CN115594647A - New preparation method of Qu Faluo heater - Google Patents
New preparation method of Qu Faluo heater Download PDFInfo
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- CN115594647A CN115594647A CN202110771710.4A CN202110771710A CN115594647A CN 115594647 A CN115594647 A CN 115594647A CN 202110771710 A CN202110771710 A CN 202110771710A CN 115594647 A CN115594647 A CN 115594647A
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- Prior art keywords
- faluo
- key intermediate
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- heater
- synthesis
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 10
- AEIOZWYBDBVCGW-UHFFFAOYSA-N 2-tert-butylaniline Chemical compound CC(C)(C)C1=CC=CC=C1N AEIOZWYBDBVCGW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000005885 boration reaction Methods 0.000 claims abstract description 3
- DUWXVDDCFJIKBU-UHFFFAOYSA-N ethyl 4-[4-(2-acetyloxyethoxy)-3-bromophenyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1C1=CC=C(OCCOC(C)=O)C(Br)=C1 DUWXVDDCFJIKBU-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000026030 halogenation Effects 0.000 claims abstract description 3
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 4
- 235000011056 potassium acetate Nutrition 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 abstract description 5
- 238000004440 column chromatography Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 7
- 239000012535 impurity Substances 0.000 description 6
- 238000009776 industrial production Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 208000002874 Acne Vulgaris Diseases 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229960001727 tretinoin Drugs 0.000 description 3
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 2
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical compound OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 description 2
- MFBCDACCJCDGBA-UHFFFAOYSA-N 4-[3-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)-4-(2-hydroxyethoxy)phenyl]benzoic acid Chemical compound CC(C)(C)C1=CC(C=2C(=CC=C(C=2)C=2C=CC(=CC=2)C(O)=O)OCCO)=CC=C1N1CCCC1 MFBCDACCJCDGBA-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940045997 vitamin a Drugs 0.000 description 2
- -1 2-hydroxy-ethoxy Chemical group 0.000 description 1
- 101001132658 Homo sapiens Retinoic acid receptor gamma Proteins 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- 102100033912 Retinoic acid receptor gamma Human genes 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 description 1
- 229960002916 adapalene Drugs 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 1
- 229960005032 treprostinil Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of trematodine, which uses commercially available 2-tert-butyl aniline as a raw material to obtain a key intermediate (Ia) through halogenation, substitution and Miyaura-Ishiyama boration reaction. The key intermediate (Ia) and common 4' - (2-acetoxy ethoxy) -3' -bromo- [1,1' -biphenyl ] -4-carboxylic acid ethyl ester are used for synthesizing Qu Faluo tin under certain conditions. The preparation method of the invention focuses on synthesizing the key intermediate (Ia), and Qu Faluo statin is prepared by designing different starting materials to obtain a unique intermediate Ia. The method can directly obtain the high-purity Qu Faluo heater without harsh reaction conditions and column chromatography.
Description
Technical Field
The invention relates to a novel preparation method of trefarotene.
Background
Qu Faluo was an RARG agonist, developed by Gaodemei, switzerland under the trade designation Aklief, under the code designation CD-5789. Us FDA approved Qu Faluo tine emulsion for the treatment of acne vulgaris on day 4, 10 months 2019 [1]. Qu Faluo tins was the first retinoid acne vulgaris therapy approved by the FDA in the united states for 20 years. Qu Faluo Tint this time obtained U.S. FDA accelerated approval phase III clinical study (PERFECT 1 study, NCT02566369; PERFECT2 study, NCT 02556788) results based on 2 large randomized, multicenter, double-blind, placebo-controlled. 2420 acne subjects were enrolled in a 2 study, randomized into a treprostinil treatment group and a placebo control group, for a period of 12 weeks, and evaluated for the safety and efficacy of Qu Faluo statin. The research reaches all the main and secondary endpoint indexes, and the trebrogliptin shows good safety and effectiveness. Tretinoin is a class of drugs that are structurally and functionally similar to vitamin a, although the latter generation of tretinoin, such as trifalotan and adapalene, have little structural similarity to vitamin a, but are functionally similar. Due to its unique selective activity, trifartam is considered the first generation of "fourth generation" retinoic acid-this selectivity appears to improve efficacy and reduce side effects compared to older, less selective retinoic acid.
Qu Faluo tin chemical name: 3"-tert-Butyl-4' - (2-hydroxy-ethoxy) -4" -pyrrolidin-1-yl- [1,1',3',1"] tert-phenyl-4-carboxylic acid.
Structural formula thereof
The only methods reported to date for the preparation of Qu Faluo is as follows: (original research compound patent CN 101087752B)
Route: 2-tert-butyl aniline is used as a raw material and is subjected to para-bromination, alkylation and boronization (the boronization step involves ultralow temperature: 70 to 78 DEG below zero) o C) Obtaining an arylboronic acid intermediate (I); carrying out one-step O-alkylation on diphenol (II) serving as a raw material to obtain an intermediate (III); (I) And (III) obtaining (IV) through SuzukiCoppling, and finally hydrolyzing two ester groups step by step to obtain a product (V).
The reaction process involves ultralow temperature reaction, and industrialization and safety are not realized in the production process. Therefore, it is necessary to find a synthetic route which has mild conditions and simple post-treatment and is suitable for industrial production.
Disclosure of Invention
Aiming at the defects of the prior art, the technical scheme provided by the invention is to provide the preparation method of trematodine, which is suitable for industrial production, does not need harsh reaction conditions and is safe. The method has the advantages of high yield, simple and convenient post-treatment, low production cost and suitability for industrial production.
The invention provides a preparation method of trematodine, which uses commercially available 2-tert-butyl aniline as a raw material to obtain a key intermediate (Ia) through halogenation, substitution and Miyaura-Ishiyama boration reaction. The key intermediate (Ia) and common 4' - (2-acetoxy ethoxy) -3' -bromo- [1,1' -biphenyl ] -4-carboxylic acid ethyl ester are used for synthesizing Qu Faluo tin under certain conditions. The preparation method of the invention focuses on synthesizing the key intermediate (Ia), and Qu Faluo statin is prepared by designing different starting materials to obtain a unique intermediate Ia. The method can directly obtain the high-purity Qu Faluo heater without harsh reaction conditions and column chromatography.
The synthesis route is as follows:
in the first step of the synthesis of the key intermediate (Ia), the halogenating agent is I 2 ,Br 2 HBr, HI, preferably one of them.
In the third step of synthesizing the key intermediate (Ia), the alkaline reagent is preferably potassium carbonate and potassium acetate.
In the third step of the synthesis of the key intermediate (Ia), the catalyst is preferably Pd 2 (dba) 3 ，Pd(dppf)Cl 2 。
The preparation method provided by the invention has the advantages of mild conditions, suitability for industrial production, no need of ultralow temperature reaction, simple post-treatment and high purity. 5363 the total impurity of Qu Faluo is less than 0.3%, and the single impurity is less than 0.1%, which reaches the grade of raw material drug (API), and is suitable for industrial production. The invention relates to a green synthesis process.
Detailed Description
The present patent is further illustrated below by way of examples, without thereby restricting the invention to the scope of the examples described.
Experimental procedures without specific conditions are not shown in the following examples, and are selected according to conventional procedures and conditions, or according to the commercial instructions.
