CN110790730A - Preparation method of (R) -4-propyl-dihydrofuran-2-ketone - Google Patents
Preparation method of (R) -4-propyl-dihydrofuran-2-ketone Download PDFInfo
- Publication number
- CN110790730A CN110790730A CN201810862327.8A CN201810862327A CN110790730A CN 110790730 A CN110790730 A CN 110790730A CN 201810862327 A CN201810862327 A CN 201810862327A CN 110790730 A CN110790730 A CN 110790730A
- Authority
- CN
- China
- Prior art keywords
- compound
- process according
- reaction
- aqueous solution
- amount
- 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
Classifications
-
- 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
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of a brivaracetam intermediate, and relates to a compound shown as a formula I.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a preparation method of (R) -4-propyl-dihydrofuran-2-ketone shown in a formula I,
background
Brivaracetam (ii), chemically known as (2S) -2- [ (4R) -2-oxo-4-propylpyrrolidin-1-yl ] butanamide, is a third-generation antiepileptic drug developed by the company UCB, belgium, and has a chemical structure and mechanism of action very similar to those of the previous-generation drug levetiracetam. The FDA has formal approval for marketing in month 2 of 2016 and has been used as an adjunctive therapeutic for the treatment of partial seizures, with or without secondary generalized seizures, in adults and juvenile epileptic patients over the age of 16. II is a second generation SV2A ligand with high selectivity and high affinity, influences synaptic function by combining with central synaptobrevin 2A (SV 2A), and is used as a sodium channel inhibitor with high affinity to obviously improve anti-epileptic activity. The compound has unique antiepileptic mechanism, better pharmacokinetic property, safety and high-efficiency clinical effect, and becomes one of the most promising novel antiepileptic drugs.
In the process of preparing the brivaracetam, a compound (I) is discovered, the preparation method of the compound is rarely reported in domestic and foreign literatures,
disclosure of Invention
The invention provides a preparation method of (R) -4-propyl-dihydrofuran-2-ketone, which is shown in formula I.
The preparation method comprises the following steps:
1. in an organic solvent, dimethyl fumarate (II) and nitropropane (III) react to obtain a compound shown as a formula (IV).
2. And (3) carrying out hydrolysis reaction on the compound of the formula (IV) to obtain the compound of the formula (V).
3. The compound of the formula (V) is subjected to catalytic hydrogenation reaction and resolution respectively to obtain the compound of the formula (VI).
4. The compound of formula (VI) is reduced and acidified to lactone to obtain the compound of formula (I).
The compound IV is 2- (acetoxy methane) amyl-2-olefine acid methyl ester
The compound V is 3- (methoxycarbonyl) hex-3-olefine acid
The compound VI is (S) -3- (methoxycarbonyl) hexanoic acid
Wherein the step 1 adopts a conventional Michael addition-elimination method to carry out the reaction:
the reaction solvent is preferably acetonitrile or tetrahydrofuran, preferably acetonitrile;
the dosage of the solvent is 1 to 30 times of that of the compound II, preferably 5 to 10 times (volume to mass ratio);
the reaction temperature is 20-35 ℃;
after the nitropropane (III) is dripped, the reaction time is 0.1-2.5 h, preferably 0.5-1 h.
Step 2 may be carried out using conventional conditions and methods for selective monoester hydrolysis, preferably the following conditions:
the solvent used in the reaction is THF/H2O mixed solution;
the dosage of the solvent is recommended to be 5-50 times, preferably 15-20 times (volume-mass ratio) of the compound IV;
the reaction temperature of adding the inorganic alkaline water solution is recommended to be 0-5 ℃;
the reaction time is recommended to be 3-12 hours, preferably 5-7 hours;
the inorganic alkaline water solution is sodium carbonate water solution, potassium hydroxide water solution, sodium hydroxide water solution, potassium bicarbonate water solution, sodium bicarbonate water solution, etc., preferably sodium hydroxide water solution;
adjusting the pH of the reaction solution to about 3.0-4.0 by using inorganic acid in the post-treatment process of the reaction system;
the inorganic acid aqueous solution is an aqueous hydrochloric acid solution, an aqueous sulfuric acid solution, or the like, and an aqueous hydrochloric acid solution is preferable.
