CN114249690A - Synthesis method of Rosxastat - Google Patents
Synthesis method of Rosxastat Download PDFInfo
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- CN114249690A CN114249690A CN202010994236.7A CN202010994236A CN114249690A CN 114249690 A CN114249690 A CN 114249690A CN 202010994236 A CN202010994236 A CN 202010994236A CN 114249690 A CN114249690 A CN 114249690A
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- reaction
- dbu
- crude product
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000012043 crude product Substances 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 9
- 239000007788 liquid Substances 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 8
- 239000000047 product Substances 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 238000004537 pulping Methods 0.000 claims abstract description 4
- 230000035484 reaction time Effects 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 238000001035 drying Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 239000008213 purified water Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- 239000012071 phase Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 7
- 150000007530 organic bases Chemical class 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000003321 amplification Effects 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- DOUMFZQKYFQNTF-WUTVXBCWSA-N (R)-rosmarinic acid Chemical compound C([C@H](C(=O)O)OC(=O)\C=C\C=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-WUTVXBCWSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- ZZAFFYPNLYCDEP-HNNXBMFYSA-N Rosmarinsaeure Natural products OC(=O)[C@H](Cc1cccc(O)c1O)OC(=O)C=Cc2ccc(O)c(O)c2 ZZAFFYPNLYCDEP-HNNXBMFYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- DOUMFZQKYFQNTF-MRXNPFEDSA-N rosemarinic acid Natural products C([C@H](C(=O)O)OC(=O)C=CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 DOUMFZQKYFQNTF-MRXNPFEDSA-N 0.000 description 1
- TVHVQJFBWRLYOD-UHFFFAOYSA-N rosmarinic acid Natural products OC(=O)C(Cc1ccc(O)c(O)c1)OC(=Cc2ccc(O)c(O)c2)C=O TVHVQJFBWRLYOD-UHFFFAOYSA-N 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of roxasistat, wherein a compound (I) takes 1, 8-diazabicycloundecen-7-ene (DBU) as alkali and toluene as a reaction solvent to react with glycine; and after the reaction is finished, cooling, adding water, separating liquid, washing, adjusting acid, pulping, filtering and drying to obtain the crude product (II) of the target product of the roxasistat. The reaction of the present invention is modified with a liquid organic base DBU and preferably with a molar equivalent; toluene is used as a reaction solvent, and the solvent amount is optimized; the reaction temperature is reduced and the reaction time is shortened through the improvement. Meanwhile, the post-treatment is simplified, and the liquid is directly separated without being concentrated under reduced pressure.
Description
Technical Field
The invention belongs to the technical field of synthesis of raw material medicines and intermediates, and particularly relates to a method for synthesizing crude product of rosmarinic acid.
Background
In the past, the quality is firstly focused on from the perspective of raw medicines, but under the current policy of purchasing the 4+7 belt quantity of the imitation drugs, the quality is not enough, and whether the synthesis process of the raw medicines is suitable for industrial scale-up production is focused on. Aiming at the step of the condensation reaction of the urethane in the synthesis process of the roxasistat, the analysis of the existing main synthesis method is as follows:
on the one hand, the polyurethane condensation reaction is completed under an organic base/methanol system, and the reaction is carried out overnight at 100-110 ℃ (CN108794397, WO2014114834 and CN108341777), and the yield is 65-86%. The method requires higher reaction temperature, and the solvent methanol is selected, and the conventional condition cannot reach the temperature. Therefore, special pressure equipment (such as a stainless steel muzzle) must be used, which increases the difficulty and danger of industrial scale-up production. The reaction conditions are harsh, the amplification production is not facilitated, and the yield is not high
On the other hand, the reaction solvent is changed to a high boiling point solvent such as 1, 4-dioxane, ethylene glycol monomethyl ether and the like to remove the special pressure equipment. However, the solubility of the solvents to sodium methoxide is poor, and the reaction effect is poor; and the concentration temperature requirement is higher during the post-treatment reduced pressure concentration, the concentration time is longer, and the ether solvent is risky to concentrate at high temperature, which also increases the cost and the risk of industrial production and is not suitable for industrial amplification.
In addition, the process of patent CN 104024227A requires too long steps to obtain the target product (3 steps from compound 7 to compound 10), and the patent uses dangerous reagents such as borane.
Disclosure of Invention
In combination with the technical problems in the prior art, the method provided by the invention can complete the reaction at a lower reaction temperature, and improve the reaction yield. And no special equipment requirement exists, the post-treatment is simple and feasible, the production cost is saved, and the method is suitable for industrial amplification.
The invention provides a synthesis method of crude product of roxasistat, which has the chemical reaction formula:
the compound (I) takes 1, 8-diazabicycloundecen-7-ene (DBU) as alkali and toluene as reaction solvent to react with glycine, thus obtaining the target product of crude product of the roxasistat (II).
Further, the DBU of the present invention is used in a molar amount of 2.0 to 5.0 times, preferably 3.0 times, the compound (I). If it is lower than this range, the reaction cannot proceed, and if it is higher than this range, the post-treatment is difficult.
Further, the molar ratio of DBU and glycine in the reaction of the DBU and the glycine is as follows: (0.8-1.2): 1, preferably 1: 1.
The reaction solvent is toluene, and the toluene is selected as the solvent, so that the post-treatment is simpler, special pressure equipment is avoided, and the industrialization cost and the risk are effectively reduced.
