CN115650965B - Preparation method of Ruogeli key intermediate - Google Patents
Preparation method of Ruogeli key intermediate Download PDFInfo
- Publication number
- CN115650965B CN115650965B CN202211670911.6A CN202211670911A CN115650965B CN 115650965 B CN115650965 B CN 115650965B CN 202211670911 A CN202211670911 A CN 202211670911A CN 115650965 B CN115650965 B CN 115650965B
- Authority
- CN
- China
- Prior art keywords
- formula
- preparation
- key intermediate
- dic
- diisopropylcarbodiimide
- 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.)
- Active
Links
Images
Classifications
-
- 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 relates to a preparation method of a Ruogeli key intermediate, in particular to a preparation method of (2, 6-difluorobenzyl) - [ 4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophene-2-yl ] carbamate (formula I), and belongs to the field of organic chemical synthesis. The preparation method provided by the invention has the advantages of easily obtained raw materials, low cost, simple and convenient operation, environmental friendliness, stable yield and related substances, and is easy for industrial production amplification.
Description
Technical Field
The invention relates to a preparation method of a Ruogeli key intermediate, in particular to a preparation method of (2, 6-difluorobenzyl) - [ 4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophene-2-yl ] carbamate (formula I), and belongs to the field of organic chemical synthesis.
Background
Ruogeli is an oral gonadotropin releasing hormone (GnRH) receptor antagonist, can inhibit the production of testosterone in testis, and is approved for the treatment and symptom relief of hysteromyoma. In addition, rilogelix also reduces the production of ovarian estradiol by blocking GnRH receptors in the pituitary gland, a hormone that stimulates the growth of uterine fibroids and endometriosis. The chemical name of Ruugeli is: 1- [4- [1- (2, 6-difluorobenzyl) -5-dimethylaminomethyl-3- (6-methoxypyridazin-3-yl) -2, 4-dioxo-1, 2,3, 4-tetrahydrothieno [2,3-d ] pyrimidin-6-yl ] phenyl ] -3-methoxyurea; the (2, 6-difluorobenzyl) - [ 4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl ] carbamate (formula I) is a key intermediate of rilogeli.
The preparation method of the compound shown in the formula I is generally disclosed and reported at present to introduce 3-amino-6-methoxypyridazine, and the step is generally to adopt propylphosphonic anhydride (T) 3 P) is a condensing agent and DMAc is a solvent.
As described in example 4 of CN 104703992B: under nitrogen atmosphere, 2- [ (2, 6-difluorobenzyl) ethoxy carbonyl amino]-4-dimethylaminomethylPhenyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid (6.5g, 12.51mmol) and 3-amino-6-methoxypyridazine hydrochloride (2.43g, 15.01mmol, 1.2eq) were added to N, N' -dimethylacetamide (DMAc, 29.25 mL), followed by addition of ethyldiisopropylamine (4.03g, 31.28mmol, 2.5eq) thereto at 25. + -. 15 ℃. The mixture was warmed to an internal temperature of 55 ± 5 ℃ and stirred for 30 minutes. Adding 50.5% propylphosphonic anhydride (T) dropwise thereto at an internal temperature of 60 ℃ or lower 3 P) ethyl acetate solution (9.55g, 15.01mmol, 1.2eq), and the container used for the reagents was washed with DMAc (3.25 mL). The mixture was stirred at an internal temperature of 55. + -. 5 ℃ for 1 hour. The reaction mixture was cooled to 25 ± 5 ℃, and tap water (48.75 mL) was added dropwise thereto at the same temperature. Then, an 8N aqueous sodium hydroxide solution was added thereto at 25. + -. 5 ℃ with vigorous stirring, the pH of the mixture was adjusted to 7.5-8.5, and the mixture was stirred at 25. + -. 5 ℃ for 30 minutes. The crystals were collected by filtration, washed with methanol (26 mL) and dried under reduced pressure at 40. + -. 5 ℃ until the weight became constant to give (2, 6-difluorobenzyl) - [ 4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl]Ethyl carbamate (7.61 g, yield: 97.0%, HPLC area percentage: 98.5%) was yellow crystals.
