CN113583074A - Novel preparation method of 6-methyl-17 alpha-hydroxyprogesterone and precursor thereof - Google Patents
Novel preparation method of 6-methyl-17 alpha-hydroxyprogesterone and precursor thereof Download PDFInfo
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- CN113583074A CN113583074A CN202110717924.3A CN202110717924A CN113583074A CN 113583074 A CN113583074 A CN 113583074A CN 202110717924 A CN202110717924 A CN 202110717924A CN 113583074 A CN113583074 A CN 113583074A
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- 229950000801 hydroxyprogesterone caproate Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000002243 precursor Substances 0.000 title abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 239000002808 molecular sieve Substances 0.000 claims abstract description 14
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 12
- 239000011591 potassium Substances 0.000 claims abstract description 12
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 11
- 239000010948 rhodium Substances 0.000 claims abstract description 11
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 9
- DBPWSSGDRRHUNT-UHFFFAOYSA-N 17alpha-hydroxy progesterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)(O)C1(C)CC2 DBPWSSGDRRHUNT-UHFFFAOYSA-N 0.000 claims abstract description 8
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 claims abstract description 8
- 239000007868 Raney catalyst Substances 0.000 claims abstract description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 5
- 238000007037 hydroformylation reaction Methods 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 37
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Natural products C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims description 11
- 238000006722 reduction reaction Methods 0.000 claims description 11
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 229960003387 progesterone Drugs 0.000 claims description 9
- 239000000186 progesterone Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- -1 hydroxyl progesterone Chemical compound 0.000 claims description 7
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 abstract 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 8
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 229960004296 megestrol acetate Drugs 0.000 description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 6
- 230000000694 effects Effects 0.000 description 4
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 3
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 3
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 3
- 238000006683 Mannich reaction Methods 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000002085 enols Chemical class 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 229960004616 medroxyprogesterone Drugs 0.000 description 2
- 230000001817 pituitary effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000003756 cervix mucus Anatomy 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 231100000546 inhibition of ovulation Toxicity 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- 210000002394 ovarian follicle Anatomy 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 230000000757 progestagenic effect Effects 0.000 description 1
- RJKFOVLPORLFTN-UHFFFAOYSA-N progesterone acetate Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 RJKFOVLPORLFTN-UHFFFAOYSA-N 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- 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
- C07J7/004—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 substituted in position 17 alfa
- C07J7/0045—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 substituted in position 17 alfa not substituted in position 16
-
- 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
- Y02P20/584—Recycling of catalysts
Abstract
The invention discloses a new preparation method of 6-methyl-17 alpha-hydroxyprogesterone and a precursor thereof, namely 6-methylene-17-alpha-hydroxyprogesterone, wherein the 6-methylene-17-alpha-hydroxyprogesterone takes 17-alpha-hydroxyprogesterone as a raw material, a rhodium-loaded molecular sieve as a catalyst and CO/H (carbon monoxide/hydrogen) as2Performing hydroformylation reaction, and reducing with potassium borohydride to obtain the product; the 6-methyl-17 alpha-hydroxyprogesterone is prepared by using 6-methylene-17-alpha-hydroxyprogesterone as a raw material and using cheap catalyst Raney nickel for hydrogenation. The invention adopts the introduction of formyl for reducibility and hydrogenation to obtain 6-methyl, the catalyst can be recycled, and the method has the advantages of environment friendliness, simple process, high yield and low cost.
Description
Technical Field
The invention belongs to the technical field of steroid medicines and chemical engineering, and particularly relates to a novel preparation method of 6-methyl-17 alpha-hydroxyprogesterone and a precursor thereof.
Background
Megestrol acetate (Megestrol) belongs to 17 alpha-hydroxypregone derivatives, is a highly efficient synthetic progestogen, and has a progestogenic effect of about 75 times that of progesterone when taken orally and about 50 times that of progesterone when injected. The product has obvious antiestrogenic effect, no estrogen or androgen activity, and no protein assimilation effect. Can inhibit the release of hypothalamic gonadotropin releasing hormone (GnRH), act on adenohypophysis and reduce the sensitivity of adenohypophysis to GnRH, thereby blocking the release of pituitary gonadotropin and generating obvious ovulation inhibition effect, so that the composition is used as a short-acting contraceptive together with ethinylestradiol. When used singly in a larger dosage, the product can also make cervical mucus sticky, is not beneficial to sperm passing, inhibits the normal development of endometrial glands and prevents implantation of fertilized eggs. In addition, the product has certain inhibition effect on hormone-dependent tumors, and the mechanism of the product is that the development and the growth of ovarian follicles are controlled through the influence on the secretion of pituitary gonadotrophin (FSH), so that the generation of estrogen is reduced; in addition, it can act on estrogen receptor, interfere its binding with estrogen, and inhibit tumor cell growth.
