CN114907204A - Synthesis method of piparidic acid - Google Patents
Synthesis method of piparidic acid Download PDFInfo
- Publication number
- CN114907204A CN114907204A CN202110181136.7A CN202110181136A CN114907204A CN 114907204 A CN114907204 A CN 114907204A CN 202110181136 A CN202110181136 A CN 202110181136A CN 114907204 A CN114907204 A CN 114907204A
- Authority
- CN
- China
- Prior art keywords
- carbonyl
- reaction
- acid
- dibromo
- nonane
- 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.)
- Pending
Links
- 239000002253 acid Substances 0.000 title claims abstract description 25
- 238000001308 synthesis method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 claims abstract description 24
- OXFXXHVVEWTMHA-UHFFFAOYSA-N O=C=C(CCCCBr)CCCCBr Chemical compound O=C=C(CCCCBr)CCCCBr OXFXXHVVEWTMHA-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 8
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 claims abstract description 7
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000007858 starting material Substances 0.000 claims abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 5
- 238000005893 bromination reaction Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- -1 carbonyl-protected 1, 9-dibromo-5-carbonyl nonane Chemical class 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- ULKFLOVGORAZDI-UHFFFAOYSA-N 3,3-dimethyloxetan-2-one Chemical compound CC1(C)COC1=O ULKFLOVGORAZDI-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 150000004795 grignard reagents Chemical class 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 3
- 238000010511 deprotection reaction Methods 0.000 abstract description 3
- 238000003747 Grignard reaction Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 241001425800 Pipa Species 0.000 abstract 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- WDAXFOBOLVPGLV-UHFFFAOYSA-N ethyl isobutyrate Chemical compound CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 4
- 238000004321 preservation Methods 0.000 description 3
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 3
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HYHMLYSLQUKXKP-UHFFFAOYSA-N bempedoic acid Chemical compound OC(=O)C(C)(C)CCCCCC(O)CCCCCC(C)(C)C(O)=O HYHMLYSLQUKXKP-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- TVQGDYNRXLTQAP-UHFFFAOYSA-N heptanoic acid ethyl ester Natural products CCCCCCC(=O)OCC TVQGDYNRXLTQAP-UHFFFAOYSA-N 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 108010036824 Citrate (pro-3S)-lyase Proteins 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 229950002974 bempedoic acid Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- SYRIIFZUZOIRNU-UHFFFAOYSA-N ethyl 7-bromo-2,2-dimethylheptanoate Chemical compound CCOC(=O)C(C)(C)CCCCCBr SYRIIFZUZOIRNU-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/367—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/16—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- 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
Abstract
The invention discloses a synthesis method of pipa acid, which provides a method that cheap 1, 5-valerolactone is used as a starting material, 1, 7-dioxa [5.5] undecane is generated under the action of sodium ethoxide, 1, 9-dibromo-5-carbonyl nonane is prepared through bromination reaction, 1, 9-dibromo-5-carbonyl nonane is subjected to carbonyl protection, Grignard reaction and 3, 3-dimethyloxy heterocyclic butane-2-ketone reaction are utilized to prepare a target compound pipa acid after deprotection and reduction, the process route is simple, the problem of reaction selectivity of the starting material is solved, and the production cost is reduced.
Description
Technical Field
The invention belongs to the field of new synthesis methods of small molecular chemical drugs, and particularly relates to synthesis of pipadiric acid.
