10 minutes, ethylene glycol in concentrated form dme, add water 150mL, stir 0.5 hour, suction filtration, water washing, drying, obtain yellow solid (compound 3) 10.3g, molar yield is 90%.
MS：m/e＝343.2[M+H]+；
1H-NMR(DMSO,δppm)：5.37(s,1H),5.11(s,1H),4.92(s,1H),3.95-4.05(m,4H),1.49-2.29,(m,16),1.25-1.35(m,2H),0.9(m,3H)。
2, the preparation of compound 4
Under room temperature, compound 3 (10.0g) is added in 500mL there-necked flask, ethanol (200mL) and water (49mL), stirred at ambient temperature to be cooled to interior temperature be 0-10 DEG C, start to add sodium borohydride solids gradually in batches, adition process need control interior temperature at 15-20 DEG C, finish, insulated and stirred is reacted, react complete (about 30 minutes), pH=7-8 is regulated with acetic acid, concentration of reaction solution, acetone 100mL is added in concentrated residue, water 20mL, be warming up to 50 degree and react 2 hours, cooling, concentrated, be dissolved in water, be extracted with ethyl acetate, merge organic phase, dry after saturated common salt water washing, filter, concentrated, obtain 9.3g compound 4, molar yield is 95%.
MS：m/e＝301.2,[M+H]+；
1H-NMR(DMSO,δppm)：5.85(s,1H),5.11(s,1H),4.92(s,1H),3.58(s,1H),3.22(m,1H),2.85-3.02(m,2H),2.17-2.19(m,2H),1.17-2.01(m,16H),0.9(m,3H)。
3, the preparation of compound 5
Under room temperature, in 500mL there-necked flask, add compound 4 (10.0g), acetic acid (200mL), water (100mL), zinc powder (56g), in stirred at ambient temperature 12 hours, filter, concentrated, after add water (200mL) dissolves, pH=7-8 is neutralized to sodium bicarbonate, with dichloromethane extraction, collect organic phase, with anhydrous sodium sulfate drying, filter, concentrated, obtain 8.7g compound 5, molar yield is 93%.
MS：m/z＝87.2；
[M+H]+；1H-NMR(DMSO,δppm)：5.37(m,1H),5.11(s,1H),4.92(s,1H),3.58(s,1H),3.22(m,1H),2.16-2.18(m,1H),1.25-2.01(m,22H),0.9(m,3H)。
4, the preparation of compound 6
Compound 5 (10g) is added in reaction flask, add tetrahydrofuran (THF) (140mL) and methylene dichloride (20mL), stirring makes clearly molten, add the aqueous sodium carbonate of 200mL10wt%, in stirred at ambient temperature 10 minutes, then 8g Losantin and 0.1gTEMPO is added respectively, in stirred at ambient temperature reaction, as TLC monitoring reaction complete (about 1 hour), leave standstill, suction filtration, separatory, collects dichloromethane layer, dry, concentrated, obtain 8.8g compound 6, molar yield is 90%.
MS：m/z＝285.2；
[M+H]+；1H-NMR(DMSO,δppm)：5.37(m,1H),5.11(s,1H),4.92(s,1H),1.42-2.29(m,22H),0.9(m,3H)。
5, the preparation of desogestrel (compound 1)
Quadrol (180g) is added in 500mL reaction flask, stirs, be warming up to 60 DEG C, divide and add metallic lithium (4.5g) for 8 times, be that after blue clarification, Temperature fall to system Inner temperature is 50 ± 2 DEG C until system, stop logical argon gas; Insulation, pass into acetylene gas reaction, the system for the treatment of is canescence clarified liq, and being cooled to temperature in system is 30 ± 2 DEG C, is added dropwise in system by tetrahydrofuran (THF) (100mL) solution of compound 6 (10g), drips and finishes, and continues reaction; When reaction completes (about 5 hours), be cooled to-50 DEG C, in ice ethanol (200mL) system, add ethyl acetate (300mL); Reaction system slowly poured in ice ethanol, slowly gradation adds ethyl acetate (50mL) simultaneously, adds ethyl acetate (50mL) and (120mL) water after reaction solution all adds again, continues stirring 10 minutes; Add dry ice adjust pH to 7 ~ 8, leave standstill, layering, aqueous phase is extracted with ethyl acetate, merge organic phase, with after saturated common salt water washing through anhydrous sodium sulfate drying, suction filtration, concentrated, obtain crude product, use normal hexane recrystallization, obtain 8.0g white crystal desogestrel (compound 1), molar yield is 80%, HPLC purity is 99.2%.
Fusing point 108-110 DEG C;
MS：m/e＝3112；
[M+H]+；1H-NMR(DMSO,δppm)：5.37(m,1H),5.11(s,1H),4.92(s,1H),1.65(s,1H),3.52(s,1H),1.42-2.29(m,20H),0.9(m,3H)。
Starting raw material (compound 2) used in the present embodiment can prepare by method described in US3927046, and concrete synthetic route is as follows:
Finally be necessary described herein: above embodiment is only for being described in more detail technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (10)
1. for the synthesis of an intermediate for desogestrel, it is characterized in that there is following chemical structure of general formula:
substituent R in general formula is selected from hydrogen, methyl or ethyl.
2. prepare a method for intermediate according to claim 1, it is characterized in that: be obtained by reacting the selective protection that compound shown in formula 2 carries out 3 carbonyls by dibasic alcohol, described dibasic alcohol has following chemical structural formula:
r is wherein selected from hydrogen, methyl or ethyl, and its reaction formula is as follows:
3. method as claimed in claim 2, it is characterized in that, described method comprises following operation: make compound dissolution shown in formula 2 in organic solvent, be cooled to-10 ~-20 DEG C, add dibasic alcohol and dioxane/hydrogen chloride solution; Insulated and stirred, after 10 ~ 15 minutes, drips dewatering agent; Drip and finish, control to continue reaction at-10 ~-15 DEG C; React complete, neutralize with alkali; After concentrated removing organic solvent, in concentrated residue, add water, carry out stirring, suction filtration, washing, drying.
4. method as claimed in claim 3, is characterized in that: described organic solvent is glycol dimethyl ether or Propylene Glycol Dimethyl Ether; Described dewatering agent is triethyl orthoformate.
5. application rights requires a method for the intermediate synthesis desogestrel described in 1, it is characterized in that, comprises following reaction scheme:
Wherein:
Reaction a carries out reduction reaction to compound shown in formula 3, obtains compound shown in formula 4;
Reaction b carries out reduction reaction to compound shown in formula 4, obtains compound shown in formula 5;
Reaction c carries out eliminative reaction to compound shown in formula 5, obtains compound shown in formula 6;
Reaction d carries out ethynylation to compound shown in formula 6, namely obtains the desogestrel shown in formula 1;
Substituent R in above-mentioned reaction formula is selected from hydrogen, methyl or ethyl.
6. method as claimed in claim 5, is characterized in that, reaction a comprises following operation: under room temperature, in compound shown in formula 3, add second alcohol and water; Being cooled to interior temperature is 0 ~ 10 DEG C, starts to add reductive agent in batches, and it is 15 ~ 20 DEG C that the adition process of reductive agent need control interior temperature; Finish, be incubated at 15 ~ 20 DEG C of stirring reactions; React complete, neutralize with acid; Concentration of reaction solution, adds acetone and water in concentrated residue, is warming up to 40 ~ 60 DEG C, continues reaction 1 ~ 3 hour; Cooling, carries out aftertreatment, obtains compound shown in formula 4.
7. method as claimed in claim 6, is characterized in that: described reductive agent is POTASSIUM BOROHYDRIDE, sodium borohydride or borine.
8. method as claimed in claim 5, is characterized in that: the reduction reaction of reaction described in b adopts Claisen reduction method or huang-Minlon reduction.
9. method as claimed in claim 5, is characterized in that, reaction c comprises following operation: in compound shown in formula 5, add tetrahydrofuran (THF) and methylene dichloride, and stirring makes clearly molten; Add the aqueous solution of mineral alkali, in stirred at ambient temperature 5 ~ 15 minutes; Add Losantin and 2,2,6,6-tetramethyl piperidine-1-oxyradical, under room temperature, continue stirring reaction; Question response is complete, leaves standstill, suction filtration, separatory, collects dichloromethane layer, dry, concentrated, obtains compound shown in formula 6.
10. method as claimed in claim 5, is characterized in that, reaction d comprises following operation: added by quadrol in reaction vessel, stirs, is warming up to 50 ~ 70 DEG C, adds metallic lithium, is after blue clarification until system, Temperature fall to 50 ± 2 DEG C; Insulation, passing into acetylene gas, is after canescence clarified liq until system, and being cooled to temperature in system is 30 ± 2 DEG C, is then added dropwise in system by the tetrahydrofuran solution of compound shown in formula 6, drips and finishes, insulation reaction; React completely, carry out aftertreatment, namely obtain the desogestrel shown in formula 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107082793A (en) * | 2017-06-16 | 2017-08-22 | 上海共拓医药化工有限公司 | The preparation method of Desogestrel important intermediate |
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