Step 3 can be carried out by adopting conventional conditions and methods of hydrogenation reduction and chiral resolution, and the following conditions are preferred:
the reaction solvent is ethyl acetate;
the dosage of the reaction solvent is recommended to be 1-30 times, preferably 5-10 times (volume-mass ratio) of the compound V;
the temperature of the hydrogenation reduction reaction is recommended to be room temperature;
the hydrogenation reduction reaction time is recommended to be 3-16 hours, and preferably 5-8 hours;
the chiral resolving agent is (R) - α -phenylethylamine;
the dosage of the resolving agent is recommended to be 1-1.5 times, preferably 1 time (molar ratio in the present case) of the compound V;
the recrystallization solvent is diethyl ether or ethyl acetate, preferably ethyl acetate;
the amount of the recrystallization solvent is preferably 1 to 20 times, preferably 5 to 10 times (volume to mass ratio) of the compound V;
the recrystallization temperature is recommended to be 0-5 ℃;
the recrystallization time is recommended to be 5 to 7 hours.
Step 4, conventional reduction reaction and acidification reaction conditions and methods are adopted for reaction, and the following conditions are preferred:
the reaction solvent is methanol;
the dosage of the solvent is 1 to 20 times, preferably 2 to 5 times (volume to mass ratio) of the compound VI;
the reaction temperature is 20-35 ℃;
the reaction time is recommended to be 8-24h, preferably 12-14 h;
adjusting the pH of the reaction solution to about 4.0-5.0 by using inorganic acid in the post-treatment process of the reaction system;
the inorganic acid aqueous solution is an aqueous hydrochloric acid solution, an aqueous sulfuric acid solution, or the like, and an aqueous hydrochloric acid solution is preferable.
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example 1 preparation of a brivaracetam intermediate of the invention:
(1) preparation of Compound IV
Dimethyl fumarate II (31.7 g, 0.22 mol), DBU (34.0 g, 0.22 mol) and 160mL of acetonitrile were added to a 250mL three-necked flask, stirring was turned on, and after complete dissolution, nitropropane III (21.4 g, 0.24 mol) was slowly added dropwise to the reaction flask, and stirred for 30 min. After the reaction, the solvent was removed by rotation, the resulting solid was dissolved in 50mL of DCM, made acidic with 100mL of 2N hydrochloric acid and then with 50mL of saturated NaHCO3Washing to be alkaline; the extraction was separated and the organic phase was washed with 50mL x 2 saturated brine and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate to obtain 37.5g crude product, and separating by column chromatography to obtain 25.2g pale yellow oily liquid (eluent V)PE:VEA=6: 1), the yield was 61.6%, and the purity was 99.3%.
(2) Preparation of Compound V
The compound IV (25.2 g, 0.135 mol), THF/H2O mixture (378 mL, volume)Volume ratio of 1: 10) into a 1L three-neck flask, stirring to mix uniformly, cooling to 0 ℃, dropwise adding 100mL of 0.1N NaOH aqueous solution into the reaction system, maintaining the reaction temperature at 0 ℃ after dropwise adding, and detecting the reaction process by TLC point plate. After the reaction, 1N HCl is added dropwise to adjust the pH of the reaction solution to 3-4, the reaction solution is extracted by 200mL of 3 EA, and the organic phase is washed by 200mL of saturated saline water and dried by anhydrous sodium sulfate. Filtration and concentration of the filtrate gave 20.8g of a colorless oily liquid in 89.6% yield and 98% purity.