Background
Bipedac acid is an adenosine triphosphate citrate lyase (ACL) inhibitor that reduces low density lipoprotein cholesterol (LDL-C) by inhibiting cholesterol synthesis in the liver and has the chemical structure:
the main synthetic route of the currently reported biparidic acid in the literature is as follows:
ethyl isobutyrate and 1, 5-dibromopentane are used as initial raw materials, and are condensed by Lithium Diisopropylamide (LDA) at low temperature to obtain ethyl 7-bromo-2, 2-dimethylheptanoate; under the strong alkaline condition, 7-bromine-2, 2-dimethyl ethyl heptanoate is used as an alkylating reagent to react with p-methyl benzenesulfonyl methyl isonitrile (TosMIC) to prepare bis (2, 2-dimethyl ethyl heptanoate) substituted p-methyl benzenesulfonyl methyl isonitrile by catalysis of tetrabutylammonium iodide (TBAI); then hydrolyzing under an acidic condition to obtain 8-carbonyl-2, 2,14, 14-tetramethyl pentadecane diacid diethyl ester; hydrolyzing 8-carbonyl-2, 2,14, 14-tetramethyl pentadecanedioic acid diethyl ester in an ethanol system to obtain 8-carbonyl-2, 2,14, 14-tetramethyl pentadecanedioic acid; and reducing by NaBH4 to obtain the target product, i.e. bempedoic acid. However, the starting materials of the method, namely ethyl isobutyrate and 1, 5-dibromopentane, inevitably generate a disubstituted diethyl 2,2,8, 8-tetramethyl-nonanedioate (the structure is shown as follows) under the action of LDA,
the raw materials are wasted greatly, LDA ultralow temperature reaction is used in the synthesis step, the synthesis method is complex, the cost is high, and industrial production is not easy to realize. It would therefore be desirable to provide a new process for the preparation of 8-hydroxy-2, 2,14, 14-tetramethyl-pentadecanedioic acid.
Disclosure of Invention
So far, the literature reports that the route is difficult to realize industrial large-scale production at ultralow temperature, the waste of starting materials is large, the production cost is high, a brand new synthetic route is designed for solving the technical problems, and the invention aims to provide a synthetic method of the pipadiric acid.
The invention relates to a synthesis method of pipadiric acid, which comprises the following steps:
step 1: 1, 5-valerolactone is used as a starting material to generate 1, 7-dioxa [5.5] undecane under the action of sodium ethoxide;
and 2, step: preparing 1, 9-dibromo-5-carbonyl nonane through bromination reaction;
and step 3: 1, 9-dibromo-5-carbonyl nonane is protected by carbonyl;
and 4, step 4: and 3, reacting the Grignard reagent prepared in the step 3 with 3, 3-dimethyloxetan-2-one, and carrying out deprotection and reduction on a product to prepare the target compound, namely the bipartite acid.
The invention relates to a synthesis method of biparidic acid, which comprises the following steps of:
adding ethanol and sodium ethoxide into a reaction container, controlling the temperature to be 0 ℃, slowly dropwise adding an ethanol solution of 1, 5-valerolactone, heating and refluxing after the addition is finished, carrying out heat preservation reaction for 5 hours, acidifying with 5% hydrochloric acid after the reaction is finished, then continuously refluxing, distilling with steam after the reaction is finished, and carrying out distillation, distillation and drying to obtain the 1, 7-di-cyclone oxa [5.5] undecane.
The invention relates to a synthesis method of pimelic acid, which comprises the following steps of:
adding 1, 7-dioxane [5.5] undecane and 48% hydrobromic acid into a reaction vessel, heating and refluxing, extracting with dichloromethane after the reaction is finished, washing the extract with sodium bicarbonate, drying, and concentrating under reduced pressure to obtain the 1, 9-dibromo-5-carbonyl nonane.
The synthesis method of the besmead acid comprises the following steps of 3, preparing 1, 9-dibromo-5-carbonyl nonane protected by carbonyl:
adding 1, 9-dibromo-5-carbonyl nonane, ethylene glycol, toluene and p-toluenesulfonic acid into a reaction vessel, heating up, refluxing and dehydrating after the addition is finished, and concentrating under reduced pressure after the reaction is finished to obtain the 1, 9-dibromo-5-carbonyl nonane protected by the ethylene glycol as an oily substance.
