CN105152925A - Synthesis method of ciprofibrate - Google Patents
Synthesis method of ciprofibrate Download PDFInfo
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- CN105152925A CN105152925A CN201510644979.0A CN201510644979A CN105152925A CN 105152925 A CN105152925 A CN 105152925A CN 201510644979 A CN201510644979 A CN 201510644979A CN 105152925 A CN105152925 A CN 105152925A
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- CN
- China
- Prior art keywords
- dichloro cyclopropyl
- reaction
- acetic acid
- synthesis method
- raw material
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- KPSRODZRAIWAKH-UHFFFAOYSA-N ciprofibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1C1C(Cl)(Cl)C1 KPSRODZRAIWAKH-UHFFFAOYSA-N 0.000 title claims abstract description 12
- KPSRODZRAIWAKH-JTQLQIEISA-N Ciprofibrate Natural products C1=CC(OC(C)(C)C(O)=O)=CC=C1[C@H]1C(Cl)(Cl)C1 KPSRODZRAIWAKH-JTQLQIEISA-N 0.000 title abstract 4
- 238000001308 synthesis method Methods 0.000 title abstract 4
- 229960002174 ciprofibrate Drugs 0.000 title abstract 3
- 239000002994 raw material Substances 0.000 claims abstract description 16
- 238000006136 alcoholysis reaction Methods 0.000 claims abstract description 11
- KOJAPEXFANADPV-UHFFFAOYSA-N [4-(2,2-dichlorocyclopropyl)phenyl] acetate Chemical compound C1=CC(OC(=O)C)=CC=C1C1C(Cl)(Cl)C1 KOJAPEXFANADPV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000010189 synthetic method Methods 0.000 claims description 9
- IUXIOXCOPJFKMQ-UHFFFAOYSA-N 2-bromo-4-methylpentane Chemical compound CC(C)CC(C)Br IUXIOXCOPJFKMQ-UHFFFAOYSA-N 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- JCHIUDLMOJNKRT-UHFFFAOYSA-N 4-(2,2-dichlorocyclopropyl)phenol Chemical compound C1=CC(O)=CC=C1C1C(Cl)(Cl)C1 JCHIUDLMOJNKRT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 abstract description 14
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract 1
- 230000029936 alkylation Effects 0.000 abstract 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- 238000000034 method Methods 0.000 abstract 1
- 239000002904 solvent Substances 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 235000015320 potassium carbonate Nutrition 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 239000001117 sulphuric acid Substances 0.000 description 3
- 235000011149 sulphuric acid Nutrition 0.000 description 3
- UAJRSHJHFRVGMG-UHFFFAOYSA-N 1-ethenyl-4-methoxybenzene Chemical compound COC1=CC=C(C=C)C=C1 UAJRSHJHFRVGMG-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical class OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
- C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of ciprofibrate. In the synthesis method, acetic acid-4-(2,2-dichlorocyclopropyl) phenyl ester is adopted as a raw material, and 2-[4-(2,2-dichlorocyclopropyl) phenoxy]-2-methylpropanoic acid is obtained through alcoholysis, alkylation and alkaline hydrolysis processes. The synthesis method of ciprofibrate, provided by the invention, has the benefits that the raw materials used in the whole reaction are inexpensive and easy to get, the reaction conditions are mild, the operation is convenient, the yield is good, all solvents used in the reaction can be recycled, and the environmental pollution degree is low.
Description
Technical field
The present invention relates to a kind of synthetic method of Win-35833.
Background technology
Win-35833 is phenoxy acetic acid class hypolipidemic, chemistry 2-[4-(2 by name, 2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid, researched and developed by French Synthelabo company, clinical in failing II type that controls and IV type hyperlipoproteinemia through sitotherapy.
Existing synthetic method is initial action raw material with 1-phenyl-2,2-bis-Cyclopropanoyl Chloride, 1-phenyl-2,2-bis-Cyclopropanoyl Chloride or 4-methoxy styrene, and the yield that there is key intermediate is on the low side, and the amplification of nitration reaction is produced exists very large operational safety risk; Yield and the quality of compound are low; Starting raw material is expensive and market supply rare, and its less stable, easily the problems such as polymerization occurs.
Therefore, need to improve existing synthetic method and synthetic technology, improve yield and the quality of product, make reaction conditions gentleer simultaneously, operate more controlled.
Summary of the invention
The technical problem to be solved in the present invention is: based on the problems referred to above, the invention provides a kind of synthetic method of Win-35833.
The present invention solves the technical scheme that its technical problem adopts: a kind of synthetic method of Win-35833, comprises the following steps for raw material with acetic acid-4-(2,2-dichloro cyclopropyl) phenyl ester:
(1) alcoholysis reaction: in the basic conditions, alcoholysis reaction obtains 4-(2,2-dichloro cyclopropyl) phenol for acetic acid-4-(2,2-dichloro cyclopropyl) phenyl ester and methyl alcohol;
(2) in the basic conditions, alkylation reaction obtains 2-[4-(2,2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid ethyl ester for alkylation reaction: 4-(2,2-dichloro cyclopropyl) phenol and isobutyl ethyl bromide;
(3) in the basic conditions, Basic fluxing raction obtains 2-[4-(2,2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid to Basic fluxing raction: 2-[4-(2,2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid ethyl ester.
Further, in step (1), the mol ratio of acetic acid-4-(2,2-dichloro cyclopropyl) phenyl ester and alkali is 1:0.3 ~ 1:0.6.
Further, in step (2), the mol ratio of isobutyl ethyl bromide and alkali is (0.9 ~ 1.1): (1 ~ 1.5).
The invention has the beneficial effects as follows: raw materials used cheap and easy to get, the mild condition of whole reaction, easy to operate, yield good; The equal recoverable of reaction solvent for use, environmental is low.
Embodiment
The invention will be further described in conjunction with specific embodiments now, and following examples are intended to the present invention instead of limitation of the invention further are described.
Embodiment 1
Alcoholysis reaction: drop into 1mol acetic acid-4-(2,2-dichloro cyclopropyl) phenyl ester, 300g methyl alcohol, 0.3mol salt of wormwood in 1L reaction flask, 20 DEG C are reacted 10 hours, and in HPLC, control is without raw material, and concentrating under reduced pressure obtains oily matter about 250g.
Alkylation reaction: drop into 1.8mol isobutyl ethyl bromide, 2mol salt of wormwood, 600g alcoholysis product in the clean reaction flask of 2L, temperature rising reflux reacts 24 hours, controls raw material <1% in HPLC, is cooled to 50 DEG C, add water 900g, separate organic layer.
Basic fluxing raction: add 400g water in organic layer, drips 400g30% liquid caustic soda, 15 DEG C of insulation reaction 1.5 hours, in HPLC, control is without raw material, and 30 DEG C drip dilute sulphuric acid 500g, adjust PH=2.0, separate organic layer, concentrating under reduced pressure, add sherwood oil 300g, analysis of material, suction filtration, centrifugal, dry to obtain 270g crude product, final product 240g is obtained, HPLC>99% again, fusing point 118-119 DEG C with normal hexane recrystallization.
Embodiment 2
Alcoholysis reaction: drop into 1mol acetic acid-4-(2,2-dichloro cyclopropyl) phenyl ester, 300g methyl alcohol, 0.5mol salt of wormwood in 1L reaction flask, 30 DEG C are reacted 11 hours, and in HPLC, control is without raw material, and concentrating under reduced pressure obtains oily matter about 255g.
Alkylation reaction: drop into 2mol isobutyl ethyl bromide, 2.5mol salt of wormwood, 600g alcoholysis product in the clean reaction flask of 2L, temperature rising reflux reacts 24 hours, controls raw material <1% in HPLC, is cooled to 50 DEG C, add water 900g, separate organic layer.
Basic fluxing raction: add 400g water in organic layer, drips 400g30% liquid caustic soda, 25 DEG C of insulation reaction 2 hours, in HPLC, control is without raw material, and 40 DEG C drip dilute sulphuric acid 500g, adjust PH=2.0, separate organic layer, concentrating under reduced pressure, add sherwood oil 300g, analysis of material, suction filtration, centrifugal, dry to obtain 280g crude product, final product 250g is obtained, HPLC>99% again, fusing point 118-119 DEG C with normal hexane recrystallization.
Embodiment 3
Alcoholysis reaction: drop into 1mol acetic acid-4-(2,2-dichloro cyclopropyl) phenyl ester, 300g methyl alcohol, 0.6mol salt of wormwood in 1L reaction flask, 40 DEG C are reacted 12 hours, and in HPLC, control is without raw material, and concentrating under reduced pressure obtains oily matter about 250g.
Alkylation reaction: drop into 2.2mol isobutyl ethyl bromide, 3mol salt of wormwood, 600g alcoholysis product in the clean reaction flask of 2L, temperature rising reflux reacts 24 hours, controls raw material <1% in HPLC, is cooled to 50 DEG C, add water 900g, separate organic layer.
