CN114716495A - Preparation method of desogestrel - Google Patents
Preparation method of desogestrel Download PDFInfo
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- CN114716495A CN114716495A CN202111631562.2A CN202111631562A CN114716495A CN 114716495 A CN114716495 A CN 114716495A CN 202111631562 A CN202111631562 A CN 202111631562A CN 114716495 A CN114716495 A CN 114716495A
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- compound
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- tetrahydrofuran
- solution
- toluene
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- RPLCPCMSCLEKRS-BPIQYHPVSA-N desogestrel Chemical compound C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 RPLCPCMSCLEKRS-BPIQYHPVSA-N 0.000 title claims abstract description 36
- 229960004976 desogestrel Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 30
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 8
- DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 98
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 86
- 238000006243 chemical reaction Methods 0.000 claims description 48
- 150000001875 compounds Chemical class 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 44
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 229940126214 compound 3 Drugs 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 24
- 238000001816 cooling Methods 0.000 claims description 23
- 239000000706 filtrate Substances 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 238000005406 washing Methods 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 15
- 239000003208 petroleum Substances 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 229940125904 compound 1 Drugs 0.000 claims description 14
- 229940125782 compound 2 Drugs 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 10
- 229910021529 ammonia Inorganic materials 0.000 claims description 10
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 239000012071 phase Substances 0.000 claims description 10
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 8
- 229940125898 compound 5 Drugs 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- 239000008399 tap water Substances 0.000 claims description 7
- 235000020679 tap water Nutrition 0.000 claims description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 claims description 5
- FWDBZJBJTDRIIY-UHFFFAOYSA-N CC(C)(C)[K] Chemical compound CC(C)(C)[K] FWDBZJBJTDRIIY-UHFFFAOYSA-N 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 3
- -1 paratoluenesulfonic acid monohydrate Chemical class 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000000110 cooling liquid Substances 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 230000001502 supplementing effect Effects 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical group C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 abstract 1
- 238000007295 Wittig olefination reaction Methods 0.000 abstract 1
- XJFRYCBJLJNONU-UHFFFAOYSA-N [K].C#C Chemical compound [K].C#C XJFRYCBJLJNONU-UHFFFAOYSA-N 0.000 abstract 1
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 150000002466 imines Chemical class 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 3
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 3
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- BKRKYEFQSANYGA-UHFFFAOYSA-N bromo-methyl-triphenyl-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Br)(C=1C=CC=CC=1)(C)C1=CC=CC=C1 BKRKYEFQSANYGA-UHFFFAOYSA-N 0.000 description 3
- 239000011651 chromium Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 229910001385 heavy metal Inorganic materials 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229940053934 norethindrone Drugs 0.000 description 3
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 3
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 2
- XDCOYBQVEVSNNB-UHFFFAOYSA-N 4-[(7-naphthalen-2-yl-1-benzothiophen-2-yl)methylamino]butanoic acid Chemical compound OC(=O)CCCNCc1cc2cccc(-c3ccc4ccccc4c3)c2s1 XDCOYBQVEVSNNB-UHFFFAOYSA-N 0.000 description 2
- 102000015779 HDL Lipoproteins Human genes 0.000 description 2
- 108010010234 HDL Lipoproteins Proteins 0.000 description 2
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 1
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000001548 androgenic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000003756 cervix mucus Anatomy 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 150000002081 enamines Chemical group 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 231100000546 inhibition of ovulation Toxicity 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 229960004400 levonorgestrel Drugs 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- 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
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The preparation method of desogestrel comprises the specific steps of using 11 alpha-hydroxy-18-methyl-estra-4-ene-3, 17-dione) as a starting material, carrying out ethanedithiol protection on 3-ketone groups, imine protection on 17-ketone groups, removing ethanedithiol from lithium liquid ammonia, IBX oxidation, wittig olefination reaction, acidolysis deprotection and acetylene potassium ethynylation to prepare desogestrel.
Description
Technical Field
The invention relates to a preparation method of a steroid compound, in particular to a synthetic method of desogestrel.