(3) Preparation of Compound VI
Compound V (20.8 g, 0.12 mol) was dissolved in 200mLEA and N was added2Displacing air for 5min, adding 10% Pd/C (0.8 g), introducing H at room temperature2To start the reaction, the progress of the reaction was monitored by TLC plates. After the reaction, Pd/C was removed by suction filtration to give a pale yellow transparent filtrate, and the solvent was removed by rotary evaporation to give 19.8g of a pale yellow oily liquid with a yield of 94.7%.
a) Dissolving the oily liquid (19.8 g, 0.11 mol) in 30 mLEA, stirring and heating to completely dissolve;
b) adding (R) - α -phenethylamine (13.3 g, 0.11 mol) and 50mLEA into a 250mL three-necked bottle, and stirring to dissolve;
c) and (c) dropwise adding the mixed solution of the step a) into the mixed solution of the step b), cooling and crystallizing for 5 hours after dropwise adding, and filtering to obtain 15.6g of crude product.
Dissolving the crude product in 50ml EA, heating and refluxing for 30min, cooling at 0-5 deg.C, and crystallizing for 5h to obtain 7.6g product, with yield of 48.7% HPLC: purity 99%, ee value 99.1%.
(4) Preparation of Compound I
Dissolving a compound VI (7.6 g, 0.044 mol) in 30mL of methanol, cooling to 0 ℃, adding 30mL of water, cooling to 0 ℃, and sequentially adding calcium chloride powder (5.3 g, 0.048 mol) and an ethanol solution of sodium borohydride (2.5 g of NaBH)435mL ethanol), stirring overnight at room temperature, adding 6N hydrochloric acid to quench the reaction, adjusting the PH of the reaction solution to 4-5, concentrating the reaction solution, adding 30mL water and 3 x 30mL dccm for extraction, combining organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate to obtain 4.9g of compound i with a yield of 86.9%, HPLC: the purity is 98%.
Claims (22)
1. A process for the preparation of formula i, comprising the steps of: dissolving dimethyl fumarate (II) in an organic solvent, adding nitropropane (III) to react to obtain a compound of a formula (IV); dissolving the compound IV in THF/H2Hydrolyzing the O mixed solution under the alkaline condition to obtain a compound shown in the formula (V), respectively carrying out Pd/C catalytic hydrogenation reaction on the compound V, and carrying out (R) - α -phenylethylamine resolution to obtain a compound shown in the formula (VI), and carrying out NaBH on the compound VI4Reducing and acidifying with hydrochloric acid to obtain lactone to obtain a compound of formula (I),
2. the process according to claim 1, wherein the organic solvent used in step 1 is preferably acetonitrile or tetrahydrofuran, and the amount of the solvent is 1 to 30 times, preferably 5 to 10 times (volume to mass ratio) that of the compound II.
3. The process according to claim 1, wherein the reaction temperature employed in step 1 is from 20 to 35 ℃.
4. The process according to claim 1, wherein the reaction time after the dropwise addition of nitropropane (III) in step 1 is from 0.1 to 2.5h, preferably from 0.5 to 1 h.
5. The process according to claim 1, wherein the reaction solvent used in step 2 is THF/H2The amount of the solvent used in the O mixed solution is 5 to 50 times, preferably 15 to 20 times (volume to mass ratio) of the amount of the compound IV.
6. The process according to claim 1, wherein the reaction temperature of the aqueous solution of the inorganic base added in step 2 is 0 to 5 ℃.
7. The process according to claim 1, wherein the reaction time employed in step 2 is 3 to 12 hours, preferably 5 to 7 hours.
8. The method according to claim 1, wherein the aqueous solution of inorganic base used in step 2 is an aqueous solution of sodium carbonate, potassium hydroxide, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, etc., preferably an aqueous solution of sodium hydroxide.
9. The method according to claim 1, wherein the pH of the reaction solution is adjusted to about 3.0 to 4.0 by an inorganic acid in the post-treatment process of step 2.
10. The method according to claim 1, wherein the aqueous solution of inorganic acid used in step 2 is an aqueous solution of hydrochloric acid, sulfuric acid, or the like, preferably an aqueous solution of hydrochloric acid.
