CN116891500A - Aidiecalcitol impurity and preparation method thereof - Google Patents
Aidiecalcitol impurity and preparation method thereof Download PDFInfo
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- CN116891500A CN116891500A CN202310849978.4A CN202310849978A CN116891500A CN 116891500 A CN116891500 A CN 116891500A CN 202310849978 A CN202310849978 A CN 202310849978A CN 116891500 A CN116891500 A CN 116891500A
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- compound
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- idecalcitol
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- 239000012535 impurity Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 8
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims abstract description 5
- JPJGNZQDELRZGE-UHFFFAOYSA-N (phenyl-$l^{2}-phosphanyl)benzene Chemical compound C=1C=CC=CC=1[P]C1=CC=CC=C1 JPJGNZQDELRZGE-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 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 6
- 238000000034 method Methods 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims 2
- 230000001590 oxidative effect Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- FZEXGDDBXLBRTD-AYIMTCTASA-N 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)[C@@H](OCCCO)[C@H](O)C1=C FZEXGDDBXLBRTD-AYIMTCTASA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 3
- 229960002535 alfacalcidol Drugs 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000003704 vitamin D3 derivatives Chemical class 0.000 description 2
- -1 (Z) -2- ((3R, 4R, 5R) -3, 5-bis ((tert-butyldimethylsilyl) oxy) -4- (3- ((tert-butyldiphenylsilyl) oxy) propoxy) -2-methylenecyclohexylidene) ethyl Chemical group 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- YFPJFKYCVYXDJK-UHFFFAOYSA-N Diphenylphosphine oxide Chemical compound C=1C=CC=CC=1[P+](=O)C1=CC=CC=C1 YFPJFKYCVYXDJK-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229950005556 eldecalcitol Drugs 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
Abstract
The invention discloses an impurity type compound of idecalcitol (I) and a preparation method thereof. The preparation method comprises the following steps: (1) The compound (II) is reduced in cyclopentyl methyl ether solution by Red-Al to obtain a compound (III); (2) The compound (III) and NCS are subjected to substitution reaction to obtain a compound (IV); (3) And (3) oxidizing the compound (IV), diphenyl phosphorus and n-butyllithium by hydrogen peroxide to obtain the compound (I).
Description
Technical Field
The invention belongs to the technical field of chemical drug analysis and drug synthesis, and particularly relates to an idecalcitol impurity and a preparation method thereof.
Background
Idecalcitol (Eldecalcitol), CAS accession number: 104121-92-8, chemical name (1R, 2R,3R, Z) -5- ((E) -2- ((1R, 3aS,7 aR) -1- ((R) -6-hydroxy-6-methylhept-2-yl) -7 a-methylhexahydro-1H-inden-4 (2H) -ylidene) ethylidene) -2- (3-hydroxypropoxy) -4-methylenecyclohexane-1, 3-diol, structural formula:
the idecalcitol is an active vitamin D3 derivative, the product is marketed in Japan in 2011, the commodity name is Edirol, the product is a vitamin D medicament which is developed by combining Japanese pharmaceutical and Zhengda pharmaceutical, and is used for treating osteoporosis, the idecalcitol is a new active vitamin D3 derivative for treating osteoporosis after the alfacalcidol, the curative effect of the idecalcitol is better than that of the alfacalcidol, the safety of the product is similar to that of the alfacalcidol, and the product has a good application prospect.
The original research patent reports a synthesis method of idecalcitol, wherein ((Z) -2- ((3R, 4R, 5R) -3, 5-bis ((tert-butyldimethylsilyl) oxy) -4- (3- ((tert-butyldiphenylsilyl) oxy) propoxy) -2-methylenecyclohexylidene) ethyl) diphenylphosphine oxide is taken as a starting material, and the idecalcitol is prepared through rearrangement and deprotection reaction. The synthetic route is as follows:
although some idecalcitol impurities are reported in the prior literature and data, further research on other impurities possibly generated in the idecalcitol synthesis process or in the subsequent preparation process and storage process is helpful for perfecting the overall quality control of idecalcitol and has great significance.
Disclosure of Invention
First, the present invention provides an impurity compound of formula (I) having a chemical structure represented by formula (I):
in order to achieve the object of the present invention, the present inventors have finally obtained the following technical scheme of impurity compound of formula (I):
secondly, the invention also provides a preparation method of the impurity compound of formula (I), which is characterized by comprising the following steps:
(1) The compound (II) is reduced in cyclopentyl methyl ether solution by Red-Al to obtain a compound (III);
(2) The compound (III) and NCS are subjected to substitution reaction to obtain a compound (IV);
(3) Oxidizing the compound (IV), diphenyl phosphorus and n-butyllithium by hydrogen peroxide to obtain a compound (I);
(4) In the step (1), the molar ratio of Red-Al to the compound (II) is 5.0:1-6.0:1, and the solvent is cyclopentyl methyl ether;
(5) In the step (2), the molar ratio of NCS to the compound (III) is 1.0:1-1.5:1, the molar ratio of triphenylphosphine to the compound (III) is 1.0:1-2.0:1, and the solvent is dichloromethane;
the beneficial effects of the invention are as follows:
the invention discovers a compound of the formula (I), which is reported for the first time and is a brand new compound. The invention also provides a preparation method of the compound.