The invention relates to a synthesis method of pipadiric acid, which comprises the following steps in step 4:
adding 1, 9-dibromo-5-carbonyl nonane protected by ethylene glycol, anhydrous tetrahydrofuran, metal magnesium, protecting nitrogen, carrying out a slight heat trigger reaction, cooling to 0 ℃ after magnesium disappears, adding cuprous chloride, then dropwise adding a tetrahydrofuran solution of 3, 3-dimethyloxetan-2-one at a controlled temperature, carrying out a heat preservation reaction after the addition is finished, quenching by using 3N dilute hydrochloric acid after the reaction is finished, then extracting for three times by using a 3N sodium hydroxide aqueous solution, combining water phases, acidifying by using concentrated hydrochloric acid, filtering, and drying to obtain 8-carbonyl-2, 2,14, 14-tetramethylpentadecanedioic acid;
adding 8-carbonyl-2, 2,14, 14-tetramethylpentadecanedioic acid and methanol into a reaction vessel, stirring and cooling to 0 ℃, slowly adding sodium borohydride at controlled temperature, stirring at controlled temperature, slowly dropwise adding 2N diluted hydrochloric acid after the reaction is finished, extracting with dichloromethane, taking a water layer, adjusting the pH value to 1, extracting with methyl tert-butyl ether, taking an organic phase, combining the organic phases, drying, and concentrating under reduced pressure to obtain a solid, namely the bipedal acid.
The invention relates to a synthesis method of piparidic acid, which comprises the following steps:
the process uses cheap 1, 5-valerolactone as a starting material, generates 1, 7-di-cyclone oxa [5.5] undecane under the action of sodium ethoxide, prepares 1, 9-dibromo-5-carbonyl nonane through bromination reaction, reacts the 1, 9-dibromo-5-carbonyl nonane with 3, 3-dimethyloxetane-2-one through Grignard reaction after carbonyl protection, and prepares the target compound, namely the bipartite acid through deprotection and reduction.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following detailed description is given with reference to the preferred embodiments of the present invention and the accompanying drawings.
Drawings
FIG. 1 is a scheme of synthesis according to the present invention.
Detailed Description
The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the invention, but are not intended to limit the scope of the invention.
Example 1) preparation of 1, 7-Dioxa [5.5] undecane
1000ml of ethanol and sodium ethoxide (68g, 1mol) are added into a 2000ml three-neck flask, the temperature is controlled to be 0 ℃, 300ml of ethanol solution of 1, 5-valerolactone (200g, 2mol) is slowly dripped, the temperature is raised and the reflux is finished, the temperature is kept for 5 hours for reaction, the reaction is finished and acidified by 5 percent hydrochloric acid, then the reflux is continued for 30 minutes, after the reaction is finished, steam distillation is carried out, the fraction is dried by anhydrous magnesium sulfate, and 120g1, 7-dioxa-oxa [5.5] undecane is prepared, the yield is 77 percent.
Example 2) preparation of 1, 9-dibromo-5-carbonylnonane
Into a 1000ml three-necked flask, 1, 7-dioxa [5.5] undecane (31.2g, 0.2mol) and 500ml of 48% hydrobromic acid were added, and the mixture was refluxed at elevated temperature for 15min, then extracted with dichloromethane after completion of the reaction, and the extract was washed with sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 40g of 1, 9-dibromo-5-carbonyl nonane with a yield of 67%.
Example 3) preparation of ethylene glycol protected 1, 9-dibromo-5-carbonyl nonane
1, 9-dibromo-5-carbonyl nonane (15g, 0.05mol), ethylene glycol (3.4g, 0.055mol), toluene (300 ml) and p-toluenesulfonic acid (0.2 g) were added to a 500ml three-necked flask, and after completion of the reaction, reflux dehydration was performed at elevated temperature for 5 hours, followed by concentration under reduced pressure to obtain an oily ethylene glycol-protected 1, 9-dibromo-5-carbonyl nonane (16.0 g, 94% yield).