11. The process according to claim 1, wherein the reaction solvent used in step 3 is ethyl acetate, and the amount of the solvent used is 1 to 30 times, preferably 5 to 10 times (volume to mass ratio) the amount of the compound V.
12. The process according to claim 1, wherein the temperature of the hydrogenation reduction reaction used in step 3 is room temperature.
13. The process according to claim 1, wherein the hydrogenation reduction reaction time used in step 3 is 3 to 16 hours, preferably 5 to 8 hours.
14. The process according to claim 1, wherein the chiral resolving agent used in step 3 is (R) - α -phenylethylamine, and the amount of the resolving agent is 1 to 1.5 times, preferably 1 time (molar ratio herein) of the compound V.
15. The process according to claim 1, wherein the recrystallization solvent used in step 3 is diethyl ether or ethyl acetate, preferably ethyl acetate, in an amount of 1 to 20 times, preferably 5 to 10 times (by volume/mass ratio) the amount of compound V.
16. The process according to claim 1, wherein the recrystallization temperature used in step 3 is 0 to 5 ℃.
17. The process according to claim 1, wherein the recrystallization time employed in step 3 is from 5 to 7 hours.
18. The process according to claim 1, wherein the reaction solvent used in step 4 is methanol, and the amount of the solvent used is 1 to 20 times, preferably 2 to 5 times (volume to mass ratio) the amount of the compound VI.
19. The process according to claim 1, wherein the reaction temperature employed in step 4 is from 20 to 35 ℃.
20. The process according to claim 1, wherein the reaction time employed in step 4 is from 8 to 24h, preferably from 12h to 14 h.
21. The method according to claim 1, wherein the post-treatment process adopted in the step 4 is inorganic acid adjustment of the pH of the reaction solution to about 4.0 to 5.0.
22. The method according to claim 1, wherein the aqueous solution of inorganic acid used in step 4 is an aqueous solution of hydrochloric acid, sulfuric acid, or the like, preferably an aqueous solution of hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810862327.8A CN110790730A (en) | 2018-08-01 | 2018-08-01 | Preparation method of (R) -4-propyl-dihydrofuran-2-ketone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810862327.8A CN110790730A (en) | 2018-08-01 | 2018-08-01 | Preparation method of (R) -4-propyl-dihydrofuran-2-ketone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110790730A true CN110790730A (en) | 2020-02-14 |
Family
ID=69425352
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810862327.8A Pending CN110790730A (en) | 2018-08-01 | 2018-08-01 | Preparation method of (R) -4-propyl-dihydrofuran-2-ketone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110790730A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5846941A (en) * | 1992-03-12 | 1998-12-08 | Boehringer Ingelheim (Canada) Ltd. | Isosteric antiherpes peptide derivatives II |
| CN106588831A (en) * | 2016-11-16 | 2017-04-26 | 上海博志研新药物技术有限公司 | Method for preparing furanone compounds |
| CN106588740A (en) * | 2016-11-16 | 2017-04-26 | 上海博志研新药物技术有限公司 | Preparing method for caproic acid derivative |
-
2018
- 2018-08-01 CN CN201810862327.8A patent/CN110790730A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5846941A (en) * | 1992-03-12 | 1998-12-08 | Boehringer Ingelheim (Canada) Ltd. | Isosteric antiherpes peptide derivatives II |
| CN106588831A (en) * | 2016-11-16 | 2017-04-26 | 上海博志研新药物技术有限公司 | Method for preparing furanone compounds |