As also described in example 10 of CN 112321602A:
A2L reaction flask was charged with N, N' -dimethylacetamide (550 mL), compound 7-a (110 g), and compound 8 (39.98 g), N 2 Protection, N' -diisopropylethylamine (66.6 g) is added dropwise at the temperature of 10 to 40 ℃, and the temperature is raised to 50 to 60 ℃ for reaction for 0.5 h. Dropping 50% T at the temperature of not higher than 60 DEG C 3 After the addition of the solution of P in ethyl acetate (157.4 g), the reaction was stirred at 50 to 60 ℃ for 1 hour. The temperature is reduced, the internal temperature is controlled to be 20 to 30 ℃, and water (825 g) is dripped in. Adjusting pH to 7.5-8.5 with 8 mol/L sodium hydroxide aqueous solution at an internal temperature of 20-30 ℃, stirring for 0.5 h, filtering, adding the filter cake into methanol (440 mL), and adjusting the temperature to 20-30 DEG CStirred at 30 ℃ for more than 2 h, filtered and the filter cake rinsed with methanol (220 mL). The material is dried in vacuum at 45 ℃ to obtain yellow solid, the yield is 78.1 percent, and the purity is 99.3 percent.
The condensing agent propylphosphonic anhydride (T) used in the process for the preparation of the 2 compounds of the formula I 3 P) belongs to a pipe product, is expensive, has large cost ratio in the production process, is complex in post-treatment operation, can generate a large amount of phosphine-containing wastewater, is not environment-friendly, has great environmental protection pressure, and has unstable yield, and the industrial production is limited by a plurality of methods. Therefore, it is still necessary to develop a preparation process with easily available raw materials, low cost, simple operation, environmental friendliness, stable yield and related substances.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation process of the compound of the formula I, which has the advantages of easily obtained raw materials, low cost, simple and convenient operation, environmental friendliness and stable yield and related substances.
The invention provides a preparation method of a Ruogeli key intermediate (I),
wherein R is selected from C 1-7 A linear or branched alkyl, substituted or unsubstituted phenyl or benzyl;
taking compounds in a formula (II) and a formula (III) as raw materials, taking N, N' -Diisopropylcarbodiimide (DIC) as a condensing agent, and carrying out an amide condensation reaction in an organic solvent to obtain a Ruogeli key intermediate (I).
Wherein R is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl or benzyl.
An embodiment of the invention is where R is selected from methyl, ethyl or propyl.
An embodiment of the invention, wherein R is selected from propyl.
Wherein the organic solvent is selected from dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, N' -dimethylformamide, acetonitrile or ethyl acetate; preferably dichloromethane.
Wherein the equivalent ratio of the formula (II) and the formula (III) to the N, N' -Diisopropylcarbodiimide (DIC) is 1.0: 1.0-1.5: 1.5-2.5.
In the embodiment of the invention, the equivalent ratio of the formula (II) to the formula (III) to the N, N' -Diisopropylcarbodiimide (DIC) is 1.0: 1.2-1.3: 2.0-2.5.
In the examples of the present invention, the equivalent ratio of the formula (II), the formula (III) and N, N' -Diisopropylcarbodiimide (DIC) is 1.0: 1.2: 2.0.
Wherein the reaction temperature is 35-45 ℃.
The invention has the beneficial effects that: the invention adopts N, N' -Diisopropylcarbodiimide (DIC) as a condensing agent, has the advantages of easily obtained raw materials, low cost, simple and convenient operation, environmental protection, stable yield and related substances, and is suitable for industrial production. Solves the problem that the prior art adopts propyl phosphonic anhydride (T) 3 P) as a condensing agent causes the technical problems of high price, high cost, complex post-treatment operation, environment-unfriendly caused by the generation of a large amount of phosphine-containing waste water and unstable yield.
Drawings
FIG. 1 shows the nuclear magnetic spectrum of compound I-1 in example 1.
Detailed Description
Example 1
662 g of methylene chloride, 50 g of 2- [ (2, 6-difluorobenzyl) propoxycarbonylamino ] -4-dimethylaminomethyl-5- (4-nitrophenyl) thiophene-3-carboxylic acid (formula II-1), 14.1 g of 3-amino-6-methoxypyridazine (formula III) and 23.65 g of N, N' -Diisopropylcarbodiimide (DIC) were charged into a reaction flask, and the reaction was stirred at 35 to 45 ℃ for 15 hours under nitrogen protection; sampling and detecting, and finishing the reaction of the raw materials. Cooling to 20-30 ℃; 250 mL of water is added to the reaction solution, 3% aqueous sodium hydroxide solution (8.5 g) is added dropwise, the mixture is stirred and then separated into layers, the aqueous phase is extracted with dichloromethane (150 mL × 1), the organic phases are combined, the mixture is concentrated to about 100 mL under reduced pressure, 450 mL of methanol is added and concentrated to 250 mL, the mixture is pulped and filtered, and the wet filter cake is dried to obtain 52.14 g of white solid with the yield of 94.13%.