Background
Desogestrel is a third-generation oral potent progestogen without androgenic and estrogenic activity. Experiments prove that the progestogen activity of the compound is 18 times stronger than that of norethindrone and 1 time stronger than that of norethindrone. The biggest characteristic is no androgen effect. High Density Lipoprotein (HDL) can also be raised: the antiestrogen activity is also stronger than norethindrone and levonorgestrel, has obvious ovulation inhibition effect, and can change consistency of cervical mucus and inhibit endometrial development and the like. The structural formula is as follows:
desogestrel processes are numerous, among which 11 α -hydroxy-18-methyl-estra-4-ene-3, 17-dione (compound 1) as starting material:
1. US 3927046: the steps are long; the 17-position glycol is unstable in protection and derives more byproducts; CrO3 is used twice, and the wastewater contains heavy metal pollution;
2. CN 101445542: the 17-glycol is unstable in protection and generates more byproducts; the Jones reagent for oxidation still relates to heavy metal Cr
3. WO2013135744, 17-ethanediol is unstable in protection and derives more by-products;
based on the problems of the desogestrel preparation method in the prior art, the new desogestrel preparation method is provided, the problems of unstable protection of 17-glycol, more derived byproducts and pollution caused by the need of using a chromium-containing oxidant in the prior art are improved, and the reaction yield can be improved, so that the problem to be solved urgently in the prior art is solved.
Disclosure of Invention
In order to solve the above problems in the prior art, the technical scheme provided by the inventor is as follows:
a preparation method of desogestrel is characterized by comprising the following reaction formula:
the R is0=
，
Or
；R1、R2、R3= H or C1~C4Alkyl of R0H is secondary amine, and the preparation method specifically comprises the following steps
1) Preparing a compound 2, namely adding 11 alpha-hydroxy-18-methyl-estra-4-ene-3, 17-dione (a compound 1) and p-toluenesulfonic acid monohydrate (PTSA) into glacial acetic acid, and dropwise adding ethanedithiol; after the reaction is finished, adding an alkali solution for neutralization, elutriating, filtering, and recrystallizing a filter cake to obtain a compound 2;
2) preparation of Compound 3 from Compound 2, R as a Secondary amine0H. Adding a solvent into the p-toluenesulfonic acid monohydrate, and reacting for 4-8 hours at 80-120 ℃; cooling to room temperature; when the solvent is toluene, carrying out suction filtration to obtain a toluene solution of a compound 3; when the solvent is not toluene, firstly evaporating the solvent and then supplementing toluene to obtain a toluene solution of a compound 3; adding silica gel into the toluene solution of the compound 3, stirring for 20-40 min, and filtering to remove the silica gel; concentrating the filtrate under reduced pressure to obtain oily substance, and recrystallizing with ethyl acetate-petroleum ether to obtain compound 3
3) Preparing a compound 4, namely cooling liquid ammonia to minus 45 ℃ to minus 50 ℃, adding metal lithium in batches, stirring for 0.8 to 1.5 hours after adding, dropwise adding a tetrahydrofuran solution of the compound 3, and carrying out heat preservation reaction at minus 40 ℃ to minus 50 ℃ after dropwise adding; slowly dripping the reaction liquid into absolute ethyl alcohol after the reaction is finished; and then adding 8-15 wt% of sodium hydroxide solution, heating to 5-15 ℃ in a gradient manner, removing ammonia at the temperature, and then removing ammonia in vacuum. Standing for layering, back-extracting the water phase with tetrahydrofuran, mixing the organic phases, washing with saturated salt water, and drying; filtering, concentrating the filtrate to paste, adding toluene to carry to obtain toluene solution of compound 4
4) Preparing a compound 5, namely cooling a toluene solution of a compound 4 to 20-25 ℃, and adding 2-iodoxybenzoic acid (IBX); after the addition, the temperature is kept until the reaction is complete; adding aqueous solution of thiosulfuric acid for quenching, and washing with water; concentrating under reduced pressure to dry, carrying acetone twice, and recrystallizing with acetone to obtain compound 5