| CN106588740A (en) * | 2016-11-16 | 2017-04-26 | 上海博志研新药物技术有限公司 | Preparing method for caproic acid derivative |
Non-Patent Citations (5)
| Title |
|---|
| MARK J. BURK ET AL.: "Practical Access to 2-Alkylsuccinates through Asymmetric Catalytic Hydrogenation of Stobbe-Derived Itaconates", ANGEW. CHEM. INT. ED., vol. 37, no. 13, pages 1931 - 1933, XP001069474, DOI: 10.1002/(SICI)1521-3773(19980803)37:13/14<1931::AID-ANIE1931>3.0.CO;2-3 * |
| ROBERTO BALLINI ET AL.: "A Direct Method for the Synthesis of Polyfunctionalized Unsaturated Carbonyl Derivatives by Michael Addition of Nitroalkanes to Enediones with the Help of DBU", TETRAHEDRON, vol. 51, no. 14, pages 4213 - 4222, XP002262809, DOI: 10.1016/0040-4020(95)00136-V * |
| ROBERTO BALLINI ET AL.: "Conjugate addition of nitroalkanes to dimethyl maleate. Regioselective formation of both monoesters of 2-alkylsuccinic acids", TETRAHEDRON, vol. 59, pages 7283 - 7289, XP004453326, DOI: 10.1016/S0040-4020(03)01175-X * |
| ZHANG DA-TONG ET AL.: "Synthesis, Resolution, and Emtiomeric Purity Assay of 2-n-ButylbutanedioicAcid 4-t-Butyl Esters", CHEM. RES. CHLNESE U., vol. 22, no. 5, pages 584 - 588 * |
| 刘冬梅 等: "α-苯乙胺拆分2 -取代丁二酸1-叔丁酯", 化学试剂, vol. 31, no. 12, pages 1018 - 1020 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114014787B (en) | Asymmetric synthesis method for preparing (2S,3R) -p-methylsulfonylphenylserine ethyl ester | |
| CN112079848A (en) | Synthesis method of baroxavir key intermediate | |
| US9771317B2 (en) | Process for preparing lacosamide and related compounds | |
| CN102911160B (en) | Method for preparing and purifying dabigatran etexilate intermediate | |
| CN113480471A (en) | Multi-chiral nitrogen-substituted piperidinol derivative and preparation method thereof | |
| CN108299216A (en) | The preparation method of 2,6- of one kind dimethyl-l-tyrosine | |
| CN109456253B (en) | Method for synthesizing (S) -3- (4-bromophenyl) -piperidine or salt thereof through chiral induction | |
| CN110790730A (en) | Preparation method of (R) -4-propyl-dihydrofuran-2-ketone | |
| CN102485722B (en) | Aliskiren, its intermediates and medicinal salt, as well as preparation method thereof | |
| CN105884625B (en) | A kind of synthetic method of R- salmeterols | |
| CN109879800B (en) | Preparation process of bepotastine drug intermediate | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN109320510B (en) | Preparation method of Maropitan free base | |
| CN103351361B (en) | The preparation method of LEVO CITRAZINE and dihydrochloride thereof | |
| CN110790731A (en) | Preparation method of 4-substituted-gamma butyrolactone | |
| CN115197178B (en) | Synthesis method of brivaracetam key intermediate | |
| CN115504893B (en) | Synthesis method of L-glutamic acid-alpha-tert-butyl ester | |
| CN103193600B (en) | The preparation method of rivastigmine intermediate | |
| CN115286504B (en) | Method for synthesizing (R) -2- (2- (tert-butoxy) -2-oxyethyl) pentanoic acid | |
| CN114989045B (en) | Intermediate for synthesizing Namactetvir and preparation method thereof and method for synthesizing Namactetvir | |
| CN115417794B (en) | Preparation method of saxagliptin intermediate | |
| CN112321451B (en) | Method for preparing cinacalcet hydrochloride drug intermediate | |
| CN103288813A (en) | Preparation method of aprepitant | |
| CN112552200B (en) | Preparation method of optical pure 4- (1-amino) ethyl benzoate and salt thereof | |
| CN103193679A (en) | Preparation method of rivastigmine intermediate (R)-N-ethyl-N-methyl carbamic acid-3-(1-hydroxyethyl) phenyl ester |
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 |