Example 2
Screening in different feeding modes
Under the protection of nitrogen, 1.0 eq of a compound of a formula II-1 and 1.2eq of a compound of a formula III are used as raw materials, N' -Diisopropylcarbodiimide (DIC) is used as a condensing agent, and dichloromethane is used as a solvent to react under reflux.
The experiment examines the influence of different feeding modes on the reaction, and the experimental result is shown in table 1:
TABLE 1
As can be seen from Table 1, the effect of different feeding modes on the product purity is not obvious, and the feeding mode of the method 1 adopting the one-pot method is more convenient and is the preferred feeding mode.
Example 3
Screening experiment for N, N' -Diisopropylcarbodiimide (DIC) usage
Under the protection of nitrogen, 1.0 eq of the compound shown in the formula II-1 and 1.2eq of the compound shown in the formula III are used as raw materials, N' -Diisopropylcarbodiimide (DIC) is used as a condensing agent, and dichloromethane is used as a solvent to react under reflux.
The effect of different equivalent of condensing agent on the reaction was examined in this experiment, and the results are shown in table 2:
TABLE 2
As can be seen from Table 2, when the equivalent of the condensing agent N, N' -Diisopropylcarbodiimide (DIC) is 1.5 to 2.5eq, the raw material II-1 can be reacted after 15 hours of reaction, and the product purity can reach more than 99.2 percent; the equivalent weight of DIC is preferably 2.0 to 2.5 eq; more preferably 2.0 eq.
Example 4
Reaction experiments with different feedstocks II
Under the protection of nitrogen, 1.0 eq of a compound in a formula II and 1.3 eq of a compound in a formula III are used as raw materials, 2.0 eq of N, N' -Diisopropylcarbodiimide (DIC) is used as a condensing agent, and dichloromethane is used as a solvent to react under reflux to prepare the corresponding compound in the formula I.
The effect of different raw materials on the reaction was investigated in this experiment, and the experimental results are shown in table 3:
TABLE 3
As shown in Table 3, the corresponding product (2, 6-difluorobenzyl) - [ 4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl) -5- (4-nitrophenyl) thiophen-2-yl ] carbamate (formula I) can be obtained by using N, N' -Diisopropylcarbodiimide (DIC) as a condensing agent and stabilizing the yield and related substances on different raw materials (formula II), and is suitable for industrial production.
Example 5
Screening experiments for other condensing Agents
1.0 eq of a compound of a formula II-1, 1.2eq of a compound of a formula III are used as raw materials, 1.8 eq of triethylamine is used as a base, 1.8 eq of different condensing agents are used respectively, and the reaction system is reacted at 50-60 ℃.
The effect of different condensing agents on the reaction was examined in this experiment, and the results are shown in table 4:
TABLE 4
As can be seen from Table 4, the reaction effect was poor when CDI and HATU were used as condensing agents, the reaction could not be completed with the raw material II-1, CDI was sensitive to moisture, HATU was expensive and the amount of by-product impurities was large.
Claims (4)
1. A preparation method of a Ruogeli key intermediate (I),
wherein R is selected from methyl, ethyl and propyl;
the method is characterized in that: taking compounds in a formula (II) and a formula (III) as raw materials, taking N, N '-Diisopropylcarbodiimide (DIC) as a condensing agent, and carrying out an amide condensation reaction in dichloromethane to obtain a Ruogeli key intermediate (I), wherein the equivalent ratio of the compounds in the formula (II) and the formula (III) to the N, N' -Diisopropylcarbodiimide (DIC) is 1.0: 1.2-1.3: 1.5-2.5, and the reaction temperature is 35-45 ℃.
2. A process for the preparation of rilogeli key intermediate (I) according to claim 1, characterized in that: r is selected from propyl.
3. A process for the preparation of rilogeli key intermediate (I) according to claim 2, characterized in that: the equivalent ratio of the formula (II) and the formula (III) to the N, N' -Diisopropylcarbodiimide (DIC) is 1.0: 1.2-1.3: 2.0-2.5.
