CN117964535A - Prostaglandin FP receptor agonist impurity and preparation method thereof - Google Patents
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- CN117964535A CN117964535A CN202211303355.9A CN202211303355A CN117964535A CN 117964535 A CN117964535 A CN 117964535A CN 202211303355 A CN202211303355 A CN 202211303355A CN 117964535 A CN117964535 A CN 117964535A
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- 229940121962 Prostaglandin FP receptor agonist Drugs 0.000 title claims abstract description 20
- 239000012535 impurity Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000012024 dehydrating agents Substances 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 2
- 229940079593 drug Drugs 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 12
- 238000011160 research Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 2
- 239000013558 reference substance Substances 0.000 abstract 1
- 150000003180 prostaglandins Chemical class 0.000 description 7
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007791 liquid phase Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 5
- -1 (Z) -7- [ (1R, 2R, 5S) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -5-hydroxycyclopent-3-en-1-yl ] -5-heptenoic acid isopropyl ester Chemical compound 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- 208000007950 Ocular Hypotension Diseases 0.000 description 3
- 102000000471 Prostaglandin F receptors Human genes 0.000 description 3
- 108050008995 Prostaglandin F receptors Proteins 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 238000010587 phase diagram Methods 0.000 description 3
- 229940044601 receptor agonist Drugs 0.000 description 3
- 239000000018 receptor agonist Substances 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000002060 circadian Effects 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical compound CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical group 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a prostaglandin FP receptor agonist impurity and a preparation method thereof. The method has the advantages of convenient operation, mild and controllable reaction conditions and higher product purity. The impurity of the formula I is used as a reference substance for researching the purity and quality of the bulk drug of the formula II and related preparations so as to ensure the quality of the drug, thereby ensuring the clinical medication safety and the life health of patients, being more beneficial to process research and quality control and having great significance and practical value.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a prostaglandin FP receptor agonist impurity and a preparation method thereof.
Background
Natural Prostaglandins (PGs) are bioactive substances synthesized in the body and functioning as local hormones with various biological activities in various tissues of the body, and their chemical nature is unsaturated fatty acids with 20 carbon atoms. The basic skeleton constituting PG is prostanoic acid, which has one cyclopentane core and two side chains. Prostaglandins can be classified into A, B, C, D, E, F, G, H, I types based on the five-membered ring or the whole molecular structure. There are many studies on type E, F, A, B, I (i.e., PGE, PGF, PGA, PGB, PGI). Shielnshantz et al report specific PGA, PGB, PGD, PGE and PGF derivatives modified by introducing a cyclic structure, which are little irritating to the eyes and rarely engorged with blood in the eyes (Japanese patent laid-open publication No. 109132 1996).
PGF is a group of natural prostaglandins, a selective FP receptor agonist, which is known to reduce intraocular pressure when topically applied to the eye and is promising as a drug for the treatment of intraocular hypertension or glaucoma (U.S. patent No.4,599,353). The pgf2α ocular hypotension effect of the prostaglandins is mainly realized by improving aqueous humor drainage of the uveoscleral pathway instead of the classical trabecular meshwork pathway, and meanwhile, the pgf2α ocular hypotension effect has good night ocular hypotension effect, can reduce the circadian ocular fluctuations, and can reduce the damage of the ocular fluctuations to visual fields and optic nerves.
However, they are irritating to the eyes and have problems of congestion and side effects of inflammation caused by injury to the cornea. Therefore, research and development of PGF derivatives having no such side effects have been widely conducted at home and abroad.
When the synthesis process of related prostaglandin FP receptor agonist drugs is studied, compounds of prostaglandin FP receptor agonist impurities shown by the following structures are discovered:
at present, no literature reports the existence and preparation method of the compound, and impurities of medicines directly affect the quality of medicines and the research of related preparations, so that the compound has great significance for the technological impurity research of prostaglandin FP receptor agonists.
Disclosure of Invention
It is a first object of the present invention to provide a process impurity for prostaglandin FP receptor agonists (compounds of formula II),
The chemical name is: (Z) -7- [ (1R, 2R, 5S) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -5-hydroxycyclopent-3-en-1-yl ] -5-heptenoic acid isopropyl ester, the chemical structural formula of which is shown in formula I:
The second object of the present invention is to provide a process for the preparation of a compound of formula I, comprising the specific synthetic steps of: (1) Taking a prostaglandin FP receptor agonist (a compound shown as a formula II) as a starting material, dissolving the prostaglandin FP receptor agonist and a water loss agent in a solvent, and uniformly mixing;
(2) Stirring the mixture obtained in the step (1) at a certain temperature for reaction;
(3) And (3) separating and purifying the reaction liquid obtained in the step (2) to obtain a target product.
Further, the solvent is one or more of toluene, tetrahydrofuran and dichloromethane; preferably dichloromethane.
Further, the dehydrating agent in the step (1) is concentrated sulfuric acid or Martin reagent (bis [ a, a-bis (trifluoromethyl) phenylethanol ] -diphenylsulfide).
Further, the dehydrating agent is a Martin reagent, and the molar ratio of the prostaglandin FP receptor agonist to the Martin reagent in the step (1) is 1:1-2, preferably 1:1.5. The reaction temperature in the step (2) is-15 ℃ to 15 ℃, preferably 0 ℃ to 5 ℃.
Further, the dehydrating agent is concentrated sulfuric acid, and the molar ratio of the prostaglandin FP receptor agonist to the concentrated sulfuric acid in the step (1) is 1:0.2-0.8, preferably 1:0.5. The reaction temperature in the step (2) is 20 to 30 ℃, preferably 20 to 25 ℃.
Further, the purification method in the step (3) comprises concentrating the reaction solution and then performing silica gel column chromatography. The mobile phase of the silica gel column chromatography is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of petroleum ether to ethyl acetate is (10-5): 1.
Compared with the prior art, the invention has the following beneficial technical effects:
The invention discloses a prostaglandin FP receptor agonist impurity and a preparation method thereof. The method has the advantages of convenient operation, mild and controllable reaction conditions and higher product purity. The impurity of the formula I is used as a control product for controlling the purity and quality of the bulk drug of the formula II and related preparations so as to ensure the quality of the drug, thereby ensuring the safety of clinical medication and the life health of patients, being more beneficial to process research and quality control, and having great significance and practical value.
Drawings
FIG. 1 is a liquid phase diagram of the compound of formula I prepared in example 1;
FIG. 2 is an MS spectrum of the compound of formula I prepared in example 1;
FIG. 3 is a hydrogen spectrum of the compound of formula I prepared in example 1;
FIG. 4 is a carbon spectrum of the compound of formula I prepared in example 1;
FIG. 5 is a liquid phase diagram of the compound of formula I prepared in example 2;
FIG. 6 is a liquid phase diagram of the compound of formula I prepared in example 3.
Detailed Description
The foregoing aspects of the invention are explained in further detail by the following description of embodiments. It should not be construed that the scope of the above subject matter of the present invention is limited to the following examples.
Preparation of (Z) -7- [ (1 r,2r,5 s) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -5-hydroxycyclopent-3-en-1-yl ] -5-heptenoic acid isopropyl ester was prepared by the following technical route:
the crude drug prostaglandin FP receptor agonist impurity (compound of formula II) used therein is self-made using the prior art.
The HPLC detection conditions were as follows:
Example 1: preparation of (Z) -7- [ (1R, 2R, 5S) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -5-hydroxycyclopent-3-en-1-yl ] -5-heptenoic acid isopropyl ester
Prostaglandin FP receptor agonist (compound of formula II) (1.10 g,2.4 mmol) was added to a 100mL three-necked flask, and then 11mL of methylene chloride was added thereto, martin reagent (bis [ a, a-bis (trifluoromethyl) phenylethanol ] -diphenylsulfide) (2.42 g,3.6 mmol) was added thereto with stirring, the reaction was stirred at 0 to 5 ℃ for 1.5 to 2 hours, after the starting materials were completely reacted, the reaction mixture was concentrated under reduced pressure at 40 to 45 ℃ and the concentrate was purified by column chromatography (eluent: petroleum ether/ethyl acetate=8:1 (V/V)) to give (Z) -7- [ (1 r,2r,5 s) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -5-hydroxycyclopent-3-en-1-yl ] -5-heptenoic acid isopropyl ester 0.38g, hplc purity 98.7%, and the liquid phase of the compound of formula I was shown in fig. 1.
MS (ESI (+), 75V) m/z:452.1, 457.1, 473.1. The MS spectrum of the compound of formula I is shown in figure 2.
1H-NMR(DMSO-d6)：δ7.31(2H,ddd)、δ6.99(3H,dd),δ6.11(1H,ddd),δ5.92(1H,dt),δ5.85-5.75(2H,m),δ5.52-5.45(1H,m),δ5.32-5.26(1H,m),δ4.90-4.84(1H,m)、δ4.54-4.47(2H,m)、δ4.35(2H,t)、δ3.11(1H,t),δ2.24-2.01(4H,m),δ2.04-1.99(2H,m),δ1.72-1.61(1H,m),δ1.58-1.51(2H,m),δ1.16(6H,d). The hydrogen spectrum of the compound of formula I is shown in figure 3.
13C-NMR(DMSO-d6)：δ172.72,δ158.16,δ140.52,δ140.43,δ135.86,δ135.50,δ130.31,δ130.01,δ129.31,δ122.62,δ121.91,δ119.42,δ115.23,δ75.01,δ68.85,δ67.32,δ49.82,δ48.15,δ33.72,δ26.45,δ25.59,δ24.93,δ22.06. The carbon spectrum of the compound of formula I is shown in figure 4.
Example 2: preparation of (Z) -7- [ (1R, 2R, 5S) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -5-hydroxycyclopent-3-en-1-yl ] -5-heptenoic acid isopropyl ester
Prostaglandin FP receptor agonist impurity (compound of formula II) (1.78 g,3.9 mmol) was added to a 100mL three-necked flask, and 18mL toluene was added thereto, and Martin reagent (bis [ a, a-bis (trifluoromethyl) phenylethanol ] -diphenylsulfide) (2.62 g,3.9 mmol) was added thereto with stirring, and reacted at 0 to 5 ℃ for 3 to 4 hours, and after the starting materials were completely reacted, the reaction mixture was concentrated under reduced pressure at 50 to 55 ℃ and the concentrate was purified by column chromatography (eluent: petroleum ether/ethyl acetate=8:1 (V/V)), to give (Z) -7- [ (1 r,2r,5 s) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -5-hydroxycyclopent-3-en-1-yl ] -5-heptenoic acid isopropyl ester 0.44g, hplc purity 98.9%, and the liquid phase of the compound of formula I was shown in fig. 5.
Example 3: preparation of (Z) -7- [ (1R, 2R, 5S) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -5-hydroxycyclopent-3-en-1-yl ] -5-heptenoic acid isopropyl ester
Prostaglandin FP receptor agonist impurity (compound of formula II) (1.50 g,3.3 mmol) was added to a 100mL three-necked flask, followed by 15mL tetrahydrofuran, concentrated sulfuric acid (0.16 g,1.65 mmol) was added with stirring, the reaction was stirred at 20 to 25 ℃ for 3 to 4 hours, after the starting materials were completely reacted, the reaction solution was concentrated at 40 to 45 ℃ under reduced pressure, and the concentrate was purified by column chromatography (eluent: petroleum ether/ethyl acetate=10:1 (V/V)), to give (Z) -7- [ (1 r,2r,5 s) -2- [ (1E) -3, 3-difluoro-4-phenoxy-1-buten-1-yl ] -5-hydroxycyclopent-3-en-1-yl ] -5-heptenoic acid isopropyl ester 0.41g, hplc purity 97.6%, the liquid phase of the compound of formula I being shown in fig. 6.
Claims (9)
1. A prostaglandin FP receptor agonist impurity, a compound of formula I:
2. The method for synthesizing the compound I according to claim 1, wherein the synthesizing step comprises:
(1) Taking a prostaglandin FP receptor agonist as a starting material, dissolving the prostaglandin FP receptor agonist and a dehydrating agent in a solvent, and uniformly mixing;
(2) Stirring the mixture obtained in the step (1) at a certain temperature for reaction;
(3) And (3) separating and purifying the reaction liquid obtained in the step (2) to obtain a target product.
3. The preparation method according to claim 2, wherein the solvent in the step (1) is one or more of toluene, tetrahydrofuran and dichloromethane, preferably dichloromethane.
4. The method according to claim 2, wherein the dehydrating agent in the step (1) is concentrated sulfuric acid or Martin reagent.
5. The method according to claim 4, wherein the dehydrating agent is a Martin reagent, and the molar ratio of the prostaglandin FP receptor agonist to the Martin reagent in the step (1) is 1:1 to 2, preferably 1:1.5.
6. The process according to claim 5, wherein the reaction temperature in step (2) is-15 ℃ to 15 ℃, preferably 0 ℃ to 5 ℃.
7. The process according to claim 4, wherein the dehydrating agent is concentrated sulfuric acid, and the molar ratio of prostaglandin FP receptor agonist to concentrated sulfuric acid in step (1) is 1:0.2-0.8, preferably 1:0.5.
8. The process according to claim 7, wherein the reaction temperature in step (2) is 20 to 30 ℃, preferably 20 to 25 ℃.
9. The method according to claim 2, wherein the purification method in step (3) comprises concentrating the reaction solution and then subjecting the concentrated reaction solution to silica gel column chromatography. The mobile phase of the silica gel column chromatography is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of petroleum ether to ethyl acetate is (10-5): 1.
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| CN202211303355.9A CN117964535A (en) | 2022-10-24 | 2022-10-24 | Prostaglandin FP receptor agonist impurity and preparation method thereof |
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| CN202211303355.9A CN117964535A (en) | 2022-10-24 | 2022-10-24 | Prostaglandin FP receptor agonist impurity and preparation method thereof |
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