Preparation method of key intermediate of lutrombopag

Abstract

The invention discloses a preparation method of a lultrombopag key intermediate, which comprises the following steps: by taking cheap and easily available 2, 6-dichlorobenzaldehyde as a starting raw material, carrying out Wittig reaction on the starting raw material and phosphorus ylide with ester carbonyl protected by dioxolane to obtain an olefin compound; then carrying out bromination reaction under the catalysis of iron powder to obtain a high-yield brominated compound; and carrying out Grignard reaction, carbon dioxide carboxylation and hydrochloric acid acidification synchronous degreasing protection, and carrying out primary crystallization to obtain the key intermediate of the lutrombopag. According to the method, lithium diisopropylamide and other strong bases are not needed, the reaction temperature is controlled to range from-10 DEG C to 30 DEG C, the requirement of the system for moisture is low, the total yield is high, the single impurity (containing Z-type isomer) of the product is smaller than 0.1%, the method has the advantages of being low in material cost, mild in reaction condition, high in stereoselectivity and easy to industrially produce, and the production cost of the lutrombopag is remarkably reduced.

Description

Technical Field

[0001] This invention relates to a method for preparing a rumbopag intermediate, belonging to the field of medicinal chemistry. Background Technology

[0002] Thrombocytopenia affects over 65% of patients with chronic liver disease, increasing not only the risk of bleeding but also leading to delayed interventional treatment in approximately 28% of patients. Lutrombopag, a second-generation small-molecule thrombopoietin receptor agonist, offers advantages such as oral administration and low hepatic metabolic dependence (CYP2C9 / CYP3A4 dependence rate of 25%). After its approval in Japan in 2015, it became the first-line treatment in clinical practice, and demand surged after entering the Chinese market in 2018. Previously, traditional therapies had significant limitations: recombinant human thrombopoietin required daily injections and had a neutralizing antibody production rate of up to 12%; platelet transfusions were limited by blood supply and posed safety risks.

[0003] Currently, the synthesis of ruzopoprobamate relies heavily on the key intermediate (E)-3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)benzoic acid (referred to as compound (VII') in patent literature 1 and compound 3 in non-patent literature 1), and the mainstream preparation process is the one-pot method. Although the one-pot method has advantages such as eliminating the need for intermediate separation and having a short production cycle, it has serious drawbacks in terms of materials, reaction conditions, isomer control, and yield, which restricts its industrialization.

[0004] High material costs and poor safety are the primary concerns. The one-pot process uses 3,5-dichlorobenzoic acid as a raw material, relying on strong bases such as lithium diisopropylaminolithium (LDA), N-formylmorpholine, and triethyl 2-phosphonopropionate. LDA is chemically unstable, decomposes violently in water, requires storage at -20°C, and has high procurement costs, necessitating a specialized corrosion-resistant reactor. N-formylmorpholine is used in quantities of 3.0-3.1 equivalents, accounting for a high cost proportion and is not recyclable. Triethyl 2-phosphonopropionate is added in excess at 1.5 equivalents. Regarding solvents, the optimized 1,2-dimethoxyethane in the literature is miscible with water but difficult to recover, further increasing costs.

[0005] The harsh reaction conditions result in poor industrial adaptability. The lithiation reaction requires ultra-low temperatures of -55°C to -75°C, far exceeding the controllable range of conventional equipment (-40°C), necessitating liquid nitrogen-assisted refrigeration, leading to high energy costs. The system moisture content must be ≤50ppm, and pretreatment requires nitrogen purging, resulting in production efficiency far lower than conventional processes. This process demands extremely high operational continuity; any refrigeration failure will lead to material spoilage.

[0006] Isomerization is a significant issue, and separation costs are high. The target intermediate contains a C=C double bond, generating an E / Z isomer. The Z-type is inactive, and pharmaceutical standards require it to be ≤0.1%. Non-patent literature 1 optimizes the E / Z ratio to 98:2, but separation is still necessary. The two isomers have similar physicochemical properties, requiring multiple recrystallization steps, which not only increases the number of steps but also leads to yield loss. Furthermore, the lithiation and formylation reactions generate a 4% formyl positional isomer and an 8% diformyl isomer, which can further react with triethyl 2-phosphonopropionate to generate positional isomers and disubstituted products, making separation even more difficult.

[0007] The total yield of the one-pot method in both patent literature 1 and non-patent literature 1 is only about 51%, mainly due to poor reaction selectivity and serious losses from multiple crystallization purification processes.

[0008] In summary, current methods for preparing key intermediates of rutrombopag have many shortcomings, leading to high production costs. Developing new processes with low material costs, mild reaction conditions, stereoselectivity, and high yields is crucial to overcoming industrialization bottlenecks and is of great significance for improving drug accessibility and reducing medication costs.

[0009] Existing technical documents Patent documents Patent Document 1: CN105992761A Non-patent literature Non-patent literature 1: Org. Process Res. Dev. 2020, 24, 11, 2651–2656 Non-patent literature 2: Synlett 1999, No.07, 1033-1036. Summary of the Invention

[0010] This invention aims to overcome many defects in the existing preparation process of key intermediates of rutrimbopag and provide a preparation method with low material cost, mild reaction conditions, high stereoselectivity, excellent yield and easy industrial production. It solves the industrialization bottlenecks of existing processes, such as expensive materials, ultra-low temperature requirements, difficulty in isomer control and low yield, reduces the production cost of rutrimbopag and improves drug accessibility.

[0011] To reduce costs, achieve mild reaction conditions, and improve product yield, the key lies in selecting suitable raw materials and enhancing reaction selectivity. Since there are multiple reactive sites on the formyl group of the benzene ring, this invention selects 2,6-dichlorobenzaldehyde with a formyl group as the raw material. This raw material is inexpensive and readily available, and the position of the formyl group is well-defined, avoiding the problems of strong base, ultra-low temperature conditions, and poor selectivity required when introducing the formyl group.

[0012] To increase the proportion of E-type olefins, the inventors experimented with various reaction reagents and solvent combinations. Surprisingly, they found that using the Wittig reaction, which typically produces Z-type products, to prepare the key intermediate of rutripopas yielded a relatively ideal proportion of E-type products. Based on this, the inventors optimized the structure of the Ylide reagent used in the Wittig reaction. To prevent the ester bond from reacting with the Grignard reagent during the subsequent preparation of the Grignard reagent, the inventors attempted to protect the ester bond. After extensive experimental research, they discovered that converting the ester carbonyl group to a dioxolane ring structure, in addition to achieving the expected effect, also significantly reduced the formation of Z-type isomers during olefination by increasing the steric hindrance of the ester.

[0013]

[0014] This invention further investigated the ester group (R group), finding that when tert-butyl ester was used, the Z-isomer obtained by the Wittesh reaction was less than 0.2%, and the Z-isomer increased sequentially when isopropyl ester, ethyl ester, and methyl ester were used; when methyl ester was used, the Z-isomer obtained by the Wittesh reaction was <0.5%. After subsequent reaction steps, the key intermediate of rutripoparaf could achieve a single impurity (containing the Z-isomer) of <0.1% after a single crystallization.

[0015] This invention achieves efficient preparation of key intermediates of rumbopag through a three-step tandem reaction. The specific technical solution is as follows: Step 1: Olefinification reaction. Using 2,6-dichlorobenzaldehyde as the starting material, ester carbonyl-protected phosphorus ylide as the olefinizing agent, and dichloromethane as the reaction solvent, the reaction is carried out at 15-25℃ without the need for cryogenic refrigeration, ensuring a mild and controllable reaction process. After the reaction is complete, the reaction solution is washed with brine to obtain a dichloromethane layer containing olefin compounds. The liquid phase content of the product is >99%, and the Z-isomer is <0.5%.

[0016] Step 2: Bromination reaction. The dichloromethane layer washed with brine was cooled, iron powder was added as a catalyst, and bromine was slowly added dropwise. After the addition was complete, the reaction was stirred. After post-treatment and distillation with toluene to remove water, the brominated compound was obtained, with a yield of >87% based on 2,6-dichlorobenzaldehyde.

[0017] Step 3: Grignard reaction - carboxylation - acidification and deprotection. Nitrogen gas is introduced into a three-necked reaction flask for protection. A tetrahydrofuran solution of the brominated compound and magnesium shavings are added to initiate the reaction. The remaining tetrahydrofuran solution of the brominated compound is then added dropwise to prepare an aryl Grignard reagent. Carbon dioxide gas is introduced into the above Grignard reagent system to achieve carboxylation conversion. Toluene is added, followed by acidification with hydrochloric acid and deesterification protection. After crystallization, the key intermediate rutripopas is obtained. The yield of this step is >90%, and the number of single impurities (including Z-isomers) is <0.1%.

[0018] The preparation method of the present invention has the following significant advantages compared with the prior art: The reaction conditions are mild and highly adaptable to industrial applications: It avoids the ultra-low temperature requirements of -55℃ to -75℃ and liquid nitrogen-assisted refrigeration in existing processes. The reaction temperature is concentrated in the range of -10℃ to 30℃, eliminating the need for special ultra-low temperature equipment and significantly reducing energy consumption costs. Since no strong alkali is used, the system has less stringent requirements for moisture, simplifying the pretreatment process and greatly improving production efficiency.

[0019] Low material cost and excellent safety: It eliminates the need for expensive and unstable strong bases, excessive N-formylmorpholine and triethyl 2-phosphonopropionate, thus reducing raw material procurement costs; it avoids the use of high-risk reagents such as strong bases, resulting in high stability of the reaction system and significantly reduced operational safety risks.

[0020] It exhibits extremely high stereoselectivity and low purification difficulty: chlorine atoms serve as meta-directing groups, while styrene compounds serve as ortho- and para-directing groups, both of which increase the position selectivity during benzene ring bromination; through reagent selection and process control in the olefination reaction, the Z-isomer content in the olefination process is reduced from 2% in existing processes to <0.5%, and subsequent post-reaction processing does not require multiple recrystallizations, achieving high purity through simple washing and a single crystallization, thus reducing yield loss.

[0021] The yield has been greatly improved: the total yield is higher than 78%, which is much higher than the approximately 51% reported in existing literature, significantly reducing raw material waste and production costs.

[0022] The process is simple and controllable: the three-step reaction process is clear, the post-processing operation is simple, the solvents (dichloromethane, toluene, tetrahydrofuran, acetonitrile) are easy to recycle and reuse, the environmental protection is good, and it meets the requirements of large-scale industrial production. Detailed Implementation Example 1

[0023]

[0024] The ester carbonyl protection of phosphorus ylide reagents can be performed under similar conditions as reported in Non-Patent Literature 2.

[0025] Step 1: At 15-25℃, add 175g of 2,6-dichlorobenzaldehyde and 434.5g of ester carbonyl-protected phosphorus ylide to 1050ml of dichloromethane, and keep the reaction at this temperature for 2 hours. The liquid phase content of the olefin compound is >99%, and the Z-isomer is <0.2%. Wash three times with 500ml of 5% saline solution and separate the layers.

[0026] Step 2: Cool the dichloromethane layer containing the olefin compound to -5°C to -10°C, add 2.2g of iron powder, and add 167.8g of bromine dropwise over 1 hour. Stir the mixture for 2 hours, then add 1400ml of water. Separate the layers. Wash the organic layer once with 500ml of 5% sodium thiosulfate solution and once with 500ml of 10% saline solution. Concentrate the organic layer to dryness under reduced pressure, and distill it three times with toluene, 300ml each time. The weight of the bromine compound is 363.8g, and the yield is 88.7% based on 2,6-dichlorobenzaldehyde.

[0027] Step 3: Add 3000 ml of tetrahydrofuran to the brominated compound to obtain a tetrahydrofuran solution. Purge nitrogen gas into a three-necked flask, add 300 ml of the tetrahydrofuran solution to the three-necked flask, add 23.7 g of magnesium shavings, stir at 25-30°C for 0.5 hours, add the remaining 2700 ml of tetrahydrofuran solution dropwise, and after the dropwise addition is complete, react at 25-30°C for 1 hour, then stop purging nitrogen gas. After introducing 117.1 g of carbon dioxide gas, the mixture was stirred for 1 hour. 2000 ml of toluene was added, and 2000 ml of 5% hydrochloric acid was slowly added below 25°C. The mixture was stirred for 30 minutes, resulting in layer separation. The aqueous layer was extracted once with 1000 ml of toluene. The organic layers were combined and washed once with 1000 ml of 10% brine. The organic layer was evaporated to dryness, and 3000 ml of acetonitrile was added. The mixture was heated to reflux to dissolve the crystals, then slowly cooled to 0-5°C and stirred to induce crystallization for 3 hours. The crystals were filtered, and the filter cake was dried at 45°C to obtain 271.2 g of the product, with a yield of 92.3%. Individual impurities (including Z-isomers) were <0.1%. The overall yield was 81.9%, significantly higher than the approximately 51% yield reported in the literature.

Claims

1. A method for preparing a key intermediate of leucovorin, characterized in that, Includes the following steps: ， Step 1: 2,6-Dichlorobenzaldehyde and ester-carbonyl-protected phosphorus ylide were olefinized in dichloromethane. Step 2: After cooling the dichloromethane layer containing the olefin compound, iron powder was added as a catalyst and bromine was added dropwise to carry out the bromination reaction. Step 3: The bromination compound was dissolved in tetrahydrofuran and prepared with magnesium shavings under nitrogen protection to prepare an aryl Grignard reagent. After carboxylation by carbon dioxide, hydrochloric acid was added for acidification and simultaneous deesterification protection. The key intermediate, rutripopas, was obtained through Grignard reaction-carboxylation-acidification and deprotection.

2. The preparation method according to claim 1, characterized in that, The ester carbonyl group described in step 1 is protected in the form of a dioxolane ring.

3. The preparation method according to claim 1, characterized in that, The ester group of the phosphorus ylide in step 1 is tert-butyl ester, isopropyl ester, ethyl ester, or methyl ester.

4. The preparation method according to claim 3, characterized in that, The ester group of the phosphorus ylide is tert-butyl ester.

5. The preparation method according to claim 1, characterized in that, The temperature of the bromination reaction in step 2 is controlled between -5°C and -10°C.

6. The preparation method according to claim 1, characterized in that, The temperature of the Grignard reaction in step 3 is controlled at 25-30℃.

7. The preparation method according to claim 1, characterized in that, In step 1, the Z-isomers of the olefin compound are less than 0.5%.

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