Example 1
The preparation method of Qu Faluo heater comprises the following process steps
2-tert-butylaniline (100.0 g, 0.670mol) and 800 ml dichloromethane were charged into a three-necked flask, sodium hydrogencarbonate (140.7 g,1.675 mol) stirring was started. Under the condition of ice-water bath, adding iodine simple substance (340.1g, 1.340 mol) into the system in batches, reacting for 10 hours in the ice-water bath, and adding water to quench after the reaction is finished. Separating, extracting the water phase with dichloromethane twice, collecting the organic phase, adding anhydrous Na 2 SO 4 Drying for 2 hours. Filtering, removing anhydrous Na 2 SO 4 The filtrate was concentrated at 50 ℃ to give 166.0g of the desired product as a light brown solid with a yield of 90.0%. The product obtained is subsequently cyclized with 1.2 equivalents of 1,4-dibromobutane to give 103.2g of the expected compound, which is taken up in 22.9g of Pd (dppf) Cl in DMF as solvent 2 36.9g of potassium acetate is added as a catalyst to be butted with B2pin2 to obtain 72.3g of a key intermediate Ia72. And carrying out suziki coupling and hydrolysis on the key intermediate Ia and III to obtain a target product Qu Faluo statin, wherein HPLC (high performance liquid chromatography) is 99.82%, single impurities are less than 0.1%, and total impurities are less than 0.3%.
Example 2
2-Tert-butylaniline (100.0 g, 0.670mol) and 800 ml dichloromethane were added to a three-necked flask, and sodium bicarbonate (140.7g, 1.675mol) was added thereto to start stirring. Under the condition of ice-water bath, adding iodine simple substance (340.1g, 1.340 mol) into the system in batches, reacting for 10 hours in the ice-water bath, and adding water to quench after the reaction is finished. Separating, extracting the water phase with dichloromethane twice, collecting the organic phase, adding anhydrous Na 2 SO 4 Drying for 2 hours. Filtering, removing anhydrous Na 2 SO 4 The filtrate was concentrated at 50 ℃ to give 166.0g of the desired product as a light brown solid with a yield of 90.0%. The product obtained is subsequently cyclized with 1.2 equivalents of 1,4-dibromobutane to give 103.2g of the expected compound, followed by 14.4g Pd in DMF solvent 2 (dba) 3 36.9g of potassium acetate was added as a catalyst and docked with B2pin2 to give 78g of key intermediate Ia. And carrying out suziki coupling and hydrolysis on the key intermediate Ia and III to obtain a target product Qu Faluo statin, wherein HPLC is 99.80%, single impurity is less than 0.1%, and total impurity is less than 0.3%.
Claims (4)
1. A preparation method of Qu Faluo heater is characterized by comprising the following steps: the preparation method is prepared by the following synthetic route: the key intermediate (Ia) is obtained by using commercially available 2-tert-butyl aniline as a raw material and performing halogenation, substitution and Miyaura-Ishiyama boration reaction. The key intermediate (Ia) and common 4' - (2-acetoxy ethoxy) -3' -bromo- [1,1' -biphenyl ] -4-carboxylic acid ethyl ester are used for synthesizing Qu Faluo tin under certain conditions.
2. The process according to claim 1, wherein in the first step of the synthesis of the key intermediate (Ia), the halogenating agent is I 2 ,Br 2 HBr, HI, preferably one of them.
3. The process according to claim 1, wherein in the third step of the synthesis of key intermediate (Ia), the basic reagent is preferably potassium carbonate, potassium acetate.
4. The process according to claim 1, wherein in the third step of the synthesis of the key intermediate (Ia), the catalyst is preferably Pd 2 (dba) 3 ，Pd(dppf)Cl 2 。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110771710.4A CN115594647A (en) | 2021-07-08 | 2021-07-08 | New preparation method of Qu Faluo heater |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110771710.4A CN115594647A (en) | 2021-07-08 | 2021-07-08 | New preparation method of Qu Faluo heater |
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| Publication Number | Publication Date |
|---|---|
| CN115594647A true CN115594647A (en) | 2023-01-13 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110771710.4A Pending CN115594647A (en) | 2021-07-08 | 2021-07-08 | New preparation method of Qu Faluo heater |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN119335104A (en) * | 2024-12-20 | 2025-01-21 | 上海瑞替诺医药科技有限公司 | Detection Methods of Related Substances in Trifarotene API |
-
2021
- 2021-07-08 CN CN202110771710.4A patent/CN115594647A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN119335104A (en) * | 2024-12-20 | 2025-01-21 | 上海瑞替诺医药科技有限公司 | Detection Methods of Related Substances in Trifarotene API |
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