5) Preparing a compound 7, namely adding potassium tert-butoxide into tetrahydrofuran protected by an inert atmosphere, stirring for 20-40 min, adding methyl triphenyl phosphine bromide, heating to 60-70 ℃, preserving heat for 1-2 h, adding a compound 5, and weakly refluxing for 30-50 h; cooling to 25-30 ℃, adding hydrochloric acid with the molar concentration of 5-7 mol/L, and preserving heat for 8-12 hours; adding 8-12% by mass of a sodium carbonate aqueous solution, stirring for 20-40 min after the addition is finished, and adding tap water; standing for layering, back-extracting the water phase with tetrahydrofuran, and combining the organic phases, and concentrating under reduced pressure to near dryness. Adding water into the residue, stirring, extracting with petroleum ether, mixing petroleum ether extractive solutions, drying, vacuum filtering, adding activated carbon into the filtrate, stirring for decolorizing, and filtering; concentrating under reduced pressure to dry to obtain crude product, and recrystallizing with methanol to obtain white crystalline compound 7
6) Preparing a compound 8, namely adding potassium tert-butoxide into tetrahydrofuran serving as a solvent under the protection of an inert atmosphere, and keeping introducing acetylene for 2 hours at the temperature of 30-40 ℃; cooling to 0-5 ℃, and dripping a tetrahydrofuran solution of the compound 8 for about 25-40 min; and after the dropwise addition is finished, continuously introducing acetylene gas, and carrying out heat preservation reaction at the temperature of 0-5 ℃ for 10-18 hours. Dropwise adding hydrochloric acid to adjust the pH value to be neutral; washing with water, washing with saturated salt water, drying with anhydrous magnesium sulfate, and filtering; concentrating the filtrate to dryness to obtain crude product, and recrystallizing with n-heptane to obtain desogestrel (compound 8)
The preparation method of desogestrel further comprises the step 1), wherein the weight ratio of the compound 1, glacial acetic acid, p-toluenesulfonic acid monohydrate and ethanedithiol is 1.4-1.6: 7-8: 0.1-0.2: 0.5-0.6, wherein the alkali solution is preferably a sodium hydroxide aqueous solution with the weight percentage concentration of 15% -25%; the reaction temperature is 20-30 ℃, and the alkali liquor is cooled to-5-0 ℃.
The preparation method of desogestrel is further characterized in that R in the step 2)0H is selected from pyrrolidine or piperidine, and the compound 1 and R0H. The weight ratio of the p-toluenesulfonic acid monohydrate is 1: 0.5-0.7: 0.08-0.12, the reaction is carried out in toluene as a solvent, and the toluene is reacted with tolueneThe weight ratio of the compound 1 is 5-7: 1, and water is separated by refluxing during reaction.
The preparation method of desogestrel is further characterized in that R in the step 2)0H is diethylamine, the diethylamine is simultaneously used as a solvent in the reaction, the reaction is carried out in a high-pressure reaction vessel, the weight ratio of the compound 1, the diethylamine and the paratoluenesulfonic acid monohydrate is 1: 0.5-0.7: 0.08-0.12, and the reaction temperature is 115-125 ℃.
The preparation method of desogestrel is further characterized in that the weight ratio of the compound 3 to the metal lithium in the step 3) is 6-7: 1, wherein the volume weight ratio of the liquid ammonia to the compound 3 is 8-12: 1; the weight volume ratio of the sodium hydroxide solution to the absolute ethyl alcohol is 8-12: 1, the volume ratio of the liquid ammonia to the absolute ethyl alcohol is 8-12: 1, and the ratio of the compound 3 to tetrahydrofuran in the tetrahydrofuran solution of the compound 3 is 0.1-0.15 g/mL.
The preparation method of desogestrel is further characterized in that in the step 4), the mass ratio of IBX to the compound 3 is 0.8-1: 1.
the preparation method of desogestrel further comprises the step 5), wherein the weight ratio of the compound 5, tert-butyl potassium, methyl triphenyl phosphine bromide and hydrochloric acid is 1: 1.8-2.2: 6-7: 0.8-1, and the weight ratio of the hydrochloric acid to the sodium carbonate aqueous solution to the tap water is 1: 2.5-3.5: 8-12.
The preparation method of desogestrel further comprises the step 6), in the tetrahydrofuran solution of the compound 7, the mass percent concentration of the compound 7 is 6-10%, and the weight ratio of the compound 7 to tert-butyl potassium is 1: 2.5-3.5; the weight ratio of the solvent tetrahydrofuran to the tetrahydrofuran solution for preparing the compound 7 is 1.8-2.2: 1.
Compared with the prior art, the synthetic method of desogestrel provided by the invention has the following beneficial effects: 1) the secondary amine and the 17-keto group are adopted to react to form an enamine protecting group, which has higher stability in a subsequent reaction system than the ethylene glycol protection; 2) IBX is adopted for 11-hydroxyl oxidation, so that a plurality of byproducts derived from the removal of a 17-protecting group part can be effectively avoided, and the yield is high; 3) the heavy metal Cr is avoided. 4) The product yield of the whole reaction route is also improved.