Basic fluxing raction: add 400g water in organic layer, drips 400g30% liquid caustic soda, 30 DEG C of insulation reaction 3 hours, in HPLC, control is without raw material, and 50 DEG C drip dilute sulphuric acid 500g, adjust PH=2.0, separate organic layer, concentrating under reduced pressure, add sherwood oil 300g, analysis of material, suction filtration, centrifugal, dry to obtain 275g crude product, final product 243g is obtained, HPLC>99% again, fusing point 118-119 DEG C with normal hexane recrystallization.
With above-mentioned according to desirable embodiment of the present invention for enlightenment, by above-mentioned description, relevant staff in the scope not departing from this invention technological thought, can carry out various change and amendment completely.The technical scope of this invention is not limited to the content on specification sheets, must determine its technical scope according to right.
Claims (3)
1. a synthetic method for Win-35833, is characterized in that:, comprise the following steps for raw material with acetic acid-4-(2,2-dichloro cyclopropyl) phenyl ester:
(1) alcoholysis reaction: in the basic conditions, alcoholysis reaction obtains 4-(2,2-dichloro cyclopropyl) phenol for acetic acid-4-(2,2-dichloro cyclopropyl) phenyl ester and methyl alcohol;
(2) in the basic conditions, alkylation reaction obtains 2-[4-(2,2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid ethyl ester for alkylation reaction: 4-(2,2-dichloro cyclopropyl) phenol and isobutyl ethyl bromide;
(3) in the basic conditions, Basic fluxing raction obtains 2-[4-(2,2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid to Basic fluxing raction: 2-[4-(2,2-dichloro cyclopropyl) phenoxy group]-2 Methylpropionic acid ethyl ester.
2. the synthetic method of Win-35833 according to claim 1, is characterized in that: in described step (1), the mol ratio of acetic acid-4-(2,2-dichloro cyclopropyl) phenyl ester and alkali is 1:0.3 ~ 1:0.6.
3. the synthetic method of Win-35833 according to claim 1, is characterized in that: in described step (2), the mol ratio of isobutyl ethyl bromide and alkali is (0.9 ~ 1.1): (1 ~ 1.5).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510644979.0A CN105152925B (en) | 2015-10-08 | 2015-10-08 | The synthetic method of ciprofibrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510644979.0A CN105152925B (en) | 2015-10-08 | 2015-10-08 | The synthetic method of ciprofibrate |
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| Publication Number | Publication Date |
|---|---|
| CN105152925A true CN105152925A (en) | 2015-12-16 |
| CN105152925B CN105152925B (en) | 2017-12-01 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3948973A (en) * | 1972-08-29 | 1976-04-06 | Sterling Drug Inc. | Halocyclopropyl substituted phenoxyalkanoic acids |
| CN1514819A (en) * | 2001-05-08 | 2004-07-21 | ���ʻ�ѧʵ��������˾ | 2-[4-2,2-dihalocyclopropyl)phenoxy]-alkanoic acids and exters thereof production process |
| CN103613498A (en) * | 2013-11-20 | 2014-03-05 | 浙江三门恒康制药有限公司 | Synthetic method of ciprofibrate |
-
2015
- 2015-10-08 CN CN201510644979.0A patent/CN105152925B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3948973A (en) * | 1972-08-29 | 1976-04-06 | Sterling Drug Inc. | Halocyclopropyl substituted phenoxyalkanoic acids |
| CN1514819A (en) * | 2001-05-08 | 2004-07-21 | ���ʻ�ѧʵ��������˾ | 2-[4-2,2-dihalocyclopropyl)phenoxy]-alkanoic acids and exters thereof production process |
| CN103613498A (en) * | 2013-11-20 | 2014-03-05 | 浙江三门恒康制药有限公司 | Synthetic method of ciprofibrate |
Non-Patent Citations (1)
| Title |
|---|
| 李景锋等: "环丙贝特的合成", 《沈阳药科大学学报》 * |
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| CN105152925B (en) | 2017-12-01 |
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Effective date of registration: 20181228 Address after: 310018 Building 3A07-3A10, 452 No. 6 Street, Baiyang Street, Hangzhou Economic and Technological Development Zone, Zhejiang Province Patentee after: HANGZHOU LUPU BIOTECHNOLOGY CO., LTD. Address before: 213000 Houyang Chemical Park No. 20, Jintan City, Changzhou City, Jiangsu Province Patentee before: CHANGZHOU QIANGDA BAOCHENG CHEMICAL ENGINEERING CO., LTD. |