The preparation method of megestrol acetate can be mainly divided into two types:
1) burn and US4544555A disclose a technical scheme of taking progesterone acetate as a starting material, introducing methylene at 6-position through enol etherification, Vilsmier reaction and reduction, and then obtaining megestrol acetate through hydrogenation reduction of Pd/C and cyclohexene, isomerization and hydrolysis; wherein, when methylene is introduced in the Vilsmier reaction, DMF/POCl is used3The system has high reaction requirement, poor reaction repeatability and serious pollution; Pd/C and cyclohexene are adopted for hydrogenation reduction, so that the price is high and the production cost is high.
2) US20090012321 discloses a technical scheme of taking 17-alpha hydroxyprogesterone as a starting material, introducing methylene at 6-position through enol etherification reaction, Mannich reaction and elimination reaction, and then obtaining megestrol acetate through Pd/C and cyclohexene hydrogenation reduction and acid catalytic isomerization reaction. The process is also a method commonly adopted in the prior large-scale production, wherein, the method adopts Mannich reaction to introduce methylene, which is improved compared with the method 1); however, the following disadvantages still exist: the formaldehyde and the N-methylaniline are used, a large amount of wastewater containing the formaldehyde and the anilines is generated, and three wastes are not easy to treat; Pd/C and cyclohexene are adopted for hydrogenation reduction, so that the price is high and the production cost is high.
In conclusion, it can be seen that 6-methyl-17 α -hydroxyprogesterone is an important intermediate for the synthesis of megestrol acetate; meanwhile, it can be seen that the two preparation methods of megestrol acetate are different in that: the methylene group at the 6 position was introduced by different methods. Both of the two methods for introducing the 6-methylene have the problems of serious pollution, environmental unfriendliness, high cost, low yield and the like.
In addition, the precursor of 6-methyl-17 alpha-hydroxyprogesterone, 6-methylene-17 alpha-hydroxyprogesterone, is also an important intermediate for the synthesis of medroxyprogesterone acetate.
Chinese patent publication No. CN102911233A discloses a method for synthesizing medroxyprogesterone, which discloses a technical scheme for obtaining 6 α -methyl-17 α -hydroxyprogesterone, an intermediate of medroxyprogesterone, from 17 α -hydroxyprogesterone through ketal reaction, epoxy reaction, grignard reaction, dilute sulfuric acid hydrolysis reaction, glacial acetic acid hydrolysis deprotection, and hydrogenation transposition reaction. In the prior art, the preparation of the 6 alpha-methyl-17 alpha-hydroxyprogesterone is carried out by multiple reactions, and the process is complex, the reaction time is long, and the production cost is high.
Disclosure of Invention
The invention aims to provide a novel preparation method of 6-methyl-17 alpha-hydroxyprogesterone and a precursor thereof, and aims to solve the technical problems that the process for introducing 6-methylene has serious pollution and difficult treatment, and the whole process is complex, the reaction time is long, the production cost is high and the yield is low in the existing preparation method of 6-methyl-17 alpha-hydroxyprogesterone and the precursor thereof, namely 6-methylene-17-alpha-hydroxyprogesterone in the background art.
In order to achieve the purpose, the invention adopts the following technical scheme:
a new preparation method of 6-methylene-17-alpha hydroxyl progesterone comprises the following reaction formula of a main synthetic route:
the method specifically comprises the following steps:
1) dissolving 17 alpha-hydroxyprogesterone as a starting material in 5.0-10.0 times of solvent tetrahydrofuran or ethyl acetate, adding into a high-pressure autoclave, and then adding 0.1-1% of molecular sieve catalyst containing 0.1% of rhodium and 0.1% of triphenylphosphine into the high-pressure autoclave;
2) in a high-pressure kettle, replacing air in the reaction kettle with nitrogen for more than 3 times to ensure that no oxygen exists in the reaction kettle;
3) after the nitrogen replacement is finished, slowly introducing CO/H into the high-pressure kettle2(V: V =1:1), and performing hydroformylation at 40-120 deg.C under 1.5-5MPa for 2-10 hr;
4) after the HPLC tracking reaction is completed, cooling and releasing pressure, and filtering out the molecular sieve catalyst containing 0.1 percent of rhodium;
5) continuously adding potassium borohydride with the molar ratio of 0.5-1 time into the high-pressure kettle, and carrying out reduction reaction at 40-70 ℃;
6) after the HPLC tracking reaction is completed, dropwise adding glacial acetic acid to consume excessive potassium borohydride;
7) the solvent is evaporated under reduced pressure, cooled and crystallized, and filtered to obtain the 6-methylene-17-alpha hydroxyl progesterone.
The invention also provides a novel method for preparing 6-methyl-17 alpha-hydroxyprogesterone by using the prepared 6-methylene-17-alpha-hydroxyprogesterone, wherein the reaction equation of the main synthetic route is as follows:
a) dissolving 6-methylene-17-alpha hydroxyl progesterone in methanol of which the weight is 3 times that of the methanol, adding 3 weight percent of Raney nickel as a catalyst, and introducing hydrogen at 45 ℃ and under 1MPa to perform hydrogenation reaction;
b) after the reaction is finished, filtering, concentrating, crystallizing, washing with methanol, and finally drying in vacuum to obtain the 6-methyl-17 alpha-hydroxyprogesterone.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention adopts 17-alpha hydroxyl progesterone as raw material, rhodium-loaded molecular sieve as catalyst and CO/H2Performing hydroformylation reaction, introducing formyl at 6 position, reducing with potassium borohydride to obtain 6 methylene, and hydrogenating with inexpensive catalyst Raney nickel to obtain 6-position addition group, so that the yield and quality of 6-methyl-17 alpha-hydroxyprogesterone and its precursor are greatly improved, the content of 6-methylene-17 alpha-hydroxyprogesterone is over 98.5%, the yield is over 90%, the content of 6-methyl-17 alpha-hydroxyprogesterone is over 98.5%, and the yield is over 85%;
2. the 6-methylene is obtained by introducing formyl for reducition, so that the process is simpler, the production cost is greatly reduced, the reaction is milder, no environmental pollution is caused, and the requirements of environmental protection are met; meanwhile, the catalyst in the invention can be recycled, thereby further reducing the production cost.
Detailed Description
In order to enhance the understanding of the present invention, the present invention will be described in further detail with reference to the following examples.
Example 1
Adding 17-alpha hydroxyprogesterone and 330g ethyl acetate solvent into autoclave, then adding 0.03g molecular sieve catalyst containing 0.1% rhodium, 0.03g triphenylphosphine; in a high-pressure kettle, replacing air in the reaction kettle with nitrogen for more than 3 times to ensure that no oxygen exists in the reaction kettle; after the nitrogen replacement is finished, slowly introducing CO/H2 (V: V =1:1) into the high-pressure kettle, reacting for 6 hours at 80 ℃ and 3.3Mpa, cooling and relieving pressure after the HPLC tracking reaction is finished, and filtering out the molecular sieve supported rhodium catalyst; adding 4g of potassium borohydride, carrying out reduction reaction at 50 ℃, and dropwise adding glacial acetic acid to consume excessive potassium borohydride after HPLC tracking reaction is completed; the solvent was evaporated under reduced pressure, cooled to crystallize, filtered, washed with 10g of ethyl acetate and the solid obtained was dried under vacuum at 50 ℃ to give 31g of 6-methylene-17-alpha-hydroxyprogesterone with a content of 98.8% (HPLC, normalization method) in 91% yield.
Example 2
Adding 17-alpha hydroxyprogesterone and 250g ethyl acetate solvent into autoclave, then adding 0.16g molecular sieve catalyst containing 0.1% rhodium, 0.03g triphenylphosphine; in a high-pressure kettle, replacing air in the reaction kettle with nitrogen for more than 3 times to ensure that no oxygen exists in the reaction kettle; after the nitrogen replacement is finished, slowly introducing CO/H2 (V: V =1:1) into the high-pressure kettle, reacting for 10 hours at 120 ℃ and 5Mpa, cooling and releasing pressure after the HPLC tracking reaction is finished, and filtering out the molecular sieve supported rhodium catalyst; adding 5.4g of potassium borohydride, carrying out reduction reaction at 50 ℃, and after the HPLC tracking reaction is completed, dropwise adding glacial acetic acid to consume excessive potassium borohydride; the solvent was evaporated under reduced pressure, cooled to crystallize, filtered, washed with 10g of ethyl acetate and the solid obtained was dried under vacuum at 50 ℃ to give 32g of 6-methylene-17-alpha-hydroxyprogesterone with a content of 99.2% (HPLC, normalization method) in 93% yield.
Example 3
Adding 17-alpha hydroxyprogesterone and 165g ethyl acetate solvent into an autoclave, and then adding 0.33g molecular sieve catalyst containing 0.1% rhodium and 0.03g triphenylphosphine; in a high-pressure kettle, replacing air in the reaction kettle with nitrogen for more than 3 times to ensure that no oxygen exists in the reaction kettle; after the nitrogen replacement is finished, slowly introducing CO/H2 (V: V =1:1) into the high-pressure kettle, reacting for 2 hours at 40 ℃ and 1.5Mpa, cooling and relieving pressure after the HPLC tracking reaction is finished, and filtering out the molecular sieve supported rhodium catalyst; adding 2.7g of potassium borohydride, carrying out reduction reaction at 50 ℃, and after the HPLC tracking reaction is completed, dropwise adding glacial acetic acid to consume excessive potassium borohydride; the solvent was evaporated under reduced pressure, cooled to crystallize, filtered, washed with 10g of ethyl acetate and the resulting solid was dried under vacuum at 50 ℃ to give 31.5g, 92% yield, of 6-methylene-17-alpha-hydroxyprogesterone having a content of 99.1% (HPLC, normalization).
Example 4
31g of 6-methylene-17-alpha hydroxyprogesterone obtained in example 1 was hydrogenated at 45 ℃ and 1MPa using 93g of methanol as solvent and 1g of Raney nickel as catalyst; after the reaction was completed, filtration, concentration, crystallization and washing with 10g of methanol gave a solid which was dried under vacuum at 50 ℃ to give 29g of 6-methyl-17 α -hydroxyprogesterone with a content of 98.7% (HPLC, normalization method) in a yield of 93.3%.
Claims (8)
1. A novel preparation method of 6-methylene-17-alpha hydroxyl progesterone is characterized by comprising the following steps:
1) dissolving 17 alpha-hydroxyprogesterone as a starting material in 5.0-10.0 times of solvent, adding into a high-pressure autoclave, and then adding 0.1-1% of molecular sieve catalyst and 0.1% of triphenylphosphine into the high-pressure autoclave;
2) in a high-pressure kettle, replacing air in the reaction kettle with nitrogen for more than 3 times to ensure that no oxygen exists in the reaction kettle;
3) slowly introducing CO and H into the autoclave2The synthesis gas of (2) is subjected to hydroformylation reaction;
4) after the HPLC tracking reaction is completed, cooling and releasing pressure, and filtering out the molecular sieve catalyst;
5) continuously adding potassium borohydride with the molar ratio of 0.5-1 time into the high-pressure kettle for reduction reaction;
6) after the HPLC tracking reaction is completed, dropwise adding glacial acetic acid to consume excessive potassium borohydride;
7) the solvent is evaporated under reduced pressure, cooled and crystallized, and filtered to obtain the 6-methylene-17-alpha hydroxyl progesterone.
2. The novel process for the preparation of 6-methylene-17-alpha hydroxyprogesterone according to claim 1, wherein the reaction equation of the novel process is as follows:
3. the novel process for the preparation of 6-methylene-17-alpha hydroxyprogesterone according to claim 1, wherein in step 1), the solvent is tetrahydrofuran or ethyl acetate, and the molecular sieve catalyst is a molecular sieve catalyst containing 0.1% rhodium.
4. The novel process for the preparation of 6-methylene-17-alpha hydroxyprogesterone according to claim 1, wherein in step 3), said CO is reacted with H2Is 1: 1.
5. The novel process for the preparation of 6-methylene-17-alpha hydroxyprogesterone according to claim 1, wherein the hydroformylation in step 3) is carried out at a temperature of 40-120 ℃, for a time of 2-10 hours and at a pressure of 1.5-5 Mpa.
6. The novel process for the preparation of 6-methylene-17-alpha hydroxyprogesterone according to claim 1, wherein the reaction temperature of the reduction reaction in step 5) is 40-70 ℃.
7. A novel process for the preparation of 6-methyl-17 α -hydroxyprogesterone, comprising the novel process for the preparation of 6-methylene-17- α -hydroxyprogesterone according to any of claims 1 to 6 and the following steps:
a) dissolving 6-methylene-17-alpha hydroxyl progesterone in methanol of which the weight is 3 times that of the methanol, adding 3 weight percent of Raney nickel as a catalyst, and introducing hydrogen at 45 ℃ and under 1MPa to perform hydrogenation reaction;
b) after the reaction is finished, filtering, concentrating, crystallizing, washing by methanol, and drying in vacuum to obtain the 6-methyl-17 alpha-hydroxyprogesterone.
8. The novel process for the preparation of 6-methyl-17 α -hydroxyprogesterone according to claim 7, wherein the reaction equation of the novel process is as follows:
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| CN114057821A (en) * | 2021-11-30 | 2022-02-18 | 黑龙江中医药大学 | Preparation method of medroxyprogesterone acetate for perimenopausal syndrome |
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