CN112552365B - Improved process for the preparation of (22E, 24R) -5α -ergosta-2, 22-dien-6-one - Google Patents
Improved process for the preparation of (22E, 24R) -5α -ergosta-2, 22-dien-6-one Download PDFInfo
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- CN112552365B CN112552365B CN202011505085.0A CN202011505085A CN112552365B CN 112552365 B CN112552365 B CN 112552365B CN 202011505085 A CN202011505085 A CN 202011505085A CN 112552365 B CN112552365 B CN 112552365B
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- PJYIUIIWDUSHEZ-XCRBHNGTSA-N (5s,8s,9s,10r,13r,14s,17r)-17-[(e,2r,5r)-5,6-dimethylhept-3-en-2-yl]-10,13-dimethyl-1,4,5,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-6-one Chemical compound C([C@@H]1C(=O)C2)C=CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)C)[C@@]2(C)CC1 PJYIUIIWDUSHEZ-XCRBHNGTSA-N 0.000 title description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 238000001816 cooling Methods 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 239000000047 product Substances 0.000 description 11
- 239000012535 impurity Substances 0.000 description 10
- 230000014759 maintenance of location Effects 0.000 description 5
- IXVMHGVQKLDRKH-QHBHMFGVSA-N 24-Epibrassinolide Natural products C1OC(=O)[C@H]2C[C@H](O)[C@H](O)C[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)[C@@H](O)[C@H](O)[C@H](C)C(C)C)CC[C@H]3[C@@H]21 IXVMHGVQKLDRKH-QHBHMFGVSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- IXVMHGVQKLDRKH-VRESXRICSA-N Brassinolide Natural products O=C1OC[C@@H]2[C@@H]3[C@@](C)([C@H]([C@@H]([C@@H](O)[C@H](O)[C@H](C(C)C)C)C)CC3)CC[C@@H]2[C@]2(C)[C@@H]1C[C@H](O)[C@H](O)C2 IXVMHGVQKLDRKH-VRESXRICSA-N 0.000 description 3
- IXVMHGVQKLDRKH-KNBKMWSGSA-N brassinolide Chemical compound C1OC(=O)[C@H]2C[C@H](O)[C@H](O)C[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)[C@@H](O)[C@H](O)[C@@H](C)C(C)C)CC[C@H]3[C@@H]21 IXVMHGVQKLDRKH-KNBKMWSGSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 229930002875 chlorophyll Natural products 0.000 description 1
- 235000019804 chlorophyll Nutrition 0.000 description 1
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000029553 photosynthesis Effects 0.000 description 1
- 238000010672 photosynthesis Methods 0.000 description 1
- 239000005648 plant growth regulator Substances 0.000 description 1
- 230000010496 root system development Effects 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
An improved process for the preparation of a compound of formula (II) wherein the compound is prepared by a reaction which is elevated in three stages by a gradientUnder the condition that the first stage: reacting for 1.5-2.5 h at 100-120 ℃, and the second stage: reacting for 1.5-2.5 h at 120-130 ℃, and the third stage: reacting for 1.5-2.5 h at 150-160 ℃.
Description
Technical Field
The present invention relates to an improved process for the preparation of (22E, 24R) -5α -ergosta-2, 22-dien-6-one.
Background
(22E, 24R) -5α -ergosta-2, 22-dien-6-one is an important intermediate for the preparation of 24-epibrassinolide.
The 24-epibrassinolide belongs to a sterol plant growth regulator, has double effects of promoting plant cell division and delaying, can promote plant root system development, enhance photosynthesis, improve chlorophyll content of crops, promote metabolism of crops and assist good growth of inferior parts of the crops, thereby promoting the growth of the crops.
Disclosure of Invention
When (22E, 24R) -5α -ergosta-2, 22-dien-6-one of formula (II) is prepared from (22E, 24R) -3α -5-cyclo-5α -ergosta-22-en-6-one of formula (I), an isomerized impurity compound of formula (III) is formed.
The present invention aims to provide an improved preparation method by which the formation of impurity compounds of formula (III) can be reduced.