Detailed Description
The invention is further illustrated with reference to the following specific examples, without limiting the scope of the invention thereto.
Example 1
Synthesis of Compound 2: in a reaction kettle, 1.5kg of 11 alpha-hydroxy-18-methyl-estra-4-ene-3, 17-dione (compound 1), 7.5kg of glacial acetic acid and 150g of p-toluenesulfonic acid monohydrate (PTSA) are added dropwise with 560g of ethanedithiol under full stirring at 20-30 ℃ for about 30 minutes; after the dropwise addition, preserving the heat for 3 hours; slowly pouring the reaction solution into a sodium hydroxide aqueous solution (prepared by 7.5kg of sodium hydroxide and 30kg of water) at the temperature of-5 ℃, carrying out water separation, stirring for 2 hours, centrifuging, and leaching a filter cake with water; recrystallization from methanol gave 1.7kg of a white solid (compound 2), 113% mass yield, HPLC purity: 98 percent.
Synthesis of compound 3 a: toluene (6.0 kg), compound 2 (1.0kg), piperidine (600 g) and PTSA (100g) were added in this order to the reaction vessel, and water was distributed under reflux for 4 hours; cooling to room temperature, and performing suction filtration; adding silica gel (500g) into the filtrate, stirring for 1 hour, and performing suction filtration; the filtrate was concentrated under reduced pressure to an oil, which was recrystallized from ethyl acetate-petroleum ether to give compound 3a (950 g) in 95% mass yield and HPLC purity: 96 percent.
Synthesis of compound 4 a: adding liquid ammonia (8.0L) into a low-temperature reaction kettle, cooling to-45-50 ℃, adding metal lithium (120g) in 3 batches, stirring for 1 hour after adding, and dropwise adding a tetrahydrofuran solution of a compound 3 (800 g of the compound 3 is dissolved in 6.4L of tetrahydrofuran) for about 1 hour; after the dripping is finished, the temperature is kept for 2 hours at the temperature of minus 40 ℃ to minus 50 ℃. Slowly dropping into absolute ethyl alcohol (160mL) for about 30 minutes; 10% aqueous sodium hydroxide (1.6 kg) was added, the temperature was increased to 10 ℃ in a gradient, ammonia was removed for 1 hour, and ammonia was removed in vacuo. Standing for layering, back extracting the water phase with tetrahydrofuran, mixing the organic phases, washing with saturated salt water, and drying with anhydrous sodium sulfate; filtering, concentrating the filtrate to paste, and carrying with toluene twice to obtain toluene solution (directly used in next step)
Synthesis of compound 5 a: adding a toluene solution of a compound 4 into a reaction kettle, cooling to 20-25 ℃, and adding IBX (2-iodoxybenzoic acid) (700 g) in batches; after the addition, the temperature is kept for 2 hours; adding aqueous solution of thiosulfuric acid for quenching, and washing with water; concentration to dryness under reduced pressure, twice entrainment with acetone, acetone recrystallization afforded compound 5a (560 g), two-step mass yield 70%, HPLC purity: 98 percent.
Synthesis of compound 7: tetrahydrofuran (10L) was added to the reaction vessel, nitrogen gas was substituted for 3 times, potassium tert-butoxide (1.0kg) was added, stirring was carried out for 30 minutes, methyltriphenylphosphorus bromide (3.2kg) was added, the temperature was raised to 66 ℃ and the temperature was maintained for 1.5 hours. Compound 5a (500g) was added and refluxed weakly for 40 hours; cooling to 25-30 ℃, adding 6N hydrochloric acid (400g), and keeping the temperature for 10 hours; adding 10% sodium carbonate aqueous solution (1.5kg), stirring for 30 min, and adding tap water (5.0 kg); standing for layering, back-extracting the water phase with tetrahydrofuran for 2 times, mixing the organic phases, and concentrating under reduced pressure to dry. Adding water 1.5kg to the residue), stirring for 10 min, transferring the feed liquid to a separating funnel, extracting with petroleum ether (1.5L) for 4 times, combining the petroleum ether extracts, drying with anhydrous magnesium sulfate (100g), suction filtering, adding activated carbon (25 g) to the filtrate, stirring for 1 hr, and filtering; concentrated to dryness under reduced pressure, recrystallized from methanol to give compound 7(400g) as a white crystal in 80.0% yield, HPLC purity: 99 percent.
Synthesis of compound 8: sequentially adding potassium tert-butoxide (900g) and tetrahydrofuran (8.0kg) into a reaction kettle, replacing with nitrogen for 5 times, and keeping introducing acetylene for 2 hours at 30-40 ℃; cooling to 0-5 ℃, and dropwise adding a tetrahydrofuran (4.0kg) solution of a compound 7(300g) for about 30 minutes; after the dropwise addition is finished, continuously keeping the introduction of acetylene gas, and keeping the temperature of 0-5 ℃ for reaction for 12 hours. Dropwise adding hydrochloric acid to adjust the pH value to be neutral; washing with water, washing with saturated salt water, drying with anhydrous magnesium sulfate, and filtering; the filtrate was concentrated to dryness and recrystallized from n-heptane to give desogestrel (compound 8) (230 g) in 77% mass yield with HPLC purity: 99 percent. Single impurity < 0.1%.
Example 2
Synthesis of Compound 2: reference example 1, 50g of (Compound 1) was charged to give 58g of (Compound 2); mass yield 116%, HPLC purity: 98 percent.
Synthesis of compound 3 b: toluene (300g), a compound 2 (50 g), pyrrolidine (30g) and PTSA (5g) were sequentially added to a reaction kettle, and water was distributed for 4 hours under reflux; cooling to room temperature, and performing suction filtration; adding silica gel (25 g) into the filtrate, stirring for 1 hour, and performing suction filtration; the filtrate was concentrated under reduced pressure to an oil, which was recrystallized from ethyl acetate-petroleum ether to give compound 3b (45 g) in 90% mass yield and HPLC purity: 97 percent.
Synthesis of compound 4 b: adding liquid ammonia (400mL) into a low-temperature reaction kettle, cooling to-45-50 ℃, adding metal lithium (6g) in 3 batches, stirring for 1 hour after the addition is finished, and dropwise adding a tetrahydrofuran solution of a compound 3b (40g of the compound 3b is dissolved in 320mL of tetrahydrofuran) for about 1 hour; after the dripping is finished, the temperature is kept for 2 hours at the temperature of minus 40 ℃ to minus 50 ℃. Slowly dropping into anhydrous ethanol (40mL) for about 30 minutes; 10% aqueous sodium hydroxide (400g) was added, the temperature was increased to 10 ℃ in a gradient, ammonia was removed for 1 hour, and ammonia was removed in vacuo. Standing for layering, back extracting the water phase with tetrahydrofuran, mixing the organic phases, washing with saturated salt water, and drying with anhydrous sodium sulfate; filtering, concentrating the filtrate to paste, and carrying with toluene twice to obtain toluene solution (directly used in the next step)
Synthesis of compound 5 b: adding a toluene solution of the compound 4b into a reaction kettle, cooling to 20-25 ℃, and adding IBX (2-iodoxybenzoic acid) (35 g) in batches; after the addition, the temperature is kept for 2 hours; adding aqueous solution of thiosulfuric acid for quenching, and washing with water; concentration to dryness under reduced pressure, twice entrainment with acetone, acetone recrystallization afforded compound 5b (25 g), 63% mass yield in two steps, HPLC purity: 98 percent.
Synthesis of compound 7: tetrahydrofuran (400mL) was added to the reaction vessel, nitrogen gas was substituted for 3 times, potassium tert-butoxide (40g) was added thereto, and the mixture was stirred for 30 minutes, followed by addition of methyltriphenylphosphorus bromide (130g), warming to 66 ℃ and holding for 1.5 hours. Compound 5b (20g) was added and refluxed weakly for 40 hours; cooling to 25-30 ℃, adding 6N hydrochloric acid (20g), and keeping the temperature for 10 hours; adding 10% sodium carbonate aqueous solution (60g), stirring for 30 min after the addition, and adding tap water (180 g); standing for layering, back-extracting the water phase with tetrahydrofuran for 2 times, mixing the organic phases, and concentrating under reduced pressure to dry. Adding 60g of water into the residue, stirring for 10 minutes, transferring the feed liquid to a separating funnel, extracting for 4 times by using petroleum ether (60mL), combining the petroleum ether extracting solutions, drying by using anhydrous magnesium sulfate (20g), filtering, adding activated carbon (2.0 g) into the filtrate, stirring for 1 hour, and filtering; concentrated to dryness under reduced pressure and recrystallized from methanol to give compound 7(15g) as a white crystal in 75% yield, HPLC purity: 99 percent.