Drawings
Fig. 1: of compounds of formula (I) 1 H-NMR spectrum
Fig. 2: liquid phase pattern of the compound of formula (I)
Detailed Description
The following examples will provide those skilled in the art with a more complete understanding of the present invention and are not intended to limit the invention to the embodiments described.
1. Synthesis of (III): 1.05g of (II) are completely dissolved in 12.3ml of cyclopentylmethyl ether. Cooling to 0 ℃, dropwise adding 2.32ml of Red-Al, and stirring for 12 hours after the dropwise adding is finished. After the reaction is finished, the reaction solution is quenched and washed by saturated potassium sodium tartrate, extracted by ethyl acetate, separated, the organic phase is decompressed and concentrated to obtain crude product, and the crude product is subjected to column chromatography to obtain 630m g light yellow oily substance (III).
2. And (IV) synthesis: 630m g (III) was completely dissolved in dichloromethane. 348mg of triphenylphosphine and 144mg of NCS in methylene chloride were added dropwise under argon and stirred for 6h at 25 ℃. After the reaction, water was added, the mixture was separated, the aqueous phase was extracted with methylene chloride, the organic phases were combined, and concentrated under reduced pressure to give 1.2g of crude product.
3. Synthesis of (I): 367mg of diphenylphosphine are completely dissolved in 8ml of tetrahydrofuran. And (3) under the protection of argon, cooling to 0 ℃ by an ice salt bath, dropwise adding 0.71ml of 2.5M n-butyllithium, stirring for 2h, dissolving 1.2g of compound (IV) in tetrahydrofuran, cooling to-65 ℃, dropwise adding a tetrahydrofuran solution of the compound (IV), after the stirring reaction is finished, dropwise adding a saturated ammonium chloride solution for quenching, separating liquid, extracting an aqueous phase with tetrahydrofuran, merging organic phases, and concentrating to dryness under reduced pressure. To the concentrated residue, 20ml of chloroform was added for dissolution, the temperature was lowered to 0℃in an ice bath, 0.536ml of hydrogen peroxide was added dropwise, the temperature was raised to room temperature after completion of the dropwise addition, stirring was carried out for 0.5h, the reaction solution was quenched with saturated sodium thiosulfate solution, the separated liquid was separated, the aqueous phase was extracted with methylene chloride, the organic phases were combined, the organic phases were washed with saturated saline solution, the separated liquid was concentrated under reduced pressure to obtain 1g of a crude product, 468mg of colorless oily substance was obtained by column chromatography, and the purity was 98.7%.
The foregoing embodiments and description are merely illustrative of the principles of this invention, and the invention is susceptible to various modifications and alternative forms without departing from the spirit and scope of the invention, and these modifications and alternative forms fall within the scope of the invention as hereinafter claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (4)
1. An idecalcitol impurity having the structure of formula (I):
2. a process for the preparation of an idecalcitol impurity having the structure of formula (I) according to claim 1, characterized by comprising the steps of:
(1) The compound (II) is reduced in cyclopentyl methyl ether solution by Red-Al to obtain a compound (III):
(2) The compound (III) and NCS are subjected to substitution reaction to obtain a compound (IV):
(3) The compound (IV) is oxidized with diphenyl phosphorus and n-butyl lithium by hydrogen peroxide to obtain a compound (I):
the resulting compound of formula (I) is an idecalcitol impurity.
3. The method for preparing the idicalcitol impurity according to claim 2, which is characterized in that: the reaction temperature in the step (1) is 5 ℃, the reaction time is 12h, and the molar ratio of Red-Al to the compound (II) is 5.0:1-6.0:1.
4. The method for preparing the idicalcitol impurity according to claim 2, which is characterized in that: the reaction temperature in the step (2) is 25 ℃, the reaction time is 6h, the molar ratio of NCS to the compound (III) is 1.0:1-1.5:1, and the molar ratio of triphenylphosphine to the compound (III) is 1.0:1-2.0:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310849978.4A CN116891500A (en) | 2023-07-11 | 2023-07-11 | Aidiecalcitol impurity and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310849978.4A CN116891500A (en) | 2023-07-11 | 2023-07-11 | Aidiecalcitol impurity and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116891500A true CN116891500A (en) | 2023-10-17 |
Family
ID=88314399
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310849978.4A Pending CN116891500A (en) | 2023-07-11 | 2023-07-11 | Aidiecalcitol impurity and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116891500A (en) |
-
2023
- 2023-07-11 CN CN202310849978.4A patent/CN116891500A/en active Pending
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