Furthermore, the amount of the reaction solvent used in the present invention is 4 to 7ml/g of the compound (I), preferably 6ml/g of the compound (I).
Furthermore, the reaction temperature used in the invention is 25-100 ℃, preferably 80-85 ℃.
Furthermore, the reaction time is 1-5 hours, preferably 3 hours.
In some embodiments, the reaction of the present invention is completed with a post-treatment step, and in a specific embodiment, the post-treatment step is specifically: after the reaction is finished, the crude product (II) of the target product, namely the roxasistat, is obtained through cooling, water adding, liquid separation, washing, acid adjustment, pulping, filtering and drying.
Further, after the reaction is finished, cooling to 35-40 ℃, adding water for dissolving, separating liquid, and washing the water phase with ethyl acetate for 1-3 times.
Further, the pH of the water phase is adjusted to 3.8-4.2, preferably 4 by glacial acetic acid.
Further, adjusting acid to separate out solid, pulping at room temperature for 1.5-2.5 h h, filtering, washing a filter cake with purified water until the pH value is 5.8-6.2, and vacuum-drying at 55-60 ℃ for more than 12h to obtain a crude product of the roxasistat.
In summary, the method of the present invention is improved mainly from the following aspects: 1) the reaction is modified with a liquid organic base DBU and preferably with a molar equivalent; 2) toluene is used as a reaction solvent, and the solvent amount is optimized; 3) the reaction temperature is reduced and the reaction time is shortened by the improvement of the first two points. Meanwhile, the post-treatment is simplified, and the liquid is directly separated without being concentrated under reduced pressure.
Detailed Description
The following examples are given to facilitate a better understanding of the invention, but do not limit the invention. The experimental procedures in the following examples are conventional unless otherwise specified. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
Example 1
Preparation of the crude product (II) of the roxasistat: adding 150ml of toluene into a 500ml three-neck flask, and starting stirring; then 25g of compound (I), 17.97g of glycine are added; 42.27g of DBU are added dropwise at a temperature below 45 ℃; and (4) starting to heat to 80-85 ℃, keeping the temperature and reacting for 3h, and monitoring the reaction end point by TLC. After the reaction is finished, cooling to 30-40 ℃, then stirring for 15min with 150ml of water. Separating, discarding the toluene phase, washing the water phase with 100ml ethyl acetate once again, and separating the water phase; 19.17g of glacial acetic acid is quickly added into the water phase under stirring, the pH value is adjusted to be 4, a solid is separated out, and the stirring is continued for 2 h; filtering, washing a filter cake with purified water until the pH value is approximately equal to 6, and draining; transferring the filter cake to a vacuum drying oven, and vacuum drying at 55-60 ℃ for 12h to obtain crude product (II) (purity: 99.7%; yield: 95%).
Claims (10)
1. A method for synthesizing crude product of Rosemastat is characterized in that,
and reacting the compound (I) with glycine by taking DBU as alkali and toluene as a reaction solvent to obtain a target product, namely the crude product (II) of the roxasistat.
2. The synthesis process according to claim 1, characterized in that DBU is used in a molar amount of 2.0 to 5.0 times, preferably 3.0 times, that of compound (I).
3. The synthesis method according to claim 1, wherein the molar ratio of DBU to glycine reaction is: (0.8-1.2): 1, preferably 1: 1.
4. The synthesis process according to claim 1, wherein the amount of the reaction solvent is 4 to 7ml/g, preferably 6ml/g, of the compound (I).
5. The synthesis process according to claim 1, characterized in that the reaction temperature is between 25 ℃ and 100 ℃, preferably between 80 ℃ and 85 ℃.
6. The synthesis process according to claim 1, characterized in that the reaction time is 1 to 5 hours, preferably 3 hours.
7. The synthesis method according to claim 1, wherein after the reaction is completed, the crude product (II) of the target product, namely the Rosemastat, is obtained through cooling, water addition, liquid separation, washing, acid adjustment, pulping, filtering and drying.
8. The synthesis method according to claim 7, wherein after the reaction is completed, the temperature is reduced to 35-40 ℃, water is added for dissolution, liquid separation is carried out, and ethyl acetate is used for washing the water phase for 1-3 times.
9. The synthesis process according to claim 8, wherein the aqueous phase is adjusted to a pH of 3.8 to 4.2, preferably 4, with glacial acetic acid.
10. The synthesis method according to claim 9, wherein the acid is adjusted to separate out a solid, the solid is pulped at room temperature for 1.5-2.5 h and then filtered, and the filter cake is washed by purified water until the pH value is 5.8-6.2, and vacuum drying is carried out at 55-60 ℃ for more than 12h, so as to obtain the crude product of the roxasistat.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010994236.7A CN114249690A (en) | 2020-09-21 | 2020-09-21 | Synthesis method of Rosxastat |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010994236.7A CN114249690A (en) | 2020-09-21 | 2020-09-21 | Synthesis method of Rosxastat |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114249690A true CN114249690A (en) | 2022-03-29 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010994236.7A Pending CN114249690A (en) | 2020-09-21 | 2020-09-21 | Synthesis method of Rosxastat |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114249690A (en) |
-
2020
- 2020-09-21 CN CN202010994236.7A patent/CN114249690A/en active Pending
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Application publication date: 20220329 |