Synthesis of compound 8: sequentially adding potassium tert-butoxide (30g) and tetrahydrofuran (250g) into a reaction kettle, replacing with nitrogen for 5 times, and keeping introducing acetylene for 2 hours at 30-40 ℃; cooling to 0-5 ℃, and dropwise adding a tetrahydrofuran (100g) solution of a compound 7(10g) for about 30 minutes; after the dropwise addition is finished, continuously keeping the introduction of acetylene gas, and keeping the temperature of 0-5 ℃ for reaction for 12 hours. Dropwise adding hydrochloric acid to adjust the pH value to be neutral; washing with water, washing with saturated salt water, drying with anhydrous magnesium sulfate, and filtering; the filtrate was concentrated to dryness and recrystallized from n-heptane to give desogestrel (compound 8) (7.5 g) in 75% mass yield with HPLC purity: 99 percent. Single impurity < 0.1%.
Example 3
Synthesis of Compound 2: reference example 1, 50g of (Compound 1) was charged to give 58g of (Compound 2); mass yield 116%, HPLC purity: 98 percent.
Synthesis of compound 3 c: adding the compound 2 (50 g), diethylamine (300g) and PTSA (5g) in sequence into a high-pressure reaction kettle, and reacting for 8 hours at 120 ℃; cooling to room temperature, relieving pressure, opening the kettle, performing suction filtration, concentrating, adding toluene to dissolve, adding silica gel (25 g), stirring for 1 hour, and performing suction filtration; the filtrate was concentrated under reduced pressure to an oil, which was recrystallized from ethyl acetate-petroleum ether to give compound 3c (15g) in 30% mass yield and HPLC purity: 92 percent.
Synthesis of compound 4 c: adding liquid ammonia (100mL) into a low-temperature reaction kettle, cooling to-45-50 ℃, adding metal lithium (1.5g) in 3 batches, stirring for 1 hour after the addition is finished, and dropwise adding a tetrahydrofuran solution of a compound 3b (10g of the compound 3b is dissolved in 80mL of tetrahydrofuran) for about 1 hour; after the dripping is finished, the temperature is kept for 2 hours at the temperature of minus 40 ℃ to minus 50 ℃. Slowly dropping into anhydrous ethanol (10mL) for about 30 minutes; 10% aqueous sodium hydroxide (100g) was added, the temperature was increased to 10 ℃ in a gradient, ammonia was removed for 1 hour, and ammonia was removed in vacuo. Standing for layering, back extracting the water phase with tetrahydrofuran, mixing the organic phases, washing with saturated salt water, and drying with anhydrous sodium sulfate; filtering, concentrating the filtrate to paste, and carrying with toluene twice to obtain toluene solution (directly used in next step)
Synthesis of compound 5 c: adding a toluene solution of the compound 4b into a reaction kettle, cooling to 20-25 ℃, and adding IBX (2-iodoxybenzoic acid) (8 g) in batches; after the addition, the temperature is kept for 2 hours; adding aqueous solution of thiosulfuric acid for quenching, and washing with water; concentration to dryness under reduced pressure, twice entrainment with acetone, and recrystallization from acetone gave compound 5c (7.0 g) in 70% mass yield over two steps, HPLC purity: 96 percent.
Synthesis of compound 7: tetrahydrofuran (100mL) was added to the reaction vessel, nitrogen gas was substituted for 3 times, potassium tert-butoxide (10g) was added thereto, and the mixture was stirred for 30 minutes, followed by addition of methyltriphenylphosphorus bromide (30g), warming to 66 ℃ and holding for 1.5 hours. Compound 5c (5g) was added and refluxed weakly for 40 hours; cooling to 25-30 ℃, adding 6N hydrochloric acid (5g), and keeping the temperature for 10 hours; adding 10% sodium carbonate aqueous solution (15g), stirring for 30 minutes after the addition, and adding tap water (50 g); standing for layering, back-extracting the water phase with tetrahydrofuran for 2 times, mixing the organic phases, and concentrating under reduced pressure to dry. Adding 15g of water to the residue), stirring for 10 minutes, transferring the feed liquid to a separating funnel, extracting for 4 times by using petroleum ether (15mL), combining the petroleum ether extract, drying by using anhydrous magnesium sulfate (5g), filtering, adding activated carbon (0.5 g) into the filtrate, stirring for 1 hour, and filtering; concentrated to dryness under reduced pressure, recrystallized from methanol to give compound 7(12g) as a white crystal in 80% yield, HPLC purity: 99 percent.