4. The process for the preparation of Ruugeli key intermediate (I) according to claim 3, characterized in that: the equivalent ratio of the formula (II), the formula (III) and N, N' -Diisopropylcarbodiimide (DIC) is 1.0: 1.2: 2.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211670911.6A CN115650965B (en) | 2022-12-26 | 2022-12-26 | Preparation method of Ruogeli key intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211670911.6A CN115650965B (en) | 2022-12-26 | 2022-12-26 | Preparation method of Ruogeli key intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115650965A CN115650965A (en) | 2023-01-31 |
| CN115650965B true CN115650965B (en) | 2023-03-31 |
Family
ID=85023311
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211670911.6A Active CN115650965B (en) | 2022-12-26 | 2022-12-26 | Preparation method of Ruogeli key intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115650965B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104703992B (en) * | 2012-09-28 | 2019-03-05 | 武田药品工业株式会社 | The preparation method of Thienopyrimidine derivative |
| CN111440188B (en) * | 2020-04-10 | 2022-03-08 | 江苏海悦康医药科技有限公司 | Preparation method of Relugol (Relugolix) key intermediate |
| CN114907370B (en) * | 2021-02-10 | 2023-11-03 | 奥锐特药业(天津)有限公司 | High purity thienopyrimidine compounds and process for their preparation |
| CN114380810A (en) * | 2021-12-27 | 2022-04-22 | 南京方生和医药科技有限公司 | Rugosril intermediate impurity and preparation method thereof |
-
2022
- 2022-12-26 CN CN202211670911.6A patent/CN115650965B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN115650965A (en) | 2023-01-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2900675B1 (en) | Production method of thienopyrimidine derivative | |
| CN115650965B (en) | Preparation method of Ruogeli key intermediate | |
| WO1987004433A1 (en) | Preparation of 3-dimethylamino-7-methyl-1,2,4-benzotriazine-1-oxide and azapropazone | |
| JP2013121958A (en) | Method of producing 2-(2-amino-pyrimidin-4-yl)-1h-indole-5-carboxylic acid derivative | |
| EP0983246B1 (en) | Synthesis of acridine derivative multidrug-resistant inhibitors | |
| CN111320552A (en) | Preparation method of enzalutamide intermediate | |
| CN115197150B (en) | Preparation method of L-carnosine | |
| EP2328884A2 (en) | A process for the preparation of strontium ranelate | |
| RU2291150C1 (en) | Method for preparing 5-acylperhydro-1,3,5-dithiazines | |
| WO1987005902A1 (en) | Synthesis of antiulcer compounds | |
| CA2203435A1 (en) | N-sulfoxy anhydrides, a process for the preparation thereof and its use for the preparation of bioactive substances having ace inhibitory action | |
| AU7235287A (en) | Synthesis of antiulcer compounds | |
| Bátori et al. | Novel synthesis of pyrido [2, 1‐f]‐as‐triazinium system and its zwitterionic derivatives. Different reactivities of 1‐and 3‐olates with electrophiles | |
| KR20200088570A (en) | Process for Preparation of Fimasartan and Intermediate for Preparing the Same | |
| Kohl et al. | New synthetic routes for 1-benzyl-1, 4, 7, 10-tetraazacyclododecane and 1, 4, 7, 10-tetraazacyclododecane-1-acetic acid ethyl ester, important starting materials for metal-coded DOTA-based affinity tags | |
| CN112375015B (en) | Preparation method of di-tert-butyloxycarbonyl aminooxy acetic acid | |
| Li et al. | Syntheses of di‐heterocyclic compounds; pyrazolylimidazoles and isoxazolylimidazoles | |
| Glotova et al. | Dithiobiuretes in reactions with electrophilic acetylenes. New derivatives of 1, 3, 5-dithiazines,-thiadiazines and-triazines as the products of competing reactions of nucleophilic cycloaddition | |
| CN117466818B (en) | Method for preparing 2-aryl imidazoline compounds by solvent-free method | |
| CN114105961B (en) | Preparation method of IDO1 inhibitor (LY-3381916) | |
| RU2227141C2 (en) | Method for preparing benzylamine | |
| KR960001477B1 (en) | Improved process for the preparation of benzo(chalcogeno) | |
| CN115141251A (en) | Raltitrexed impurity, and preparation method and application thereof | |
| CA2610665A1 (en) | Hydrates of alkaline-earth salts of irbesartan and the preparation thereof | |
| Abdelaal et al. | Synthesis of 2‐amino‐4‐imino‐4, 5‐dihydrothiazoles from N‐sulfonyl‐α‐chloroamidines and thiourea |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |