CN114671838A - Preparation method of travoprost impurity - Google Patents
Preparation method of travoprost impurity Download PDFInfo
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- CN114671838A CN114671838A CN202011553857.8A CN202011553857A CN114671838A CN 114671838 A CN114671838 A CN 114671838A CN 202011553857 A CN202011553857 A CN 202011553857A CN 114671838 A CN114671838 A CN 114671838A
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- China
- Prior art keywords
- formula
- compound
- hypochlorite
- tvp
- travoprost
- Prior art date
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- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 title claims abstract description 29
- 229960002368 travoprost Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000012535 impurity Substances 0.000 title abstract description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 31
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 14
- 239000013067 intermediate product Substances 0.000 claims description 12
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- SATVIFGJTRRDQU-UHFFFAOYSA-N potassium hypochlorite Chemical compound [K+].Cl[O-] SATVIFGJTRRDQU-UHFFFAOYSA-N 0.000 claims description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims 3
- 238000003908 quality control method Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000012797 qualification Methods 0.000 abstract description 2
- 238000011002 quantification Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000012071 phase Substances 0.000 description 21
- 239000000047 product Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 description 2
- 238000010268 HPLC based assay Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- DZUXGQBLFALXCR-UHFFFAOYSA-N (+)-(9alpha,11alpha,13E,15S)-9,11,15-trihydroxyprost-13-en-1-oic acid Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CCCCCCC(O)=O DZUXGQBLFALXCR-UHFFFAOYSA-N 0.000 description 1
- 206010018307 Glaucoma and ocular hypertension Diseases 0.000 description 1
- AKKLAJYCGVIWBS-UHFFFAOYSA-N O=[N].CC1(C)CCCC(C)(C)N1 Chemical compound O=[N].CC1(C)CCCC(C)(C)N1 AKKLAJYCGVIWBS-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 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
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- PXGPLTODNUVGFL-UHFFFAOYSA-N prostaglandin F2alpha Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CC=CCCCC(O)=O PXGPLTODNUVGFL-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
- C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N30/14—Preparation by elimination of some components
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/50—Conditioning of the sorbent material or stationary liquid
- G01N30/52—Physical parameters
- G01N30/54—Temperature
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/062—Preparation extracting sample from raw material
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
Abstract
The invention relates to the technical field of pharmacy, and particularly relates to a travoprost impurity and a preparation method thereof. The invention provides impurities in a preparation process of travoprost and a preparation method thereof. The impurity is generated when the TVP-5 is prepared by using the intermediate TVP-4 in the preparation process of the travoprost. The prepared high-purity travoprost impurity is used as an impurity standard for TVP-5 detectionThe product is beneficial to the quantification and the qualification of the intermediate TVP-5, and improves the quality control of the TVP-5 and the travoprost bulk drugs. The impurities are of the formula (I)
Description
Technical Field
The invention relates to the technical field of pharmacy, and particularly relates to a travoprost impurity and a preparation method thereof.
Background
Travoprost (TVP) is a highly selective prodrug that completely blocks the prostaglandin F (fp) receptor, and is a prostaglandin F2 α (PGF2 α) analog, a known prostaglandin derivative used for the treatment of glaucoma and ocular hypertension. Its chemical name is:
isopropyl (Z) -7- [ (1R,2R,3R,5S) -3, 5-dihydroxy-2- [ (1E,3R) -3-hydroxy-4- [ (α, α, α -trifluoro-m-methylpropyl) oxy ] -1-butenyl ] cyclopentyl ] -5-heptenoic acid.
The production process of travoprost is complex and is carried out in multiple steps, and in order to ensure the recovery rate of the final product, the purity of the intermediate product obtained in the intermediate process needs to be controlled. However, in the quality control of the intermediate product, some impurities are difficult to purchase in the market due to low commercial value.
Some impurities possibly existing in travoprost are listed in the United states pharmacopoeia, and related researches on other impurities possibly existing in the process are not reported at present, for example, some impurities may be generated in the process of preparing the intermediate TVP-5 by using the intermediate TVP-4, and a preparation method for identifying the impurities and obtaining the impurities is needed to prepare an impurity standard substance, so that the quantitative and qualitative properties of the intermediate TVP-5 are facilitated, and the quality control on the TVP-5 and travoprost bulk drugs is improved.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, an object of the present invention is to provide an impurity in the process of producing travoprost and a method for producing the same. The impurity is generated when the TVP-5 is prepared by using the intermediate product TVP-4 in the preparation process of the travoprost, and the impurity standard substance can be used for detecting the purity of the TVP-5 by preparing the impurity standard substance. The prepared high-purity travoprost impurity is used as an impurity standard substance for TVP-5 detection, is beneficial to the quantification and the qualification of an intermediate, and improves the quality control of TVP-5 and travoprost bulk drugs.
To this end, the invention provides, in a first aspect, a process for the preparation of a compound of formula (I). According to an embodiment of the invention, the method comprises:
1) the compound shown in the formula (II) and hypochlorite are subjected to oxidation reaction to obtain an intermediate A,
2) reacting the intermediate A with hydrochloric acid to obtain a compound shown as a formula (I),
wherein the oxidation reaction is carried out under the catalysis of a TEMPO catalyst.
The invention creatively discovers that the impurity of the compound shown in the formula (I) is generated in the process of preparing the travoprost, in particular in the process of preparing the intermediate TVP-5 from the intermediate TVP-4, and if the purity of the TVP-5 is not measured, the yield of the finally obtained travoprost is low, and the production cost is wasted. When the purity of TVP-5 as an intermediate is determined by HPLC, a standard sample of the compound of formula (I) is required, however, this compound has not been reported in the literature and is not commercially available. The inventor finds out the impurity of the compound shown in the formula (I) on one hand, and obtains a method for preparing the impurity, the obtained impurity can be used for determining the purity of TVP-5, and the quality control of TVP-5 and travoprost bulk drug is improved by quantifying and determining the intermediate TVP-5.
According to an embodiment of the invention, the process for preparing the compounds of formula (i) also has the following additional technical features:
according to an embodiment of the invention, the hypochlorite is selected from sodium hypochlorite, potassium hypochlorite.
According to the embodiment of the invention, the hypochlorite is sodium hypochlorite, and the molar ratio of the sodium hypochlorite to the compound shown in the formula (II) is (2-5): 1.
according to the embodiment of the invention, the intermediate A reacts with hydrochloric acid under the condition that the pH value is 2-3.
According to the embodiment of the invention, the oxidation reaction system further comprises potassium bromide and sodium bicarbonate.
According to the embodiment of the invention, the weight ratio of the TEMPO catalyst to the potassium bromide to the sodium bicarbonate is (0.8-1): 10: 10.
if the weight ratio of the TEMPO catalyst to the potassium bromide to the sodium bicarbonate is out of the above range, the catalysis will be incomplete, the reaction will not proceed well, and the yield and purity of the resulting impurity compound of formula (I) will be low.
According to the embodiment of the invention, the weight ratio of the TEMPO catalyst to the compound shown in the formula (II) is (0.028-0.030): 5.
according to the embodiment of the invention, the compound shown in the formula (II) reacts with hypochlorite at the temperature of-5-0 ℃ for 30-60 min.
The sodium hypochlorite is decomposed due to the over-high reaction temperature, so that the compound shown in the formula (II) is not excessively oxidized, the quality of the generated product is low, and the yield and the purity are reduced; the reaction temperature is too low, the reaction is incomplete, and the yield and the purity are influenced.
According to an embodiment of the invention, the compound of formula (II) is reacted with hypochlorite in an organic solvent;
according to an embodiment of the invention, the organic solvent is dichloromethane.
According to the embodiment of the invention, the mass concentration of the compound shown in the formula (II) in dichloromethane is 8-10%.
According to an embodiment of the present invention, the method further comprises a step of extracting the prepared compound represented by formula (i) with toluene at least once.
According to the embodiment of the invention, the volume-to-mass ratio of the total amount of the toluene to the compound shown in the formula (II) is (60-70) ml: 5g of the total weight.
The dosage of toluene is too small, the extraction is incomplete, the product obtained by post-treatment has low quantity, and the yield and the purity do not meet the requirements; too much toluene is used and other impurities are also extracted into the product, resulting in a decrease in yield and purity.
In a second aspect, the present invention provides a compound prepared by the process of the first aspect. According to an embodiment of the invention, the compound has the formula
The compound shown in the formula (I) is prepared by the preparation method, and can be used as a standard substance for determining the purity of an intermediate product TVP-5 in the TVP preparation process. The purity of the TVP-5 is detected, so that a reference is provided for the production of TVP.
In a third aspect, the present invention provides the use of a compound of the second aspect in the quantitative and qualitative determination of an intermediate product in the production of travoprost, wherein the intermediate product is a compound of formula (iii):
additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 shows the HPLC assay of compounds of formula (I) containing impurities prepared from TVP-4.
Detailed Description
The following describes embodiments of the present invention in detail. The following examples are illustrative only and are not to be construed as limiting the invention.
In some embodiments of the invention, the reaction of a compound of formula (ii):
in some specific embodiments of the present invention, the molar ratio of the sodium hypochlorite to the compound represented by formula (ii) is (2-5): 1.
in some specific embodiments of the invention, the system of the oxidation reaction comprises a TEMPO catalyst, potassium bromide and sodium bicarbonate, and the weight ratio of the TEMPO catalyst to the potassium bromide to the sodium bicarbonate is (0.8-1): 10: 10;
in some specific embodiments of the invention, the weight ratio of the TEMPO catalyst to the compound of formula (II) is (0.028-0.030): 5.
in some specific embodiments of the present invention, the compound represented by formula (II) is reacted with hypochlorite at a temperature of-5 to 0 ℃ for 30 to 60 min.
In some specific embodiments of the present invention, the compound represented by formula (ii) is reacted with sodium hypochlorite in dichloromethane, and the mass concentration of the compound represented by formula (ii) in dichloromethane is 8% to 10%.
In some specific embodiments of the present invention, the method further comprises a step of performing at least one extraction on the prepared compound represented by the formula (i) by using toluene, wherein the volume mass ratio of the total amount of the toluene to the compound represented by the formula (ii) is (60-70) ml: 5g of the total weight.
In some embodiments of the present invention, the intermediate TVP-4 in the reaction feed may be a pure TVP-4 product, or an intermediate TVP-4 product in the TVP production process (i.e., containing some impurities, but having a major component of TVP-4).
In some embodiments of the present invention, the purity of the reaction product obtained by reacting TVP-4 with sodium hypochlorite and TVP-5, an intermediate product in the production process of travoprost, is determined by HPLC conditions:
mobile phase: phase A: water;
phase B: methanol
Gradient elution conditions:
| Time | phase A | Phase B |
| 0 | 40 | 60 |
| 5 | 10 | 90 |
| 15 | 10 | 90 |
| 15.1 | 40 | 60 |
| 25 | 40 | 60 |
A chromatographic column: agilent XDB-C18(150X4.6, 5 μm)
A detector: UV detector
Wavelength: 220nm
Flow rate: 1.0ml/min
Column temperature: 30 deg.C
Preparing a test sample: taking 5mg of a sample to be detected, placing the sample in a 10ml measuring flask, dissolving and diluting the sample to 10ml scales by using methanol, precisely measuring 20uL, injecting the solution into a liquid chromatograph, recording a chromatogram, and calculating according to an area normalization method.
The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
1) Weighing 5.0g of TVP-4 into a 250mL three-neck flask, adding 50mL of dichloromethane (methylene chloride) for dissolving, adding 0.03g of TEMPO (2, 2, 6, 6-tetramethyl piperidine nitrogen oxide), placing in a cold bath at the temperature of-5 ℃, cooling, adding 0.3g of KBr and 0.3g of NaHCO31mL of purified water;
2) when the temperature is reduced to-5 ℃, 4.1g of NaClO solution is dripped, the reaction solution is changed into wine red from colorless and transparent, and the temperature is controlled to-5 ℃ along with obvious heat release;
3) after the dropwise addition, the temperature is controlled to be minus 5 ℃ for heat preservation reaction (monitored by a TLC method);
4) after TLC monitoring material basically reacted, the reaction was stopped, the reaction solution was transferred to a separating funnel, floc was present in the reaction solution, pH was determined to be about 7, and 40mL of 5% Na was added2CO3Shaking the solution to dissolve the floccules, standing for layering, washing the organic layer once by using 30mL of purified water, and combining the water layers;
5) dropwise adding concentrated hydrochloric acid into the water phase to adjust the pH value to 3, adding 30mL of toluene to extract for 2 times, combining organic phases, adding 30g of anhydrous sodium sulfate, standing and drying;
6) after drying, carrying out suction filtration, leaching a filter cake with 30mL of toluene, collecting filtrate, and concentrating the filtrate under reduced pressure at 40 ℃ and-0.1 MPa;
7) after most of the solvent is concentrated and dried, the temperature is reduced at normal temperature, and partial crystals are separated out:
8) and (3) after normal temperature crystallization is carried out for about 3 hours, a large amount of crystals are separated out, suction filtration is carried out, a filter cake is leached by 30mL of ethyl acetate, and the filter cake is dried for 30min after suction filtration to obtain white crystals, wherein the purity is more than 98%, and the yield is 87.5%.
The purity of the product is detected by HPLC, and the purity of the intermediate product TVP-5 is detected at the same time, and the conditions of the high performance liquid chromatography are as follows:
mobile phase: phase A: water;
phase B: methanol
Gradient elution conditions:
| Time | phase A | Phase B |
| 0 | 40 | 60 |
| 5 | 10 | 90 |
| 15 | 10 | 90 |
| 15.1 | 40 | 60 |
| 25 | 40 | 60 |
A chromatographic column: agilent XDB-C18(150X4.6, 5 μm)
A detector: UV detector
Wavelength: 220nm
Flow rate: 1.0ml/min
Column temperature: 30 deg.C
Preparing a test sample: taking 5mg of a sample to be detected, placing the sample in a 10ml measuring flask, dissolving and diluting the sample to 10ml scales by using methanol, precisely measuring 20uL, injecting the solution into a liquid chromatograph, recording a chromatogram, and calculating according to an area normalization method.
The HPLC assay of compounds of formula (I) containing impurities prepared from TVP-4 is shown in FIG. 1,
example 2
1) Weighing 5.0g TVP-4 in a 250mL three-neck flask, adding 55mL DCM for clearing, adding 0.029g TEMPO, placing in a-3 ℃ cold bath for cooling, adding 0.29g KBr, 0.29g NaHCO31mL of purified water;
2) when the temperature is reduced to-3 ℃, 2.7g of NaClO solution is dripped, the reaction solution is changed into wine red from colorless and transparent, and the temperature is controlled to be-3 ℃ along with obvious heat release;
3) after the dropwise addition, the temperature is controlled to be minus 3 ℃ for heat preservation reaction (monitored by a TLC method);
4) after the TLC monitoring material basically reacted, the reaction was stopped, the reaction solution was transferred to a separating funnel, the reaction solution was flocculated and the pH was determined to be about 7, and 40mL of 5% Na was added2CO3Shaking the solution to dissolve the floccules, standing for layering, washing the organic layer once by using 30mL of purified water, and combining the water layers;
5) dropwise adding concentrated hydrochloric acid into the water phase to adjust the pH value to 3, adding 32mL of toluene, extracting for 2 times, combining organic phases, adding 30g of anhydrous sodium sulfate, standing and drying;
6) after drying, carrying out suction filtration, leaching a filter cake with 30mL of toluene, collecting filtrate, and concentrating the filtrate under reduced pressure at 40 ℃ and-0.1 MPa;
7) after most of the solvent is concentrated and dried, the temperature is reduced at normal temperature, and partial crystals are separated out:
8) and (3) after normal temperature crystallization is carried out for about 3 hours, a large amount of crystals are separated out, suction filtration is carried out, a filter cake is leached by 30mL of ethyl acetate, and the filter cake is dried for 30min after suction filtration to obtain white crystals, wherein the purity is more than 98%, and the yield is 87.1%.
The purity of the product is detected by HPLC, and the purity of the intermediate product TVP-5 is detected at the same time, and the conditions of the high performance liquid chromatography are as follows:
mobile phase: phase A: water;
phase B: methanol
Gradient elution conditions:
| Time | phase A | Phase B |
| 0 | 40 | 60 |
| 5 | 10 | 90 |
| 15 | 10 | 90 |
| 15.1 | 40 | 60 |
| 25 | 40 | 60 |
A chromatographic column: agilent XDB-C18(150X4.6, 5 μm)
A detector: UV detector
Wavelength: 220nm
Flow rate: 1.0ml/min
Column temperature: 30 deg.C
Preparing a test sample: taking 5mg of a sample to be detected, placing the sample in a 10ml measuring flask, dissolving the sample by using methanol and diluting the sample to 10ml scales, precisely measuring 20uL, injecting the solution into a liquid chromatograph, recording a chromatogram, and calculating according to an area normalization method.
Example 3
1) Weighing 5.0g TVP-4 in a 250mL three-neck flask, adding 60mL DCM for clearing, adding 0.03g TEMPO, placing in a cooling bath at 0 ℃ for cooling, adding 0.3g KBr and 0.3g NaHCO31mL of purified water;
2) when the temperature is reduced to 0 ℃, 6.8g of NaClO solution is dripped, the reaction solution is changed into wine red from colorless and transparent, and the temperature is controlled to be 0 ℃ along with obvious heat release;
3) after the dropwise addition, controlling the temperature to be 0 ℃ and carrying out heat preservation reaction (monitored by a TLC method);
4) after the TLC monitoring material basically reacted, the reaction was stopped, the reaction solution was transferred to a separating funnel, the reaction solution was flocculated and the pH was determined to be about 7, and 40mL of 5% Na was added2CO3Shaking the solution to dissolve the floccules, standing for layering, washing the organic layer once by using 30mL of purified water, and combining the water layers;
5) dropwise adding concentrated hydrochloric acid into the water phase to adjust the pH value to 2, adding 35mL of toluene for extraction for 2 times, combining organic phases, adding 30g of anhydrous sodium sulfate, standing and drying;
6) after drying, carrying out suction filtration, leaching a filter cake with 30mL of toluene, collecting filtrate, and concentrating the filtrate under reduced pressure at 40 ℃ and-0.1 MPa;
7) after most of the solvent is concentrated and dried, the temperature is reduced at normal temperature, and partial crystals are separated out:
8) and (3) after normal temperature crystallization is carried out for about 3 hours, a large amount of crystals are separated out, suction filtration is carried out, a filter cake is leached by 30mL of ethyl acetate, and the filter cake is dried for 30min after suction filtration to obtain white crystals, wherein the purity is more than 98%, and the yield is 87.5%.
The product is subjected to purity detection by HPLC, and meanwhile, the purity of the intermediate product TVP-5 is detected, and the conditions of high performance liquid chromatography are as follows:
mobile phase: phase A: water;
phase B: methanol
Gradient elution conditions:
a chromatographic column: agilent XDB-C18(150X4.6, 5 μm)
A detector: UV detector
Wavelength: 220nm
Flow rate: 1.0ml/min
Column temperature: 30 deg.C
Preparing a test sample: taking 5mg of a sample to be detected, placing the sample in a 10ml measuring flask, dissolving the sample by using methanol and diluting the sample to 10ml scales, precisely measuring 20uL, injecting the solution into a liquid chromatograph, recording a chromatogram, and calculating according to an area normalization method.
Comparative example 1
Travoprost impurity the compound of formula (I) was prepared according to the method of example 1, except that TEMPO, KBr, NaHCO were added3Are different (e.g., 1:9:9) as shown in table 1, and the product yield and purity are examined.
TABLE 1
| TEMPO：KBr：NaHCO3Mass ratio of | Yield of | Purity 15 |
| 1:9:9 | 72％ | (HPLC)96％ |
| 1:12:12 | 79％ | (HPLC)97％ |
The results show that TEMPO: KBr: NaHCO 23The mass ratio of (A) to (B) is not found by the inventors (0.8-1): 10: within 10, the yield and purity are relatively low.
Comparative example 2
Travoprost impurity compounds of formula (i) were prepared according to the procedure of example 1, except that the reaction temperature was varied as shown in table 2, and the product yield and purity were examined.
TABLE 2
| Reaction temperature/. degree.C | Yield of | Purity of |
| -8 | 62％ | (HPLC)94％ |
| 5 | 75％ | (HPLC)97％ |
The result shows that the decomposition of sodium hypochlorite can be caused by the over-high reaction temperature, so that the compound shown in the formula (II) can not be excessively oxidized, the quality of the generated product is low, and the yield and the purity are reduced; the reaction temperature is too low, the reaction is incomplete, and the yield and the purity are influenced.
Comparative example 3
Travoprost impurity compounds of formula (I) were prepared according to the procedure of example 1, except that the total amount of toluene used was varied in the volume to mass ratio of TVP-4, as shown in Table 3, and the product yield and purity were examined.
TABLE 3
The results show that the toluene dosage is too small, the extraction is incomplete, the product quantity obtained by post-treatment is low, and the yield and the purity do not meet the requirements; too much toluene is used and other impurities are also extracted into the product, resulting in a decrease in yield and purity.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Moreover, various embodiments or examples and features of various embodiments or examples described in this specification can be combined and combined by one skilled in the art without being mutually inconsistent.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (11)
1. A process for the preparation of a compound of formula (i), said process comprising:
1) the compound shown in the formula (II) and hypochlorite are subjected to oxidation reaction to obtain an intermediate A,
2) reacting the intermediate A with hydrochloric acid to obtain a compound shown as a formula (I),
wherein the oxidation reaction is carried out under the catalysis of a TEMPO catalyst.
2. The method of claim 1, wherein the hypochlorite is selected from the group consisting of sodium hypochlorite and potassium hypochlorite.
3. The method according to claim 1, wherein the hypochlorite is sodium hypochlorite, and the molar ratio of the sodium hypochlorite to the compound represented by the formula (II) is (2-5): 1,
optionally, the intermediate A is reacted with hydrochloric acid under the condition that the pH value is 2-3.
4. The method of claim 1, wherein the oxidation reaction system further comprises potassium bromide and sodium bicarbonate.
5. The method according to claim 4, wherein the weight ratio of TEMPO catalyst, potassium bromide and sodium bicarbonate is (0.8-1): 10: 10;
optionally, the weight ratio of the TEMPO catalyst to the compound shown in the formula (II) is (0.028-0.030): 5.
6. the method of claim 1, wherein the compound of formula (II) is reacted with hypochlorite at a temperature of-5 to 0 ℃ for 30 to 60 min.
7. The process according to claim 1, wherein the compound of formula (ii) is reacted with hypochlorite in an organic solvent;
optionally, the organic solvent is dichloromethane.
8. The method according to claim 7, wherein the mass concentration of the compound represented by the formula (II) in dichloromethane is 8-10%.
9. The method according to claim 1, further comprising the step of extracting the produced compound represented by the formula (i) with toluene at least once;
optionally, the volume-to-mass ratio of the total amount of the toluene to the compound shown in the formula (II) is (60-70) ml: 5g of the total weight.
10. A compound prepared by the method of any one of claims 1 to 9, wherein the compound has the structural formula
11. Use of a compound according to claim 9 for the quantitative and qualitative determination of an intermediate product in the production of travoprost, wherein the intermediate product is a compound of formula (iii):
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Citations (2)
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|---|---|---|---|---|
| CN103601708A (en) * | 2013-12-11 | 2014-02-26 | 武汉武药科技有限公司 | Preparation method of prostaglandin medicine impurity |
| CN104297352A (en) * | 2013-07-16 | 2015-01-21 | 天津金耀集团有限公司 | Method of analyzing travoprost content and related compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104297352A (en) * | 2013-07-16 | 2015-01-21 | 天津金耀集团有限公司 | Method of analyzing travoprost content and related compounds |
| CN103601708A (en) * | 2013-12-11 | 2014-02-26 | 武汉武药科技有限公司 | Preparation method of prostaglandin medicine impurity |
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