In particular, the invention relates to:
(1) An improved process for the preparation of a compound of formula (II) wherein it is prepared by the reaction,
the method is characterized in that the reaction is carried out under the condition of three-stage gradient temperature rise, and the first stage is as follows: reacting for 1.5-2.5 h at 100-120 ℃, and the second stage: reacting for 1.5-2.5 h at 120-130 ℃, and the third stage: reacting for 1.5-2.5 h at 150-160 ℃.
(2) The modified production method of (1) above, wherein the reaction time of the first, second and third stages is about 2 hours, respectively.
(3) The improved production process according to the above (1) or (2), wherein the solvent used in the reaction is N, N-dimethylacetamide or N, N-dimethylformamide.
(4) The improved production process according to any one of the above (1) to (3), wherein the cooling time from the completion of the reaction to the cooling of the reaction mixture to 30℃is controlled within 3 hours.
(5) The improved production process according to the above (4), wherein the cooling time is controlled within 2 hours.
Detailed Description
In the present application, "%" means mass% unless otherwise specified.
The reaction scheme in the improved preparation method of the invention is shown above, and various raw materials used in the method are also known substances, and can be prepared by using commercial products or by a known method.
Unlike the conventional constant temperature reaction, the improved method of the present invention adopts a gradient heating mode to carry out the reaction. Specifically, three-stage gradient temperature-rising reaction is implemented in the reaction, and the first stage is: reacting for 1.5-2.5 h at 100-120 ℃, and the second stage: reacting for 1.5-2.5 h at 120-130 ℃, and the third stage: reacting for 1.5-2.5 h at 150-160 ℃.
The reaction time of each of the above steps is 1.5 to 2.5 hours, and the reaction time at the temperature after the temperature is raised to the temperature of each step is not included in the time required for the temperature raising. The time for the above three reactions is preferably about 2 hours each.
By the improved process of the present invention, the content of the above-mentioned isomerically pure compound (III) in the reaction product can be reduced to less than 5%, whereas the content of the above-mentioned isomerically pure compound in the product is approximately above 8% in the case of a isothermal reaction.
The reaction temperature of the above reaction is high, and therefore a high boiling point solvent is required. Suitable solvents include, but are not limited to, N-dimethylacetamide, N-dimethylformamide, and the like.
Further, the inventors of the present application found that the cooling rate of the reaction mixture after completion of the above reaction affects the color of the objective product (22E, 24R) -5α -ergosta-2, 22-dien-6-one, and that the obtained product was earthy yellow when the cooling time was 8 hours or more, and was pale yellow when the cooling time was shortened to about 5 hours, and was off-white when the cooling time was shortened to 3 hours, and was further shortened to within 2 hours.
Thus, the improved process of the present invention preferably further comprises controlling the above cooling time to within 3 hours, more preferably to within 2 hours.
The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these specific embodiments and examples, and any modifications and alterations within the scope of the gist of the present invention fall within the scope of the present invention.
Examples
EXAMPLE 1 investigation of the reaction temperature
15g of the compound of formula (I) is added into a 10L reaction bottle, 150mL of N, N-dimethylacetamide is added, stirring is carried out, 0.88g of pyridine hydrochloride and 1.65g of lithium bromide are added, the reaction temperature and time are shown in the following table 1, nitrogen protection is carried out in the whole reaction process, after the HPLC monitoring is finished, the temperature is reduced to 25-30 ℃, the reaction product is added into 300mL of water, crystallization is carried out for 2h at 0-5 ℃, filtration is carried out, and drying is carried out at 50-60 ℃, thus obtaining the compound of formula (II). The impurity content was measured by HPLC and the results are shown in table 1.
TABLE 1
The HPLC detection conditions were as follows:
instrument: a liquid chromatograph, UV detector;
chromatographic column: ZORBAX BONUS-RP 250mm 4.6mm 5um;
mobile phase: acetonitrile: water=90:10;
wavelength: 196nm; column temperature: 30 ℃; flow rate: 1.3ml/min.
The retention time of the compound of formula (I) was 22.0min, the retention time of the compound of formula (II) was 25.0min, the retention time of impurity 1 was 20.7min, the retention time of the isomer of formula (III) was 28min, and the retention time of impurity 2 was 33.0min.
As can be seen from table 1: when the reaction is carried out at a constant temperature of 130 ℃ or higher, the impurity content of the isomer of the formula (III) in the obtained product is higher and is 8.5% or higher (batch numbers 1 to 5). On the other hand, when the reaction is carried out at a constant temperature at a relatively low temperature, the reaction rate is low and about 30% of the raw materials remain after 24 hours, so that the efficiency requirement (lot 8) in industrial production cannot be satisfied. The impurity content of the isomer of formula (III) in the product obtained by the two-stage heating method of firstly reacting for 2h at 120-130 ℃ and then reacting for 2h at 150-160 ℃ has a tendency to be reduced to about 7 percent (batch No. 6). The three-stage gradient heating reaction mode of firstly reacting for 2 hours at 100-120 ℃ and then reacting for 2 hours at 120-130 ℃ and further reacting for 2 hours at 150-160 ℃ can greatly reduce the impurity content of the isomer of formula (III) in the obtained product to about 4 percent, and meanwhile, the impurity 1 is reduced compared with the constant temperature reaction mode (batch No. 7).
Example 2 investigation of the influence of the Cooling time after the reaction on the color of the product
The procedure of example 1 was followed in the same manner as in run No. 7, and the cooling time to 30℃after the completion of the reaction was controlled as shown in Table 2.
TABLE 2
| Lot number | Cooling to 30 deg.c after reaction | Product color |
| 1 | 12h | Earthy yellow |
| 2 | 8h | Earthy yellow |
| 3 | 5h | Pale yellow |
| 4 | 3h | White-like color |
| 5 | 2h | White color |
| 6 | 1h | White color |
As shown in Table 2, the cooling time after the completion of the reaction is controlled within 3 hours, preferably within 2 hours, which is advantageous for the color of the product and also for the improvement of the production efficiency.
Industrial applicability
By the method, the isomer impurity in the preparation of (22E, 24R) -5 alpha-ergosta-2, 22-diene-6-ketone can be reduced, a product with better color can be obtained, and the quality of a downstream product 24-epibrassinolide can be improved.
Claims (4)
1. An improved process for the preparation of a compound of formula (II) wherein it is prepared by the reaction,
the method is characterized in that the reaction is carried out under the condition of three-stage gradient temperature rise, and the first stage is as follows: reacting for 1.5-2.5 h at 100-120 ℃, and the second stage: reacting for 1.5-2.5 h at 120-130 ℃, and the third stage: reacting for 1.5-2.5 h at 150-160 ℃;
the cooling time from the completion of the reaction to the cooling of the reaction mixture to 30 ℃ was controlled to be within 3 hours.
2. The improved process of claim 1 wherein the reaction times of the first, second and third stages are each about 2 hours.
3. The improved production process according to claim 1 or 2, wherein the solvent used in the reaction is N, N-dimethylacetamide or N, N-dimethylformamide.
4. The improved production process according to claim 1 or 2, wherein the cooling time is controlled within 2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011505085.0A CN112552365B (en) | 2020-12-18 | 2020-12-18 | Improved process for the preparation of (22E, 24R) -5α -ergosta-2, 22-dien-6-one |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011505085.0A CN112552365B (en) | 2020-12-18 | 2020-12-18 | Improved process for the preparation of (22E, 24R) -5α -ergosta-2, 22-dien-6-one |
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| Publication Number | Publication Date |
|---|---|
| CN112552365A CN112552365A (en) | 2021-03-26 |
| CN112552365B true CN112552365B (en) | 2023-05-19 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111004303A (en) * | 2019-12-17 | 2020-04-14 | 京博农化科技有限公司 | Method for synthesizing 24-epibrassinolide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111004303A (en) * | 2019-12-17 | 2020-04-14 | 京博农化科技有限公司 | Method for synthesizing 24-epibrassinolide |
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Address after: 052260 No.1, Hongsheng Road West, Mayu Village, Mayu Township, Jinzhou City, Shijiazhuang City, Hebei Province Patentee after: Lansheng Biotechnology Group Co.,Ltd. Patentee after: Hebei Guzhirun Technology Co.,Ltd. Address before: 052260 Mayu village, Jinzhou City, Shijiazhuang City, Hebei Province Patentee before: HEBEI LANSHENG BIOTECH Co.,Ltd. Patentee before: Hebei Guzhirun Technology Co.,Ltd. |