Example 4) preparation of 8-carbonyl-2, 2,14, 14-tetramethylpentadecanedioic acid
Adding 1, 9-dibromo-5-carbonyl nonane (34.1g, 0.1mol) protected by ethylene glycol, 300ml of anhydrous tetrahydrofuran, 4.8g of metal magnesium, protecting by nitrogen, carrying out a slight heat triggering reaction, cooling to 0 ℃ after magnesium disappears, adding 200mg of cuprous chloride, controlling the temperature, dropwise adding 100ml of tetrahydrofuran solution of 3, 3-dimethyloxetan-2-one (25g, 0.25mol), carrying out a heat preservation reaction for 2 hours, carrying out extraction and extinguishment by 3N diluted hydrochloric acid after the reaction is finished, extracting three times by 200ml of sodium hydroxide aqueous solution of 3N, combining aqueous phases, acidifying by concentrated hydrochloric acid, filtering, and drying to obtain 22.2g of 8-carbonyl-2, 2,14, 14-tetramethyl pentadecanedioic acid with the yield of 65%.
Example 5) preparation of Pataric acid
Adding 8-carbonyl-2, 2,14, 14-tetramethylpentadecanedioic acid (17.1g, 0.05mol) and 500ml of methanol into a 1000ml three-neck flask, stirring and cooling to 0 ℃, slowly adding sodium borohydride (9.5g, 0.25mol) at controlled temperature, stirring at controlled temperature for 20 hours, after the reaction is finished, slowly dropwise adding 2N diluted hydrochloric acid to extract and kill, extracting with dichloromethane, taking a water layer, adjusting the pH to 1, then extracting with methyl tert-butyl ether, taking organic phases, combining the organic phases, drying with anhydrous magnesium sulfate, concentrating under reduced pressure to obtain 13.2g of white solid, namely the besmead acid, and obtaining the yield of 77%.
The synthetic route is shown in figure 1.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (6)
1. A synthesis method of pipidic acid, which is characterized by comprising the following steps:
step 1: 1, 5-valerolactone is used as a starting material to generate 1, 7-di-cyclone oxa [5.5] undecane under the action of sodium ethoxide;
step 2: preparing 1, 9-dibromo-5-carbonyl nonane through bromination reaction;
and 3, step 3: the 1, 9-dibromo-5-carbonyl nonane is protected by carbonyl;
and 4, step 4: the Grignard reagent prepared in the step 3 reacts with 3, 3-dimethyl oxetan-2-one, and the target compound, the beipai diacid, is prepared after the product is deprotected and reduced.
2. The method for synthesizing pipadiric acid according to claim 1, wherein the preparation steps of 1, 7-dioxa [5.5] undecane are as follows:
adding ethanol and sodium ethoxide into a reaction container, controlling the temperature to be 0 ℃, slowly dropwise adding an ethanol solution of 1, 5-valerolactone, heating and refluxing after the addition is finished, keeping the temperature for reaction for 5 hours, acidifying with 5% hydrochloric acid after the reaction is finished, then continuously refluxing, distilling with steam after the reaction is finished, and distilling and drying to obtain the 1, 7-dioxaoxa [5.5] undecane.
3. The synthesis method of the besmead acid as claimed in claim 2, wherein the preparation steps of the 1, 9-dibromo-5-carbonyl nonane are as follows:
adding the 1, 7-dioxa [5.5] undecane and 48% hydrobromic acid into a reaction vessel, heating and refluxing, extracting with dichloromethane after the reaction is finished, washing an extract by sodium bicarbonate, drying, and concentrating under reduced pressure to obtain the 1, 9-dibromo-5-carbonyl nonane.