Synthesis of compound 8: sequentially adding potassium tert-butoxide (30g) and tetrahydrofuran (250g) into a reaction kettle, replacing with nitrogen for 5 times, and keeping introducing acetylene for 2 hours at 30-40 ℃; cooling to 0-5 ℃, and dropwise adding a tetrahydrofuran (100g) solution of a compound 7(10g) for about 30 minutes; and after the dropwise addition is finished, continuously introducing acetylene gas, and carrying out heat preservation reaction at the temperature of 0-5 ℃ for 12 hours. Dropwise adding hydrochloric acid to adjust the pH value to be neutral; washing with water, washing with saturated salt water, drying with anhydrous magnesium sulfate, and filtering; the filtrate was concentrated to dryness and recrystallized from n-heptane to give desogestrel (compound 8) (7.0 g) in 70% mass yield with HPLC purity: 98 percent.
Claims (8)
1. A preparation method of desogestrel is characterized by comprising the following reaction formula:
said R is0=
，
Or
；R1、R2、R3= H or C1~C4Alkyl of R0H is secondary amine, and the preparation method specifically comprises the following steps
1) Preparing a compound 2, namely adding 11 alpha-hydroxy-18-methyl-estra-4-ene-3, 17-dione (compound 1) and p-toluenesulfonic acid monohydrate (PTSA) into glacial acetic acid, and dropwise adding ethanedithiol; after the reaction is finished, adding an alkali solution for neutralization, elutriating, filtering, and recrystallizing a filter cake to obtain a compound 2;
2) preparation of Compound 3 from Compound 2, R as a Secondary amine0H. Adding a solvent into the p-toluenesulfonic acid monohydrate, and reacting for 4-8 hours at 80-120 ℃; cooling to room temperature; when the solvent is toluene, carrying out suction filtration to obtain a toluene solution of a compound 3; when the solvent is not toluene, firstly evaporating the solvent and then supplementing toluene to obtain a toluene solution of the compound 3; adding silica gel into toluene solution of compound 3, and fillingStirring for 20-40 min, and filtering out silica gel; concentrating the filtrate under reduced pressure to obtain oily substance, and recrystallizing with ethyl acetate-petroleum ether to obtain compound 3;
3) preparing a compound 4, namely cooling liquid ammonia to minus 45 ℃ to minus 50 ℃, adding metal lithium in batches, stirring for 0.8 to 1.5 hours after adding, dropwise adding a tetrahydrofuran solution of the compound 3, and carrying out heat preservation reaction at minus 40 ℃ to minus 50 ℃ after dropwise adding; slowly dripping the reaction liquid into absolute ethyl alcohol after the reaction is finished; adding 8-15 wt% of sodium hydroxide solution, gradient heating to 5-15 ℃, removing ammonia at the temperature, and then removing ammonia in vacuum; standing for layering, back-extracting the water phase with tetrahydrofuran, mixing the organic phases, washing with saturated salt water, and drying; filtering, concentrating the filtrate to paste, adding toluene to carry the paste, and obtaining a toluene solution of a compound 4;
4) preparing a compound 5, namely cooling a toluene solution of a compound 4 to 20-25 ℃, and adding 2-iodoxybenzoic acid (IBX); after the addition, the temperature is kept until the reaction is complete; adding aqueous solution of thiosulfuric acid for quenching, and washing with water; concentrating under reduced pressure to dry, carrying acetone twice, and recrystallizing the acetone to obtain a compound 5;
5) preparing a compound 7, namely adding potassium tert-butoxide into tetrahydrofuran protected by an inert atmosphere, stirring for 20-40 min, adding methyl triphenyl phosphine bromide, heating to 60-70 ℃, preserving heat for 1-2 h, adding a compound 5, and weakly refluxing for 30-50 h; cooling to 25-30 ℃, adding hydrochloric acid with the molar concentration of 5-7 mol/L, and preserving heat for 8-12 hours; adding 8-12% by mass of a sodium carbonate aqueous solution, stirring for 20-40 min after the addition is finished, and adding tap water; standing for layering, back-extracting the water phase with tetrahydrofuran, and combining the organic phases, and concentrating under reduced pressure to near dryness; adding water to the residue, stirring, extracting with petroleum ether, mixing the petroleum ether extractive solutions, drying, vacuum filtering, adding active carbon into the filtrate, stirring for decolorizing, and filtering; concentrating under reduced pressure to dry to obtain crude product, and recrystallizing with methanol to obtain white crystalline compound 7;
6) preparing a compound 8, namely adding potassium tert-butoxide into tetrahydrofuran serving as a solvent under the protection of an inert atmosphere, and keeping introducing acetylene for 2 hours at the temperature of 30-40 ℃; cooling to 0-5 ℃, and dripping a tetrahydrofuran solution of the compound 8 for about 25-40 min; after the dropwise addition is finished, continuously keeping the acetylene gas introduction, keeping the temperature of 0-5 ℃ for reacting for 10-18 hours, and dropwise adding hydrochloric acid to adjust the pH value to be neutral; washing with water, washing with saturated salt water, drying with anhydrous magnesium sulfate, and filtering; the filtrate was concentrated to dryness to give a crude product, which was recrystallized from n-heptane to give desogestrel (Compound 8).
2. The method for preparing desogestrel according to claim 1, wherein in the step 1), the weight ratio of the compound 1, glacial acetic acid, p-toluenesulfonic acid monohydrate and ethanedithiol is 1.4-1.6: 7-8: 0.1-0.2: 0.5-0.6, wherein the alkali solution is preferably a sodium hydroxide aqueous solution with the weight percentage concentration of 15% -25%; the reaction temperature is 20-30 ℃, and the alkali liquor is cooled to-5-0 ℃.
3. The method according to claim 1, wherein R in step 2) is0H is selected from pyrrolidine or piperidine, and the compound 1 and R0H. The weight ratio of the p-toluenesulfonic acid monohydrate is 1: 0.5-0.7: 0.08-0.12, the reaction is carried out in toluene serving as a solvent, the weight ratio of the toluene to the compound 1 is 5-7: 1, and water is refluxed and divided during the reaction.
4. The method according to claim 1, wherein R in step 2) is0H is diethylamine, the diethylamine is simultaneously used as a solvent in the reaction, the reaction is carried out in a high-pressure reaction vessel, the weight ratio of the compound 1, the diethylamine and the paratoluenesulfonic acid monohydrate is 1: 0.5-0.7: 0.08-0.12, and the reaction temperature is 115-125 ℃.
5. The preparation method of desogestrel according to claim 1, wherein the weight ratio of the compound 3 to the metallic lithium in the step 3) is 6-7: 1, wherein the volume weight ratio of the liquid ammonia to the compound 3 is 8-12: 1; the weight volume ratio of the sodium hydroxide solution to the absolute ethyl alcohol is 8-12: 1, the volume ratio of the liquid ammonia to the absolute ethyl alcohol is 8-12: 1, and the ratio of the compound 3 to tetrahydrofuran in the tetrahydrofuran solution of the compound 3 is 0.1-0.15 g/mL.
6. The method for preparing desogestrel according to claim 1, wherein in the step 4), the mass ratio of IBX to the compound 3 is 0.8-1: 1.
7. the method for preparing desogestrel according to claim 1, wherein in the step 5), the weight ratio of the compound 5, the tert-butyl potassium, the methyl triphenyl phosphine bromide and the hydrochloric acid is 1: 1.8-2.2: 6-7: 0.8-1, and the weight ratio of the hydrochloric acid to the sodium carbonate aqueous solution to the tap water is 1: 2.5-3.5: 8-12.
8. The method for preparing desogestrel according to claim 1, wherein in the step 6), the mass percentage concentration of the compound 7 in the tetrahydrofuran solution of the compound 7 is 6-10%, and the weight ratio of the compound 7 to the tert-butyl potassium is 1: 2.5-3.5; the weight ratio of the solvent tetrahydrofuran to the tetrahydrofuran solution for preparing the compound 7 is 1.8-2.2: 1.
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