4. The method for synthesizing the besmead acid according to claim 3, wherein the step 3 for preparing the carbonyl-protected 1, 9-dibromo-5-carbonyl nonane comprises the following steps:
adding 1, 9-dibromo-5-carbonyl nonane, ethylene glycol, toluene and p-toluenesulfonic acid into a reaction vessel, heating up, refluxing and dehydrating after the addition is finished, and concentrating under reduced pressure after the reaction is finished to obtain the 1, 9-dibromo-5-carbonyl nonane protected by the ethylene glycol as an oily substance.
5. The method for synthesizing pipidilic acid according to claim 4, wherein the step 4 comprises the following steps:
adding 1, 9-dibromo-5-carbonyl nonane protected by ethylene glycol, anhydrous tetrahydrofuran, metal magnesium, protecting nitrogen, triggering reaction by slight heat, cooling to 0 ℃ after magnesium disappears, adding cuprous chloride, dropwise adding a tetrahydrofuran solution of 3, 3-dimethyloxetan-2-one at a controlled temperature, keeping the temperature for reaction, quenching by using 3N diluted hydrochloric acid after the reaction is finished, extracting for three times by using a 3N sodium hydroxide aqueous solution, combining aqueous phases, acidifying by using concentrated hydrochloric acid, filtering, and drying to obtain 8-carbonyl-2, 2,14, 14-tetramethylpentadecanedioic acid;
adding 8-carbonyl-2, 2,14, 14-tetramethylpentadecanedioic acid and methanol into a reaction vessel, stirring and cooling to 0 ℃, slowly adding sodium borohydride at controlled temperature, stirring at controlled temperature, slowly dropwise adding 2N diluted hydrochloric acid after the reaction is finished, extracting with dichloromethane, taking a water layer, adjusting the pH value to 1, extracting with methyl tert-butyl ether, taking an organic phase, combining the organic phases, drying, and concentrating under reduced pressure to obtain a solid, namely the bipedal acid.
6. The synthesis method of the besmead acid as claimed in claim 1, wherein the synthesis route is as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110181136.7A CN114907204A (en) | 2021-02-07 | 2021-02-07 | Synthesis method of piparidic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110181136.7A CN114907204A (en) | 2021-02-07 | 2021-02-07 | Synthesis method of piparidic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114907204A true CN114907204A (en) | 2022-08-16 |
Family
ID=82761815
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110181136.7A Pending CN114907204A (en) | 2021-02-07 | 2021-02-07 | Synthesis method of piparidic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114907204A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106748723A (en) * | 2016-12-07 | 2017-05-31 | 江苏工程职业技术学院 | A kind of preparation method of Ketoprofen |
| US20170320902A1 (en) * | 2014-11-18 | 2017-11-09 | Zata Pharmaceuticals, Inc. | Phosphoramidite synthones for the synthesis of self-neutralizing oligonucleotide compounds |
| CN107446590A (en) * | 2016-05-31 | 2017-12-08 | 江苏广域化学有限公司 | A kind of technique for synthesizing the fluorine-containing dicyclohexyl alkenes liquid crystal in end |
| CN111285760A (en) * | 2020-05-12 | 2020-06-16 | 南京佰麦生物技术有限公司 | Synthesis method and intermediate of pipadiric acid |
| CN111825546A (en) * | 2020-07-11 | 2020-10-27 | 合肥市梓熤科技贸易有限公司 | Synthesis method of piparidic acid |
-
2021
- 2021-02-07 CN CN202110181136.7A patent/CN114907204A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20170320902A1 (en) * | 2014-11-18 | 2017-11-09 | Zata Pharmaceuticals, Inc. | Phosphoramidite synthones for the synthesis of self-neutralizing oligonucleotide compounds |
| CN107446590A (en) * | 2016-05-31 | 2017-12-08 | 江苏广域化学有限公司 | A kind of technique for synthesizing the fluorine-containing dicyclohexyl alkenes liquid crystal in end |
| CN106748723A (en) * | 2016-12-07 | 2017-05-31 | 江苏工程职业技术学院 | A kind of preparation method of Ketoprofen |
| CN111285760A (en) * | 2020-05-12 | 2020-06-16 | 南京佰麦生物技术有限公司 | Synthesis method and intermediate of pipadiric acid |
| CN111825546A (en) * | 2020-07-11 | 2020-10-27 | 合肥市梓熤科技贸易有限公司 | Synthesis method of piparidic acid |
Non-Patent Citations (3)
| Title |
|---|
| KAWASHIMA, MASATOSHI等: "A facile method for synthesis of three-carbon-homologated carboxylic acids by regioselective ring opening of β-propiolactones with organocopper reagents", TETRAHEDRON, vol. 45, no. 2, pages 407 * |
| KOTA, RAJESH等: "Synthesis of Donor-σ-Perylenebisimide-Acceptor Molecules Having PEG Swallowtails and Sulfur Anchors", JOURNAL OF ORGANIC CHEMISTRY, vol. 77, no. 21, pages 9643 * |
| YANACHKOV, IVAN等: "Self-neutralizing oligonucleotides with enhanced cellular uptake", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 15, no. 6, pages 1363 - 1380, XP055495011, DOI: 10.1039/C6OB02576E * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103172504B (en) | Synthetic method of 2,7-dimethyl-2,4,6-octytriene-1,8-dialdehyde | |
| CN101648887B (en) | Method for synthesizing o-trans-(3-Cl-2-propenyl) hydroxylamine hydrochloride | |
| CN101830821B (en) | Chemical synthesis method of N-alcoxyloxalyl alanine ester | |
| CN105585473B (en) | A kind of method for preparing propine acid compounds | |
| CN105348172B (en) | (S) preparation method of the preparation of the mesyl ethamine of 1 (ethyoxyl of 4 methoxyl group 3) phenyl 2 and Apremilast | |
| CN108623456B (en) | Preparation method of butylphthalide and pharmaceutical intermediate thereof | |
| CN101591247B (en) | Method for synthesizing 4-(4-carbomethoxyphenyl) butyraldehyde | |
| CN114907204A (en) | Synthesis method of piparidic acid | |
| CN102391083B (en) | Method for synthesizing decyl acetal aldehyde | |
| CN101624336A (en) | Oxo-alpha, beta-lonone preparation method | |
| CN105348044B (en) | A kind of synthetic method of hemlock extract (S)-Virol A | |
| CN113548965A (en) | Preparation method of 1, 4-eneyne compound | |
| CN108409764B (en) | Organic photosensitizer capable of forming C-X bond by concerted catalysis with metallic nickel and synthetic method thereof | |
| CN109776338A (en) | Salan ligand, metal-Salan complex and prepare chiral alpha-hydroxy-beta -one ester compound method | |
| CN109796416A (en) | A kind of synthetic method of 2- acetyl group pyrazine | |
| CN106866608B (en) | A kind of preparation method of fluoro -3,4- dihydrocoumarin derivative | |
| CN106588584A (en) | Dehydration method for ether solvent | |
| CN102875396B (en) | Preparation method of sarpogrelate hydrochloride | |
| CN102321054B (en) | Preparation method of tetrahydrofuran-3-ketone compound | |
| CN111533689A (en) | 2, 2' -biquinoline compound and one-pot preparation method thereof | |
| CN109942433A (en) | A kind of chemical synthesis process of 3 ', 4 ', 5 '-three fluoro- 2- aminobphenyls | |
| CN102531865B (en) | Preparation method of 1-(2,6,6-trimethylcyclohex-3-enyl) butyl-2-en-1-one | |
| CN103342639A (en) | Method for synthesizing 2-phenylcarboxylate | |
| CN113511966B (en) | Synthesis method of trifluoromethyl substituted dihydrophenanthrene compound | |
| CN110294664B (en) | Synthetic method of 2-tetradecyne-1-ol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |