CN110818722B

CN110818722B - Three compounds, preparation method thereof and application thereof in synthesizing suogliflozin

Info

Publication number: CN110818722B
Application number: CN201810924753.XA
Authority: CN
Inventors: 李丕旭; 王鹏; 魏强; 蒋强华; 景朝选
Original assignee: Suzhou Pengxu Pharmatech Co ltd
Current assignee: Suzhou Pengxu Pharmatech Co ltd
Priority date: 2018-08-14
Filing date: 2018-08-14
Publication date: 2022-12-02
Anticipated expiration: 2038-08-14
Also published as: CN110818722A

Abstract

The present application provides compounds of formulae IV, V, VI and methods for their preparation. The present application also provides compounds of formulae IV, V, VI and synthetic methods for the synthesis of suggestin. The method has the advantages of easily available and cheap raw materials, simple and convenient operation, saving and environmental protection, and is beneficial to industrial production.

，

，

Description

Three compounds, preparation method thereof and application thereof in synthesizing suogliflozin

Technical Field

The application relates to the field of drug synthesis, in particular to several compounds, preparation methods thereof and application thereof in synthesizing suggestin. The application also relates to a method for synthesizing the sugelliflozin.

Background

Diabetes is a metabolic disease characterized by hyperglycemia. Hyperglycemia, which is present in long-term diabetes, leads to chronic damage to, dysfunction of, various tissues, particularly, the eyes, kidneys, heart, blood vessels, nerves. Type 1 diabetes mellitus: the disease is of a light age, mostly less than 30 years old, the symptoms of polydipsia, diuresis, polyphagia and emaciation are obvious, the disease is sudden, the blood sugar level is high, and the oral medicine is not used singly for marketing at the present stage and needs to be treated by insulin. Type 2 diabetes: it is common in the middle-aged and the elderly, and obese people have high morbidity and can be accompanied by diseases such as hypertension, dyslipidemia, arteriosclerosis and the like.

Socagrelin (Sotagliflozin) is used as an experimental new drug for treating diabetes mellitus for Leishiken and Seprofene, and is likely to become a treatment option for patients with type 1 diabetes mellitus through a novel oral sodium-glucose cotransporter 1 and 2 (SGLT-1 and SGLT-2) dual inhibitor. Sotagliflozin has shown very good results in the phase 2 study for patients with type 1 diabetes compared to placebo. Phase 2 studies in type 2 diabetic patients, including those with renal impairment, have shown good therapeutic effects in lowering blood glucose (HbA 1 c), reducing weight, and improving blood pressure. Phase 3 clinical trials are currently underway.

So far, there are few relevant patent reports in foreign countries, and the main reported patent synthetic route is the synthetic route of original research lei-seiken company (WO 2009014970):

domestic patents on the synthesis of suggestin are rarely reported, and the following synthetic route is reported in Hangzhou Ke nest (CN 107540685A):

the process route reported by the Leishiken company is directly designed and is shorter; however, the compound A3 in the whole process route has good water solubility and low extraction efficiency, so that the operability and the efficiency of the process flow are reduced. The synthesis route reported by Kenesto corporation protects the hydroxyl of the compound A3, can solve the water solubility problem of the compound A3 to a certain extent, but adds two protection and deprotection reaction processes of TBS and PMB in the process, greatly prolongs the length of the synthesis route, and destroys the economy of the synthesis process route.

Therefore, it is necessary to design a more direct synthetic route that can effectively improve the production efficiency and reduce the synthetic route and the operation contents and steps in the production process. The pursuit of cost, quality and efficiency is a constant task for drug synthesis process developers.

Disclosure of Invention

The application aims to provide a compound in general formulas IV, V and VI and a preparation method thereof.

It is a further object of the present application to provide the use of compounds of general formulae IV, V, VI for the synthesis of suggestin of formula X.

In one aspect, the present application provides a compound having the structure of formula IV:

，

wherein G is a protecting group formed by a cyclic ketone compound.

Preferred G is cyclopentanone or cyclohexanone.

Furthermore, it will be understood by those skilled in the art that the compound of formula IV is synthesized from L-xylose only requiring that the 5 'position be in the (R) configuration, the 6' position be in the (S) configuration, the 6a 'position be in the (S) configuration and no particular requirement is placed on the configuration of the 3a' position, and thus the 3a 'position may be in either the (R) or (S) configuration, or a mixture of both (R) and (S) configurations at the 3a' position.

The second compound has the structure of formula V:

，

wherein G is a protecting group formed by a cyclic ketone compound.

Preferred G is cyclopentanone or cyclohexanone.

The third compound has the structure of formula VI:

，

wherein G is a protecting group formed by a cyclic ketone compound, and preferably G is cyclopentanone or cyclohexanone.

Furthermore, it will be understood by those skilled in the art that the compound of formula IV is synthesized from L-xylose only requiring that the 5 'position be in the (S) configuration, the 6' position be in the (R) configuration, the 6a 'position be in the (S) configuration and that no particular requirement is imposed on the configuration of the 1 and 3a' positions, and thus the 1 and 3a 'positions may be in either the (R) or (S) configuration, or a mixture of both the (R) and (S) configurations at the 1 and 3a' positions.

Similarly, other open-chain ketones and aldehydes capable of forming protection with vicinal diols can also be applied to the process route of soxhlet's as protecting groups.

In another aspect, the present application provides a process for preparing a compound of formula IV, V, VI, comprising the step of preparing a compound of formula IV from a compound of formula III:

，

It will be appreciated by those skilled in the art that the compound of formula IV may be prepared from the compound of formula III by dehydration condensation reaction methods known in the art, such as by DCC, EDC, and the like reagents to promote the dehydration condensation reaction.

A step of preparing a compound of formula V from a compound of formula IV:

，

wherein G is a protecting group formed by a cyclic ketone compound, and X is Br or I. Preferred G is cyclopentanone or cyclohexanone.

It will be appreciated by those skilled in the art that conversion of the compound to a nucleophilic attack compound by reactions known in the art can react with the amide carbonyl group in compound VI and ultimately produce compound V, for example by completing a halogen exchange with a Grignard reagent or a lithium reagent followed by removal of morpholine to produce carbonyl compound V.

The preparation of a compound of formula VI from a compound of formula V:

，

It will be appreciated by those skilled in the art that compounds may be reduced to the hydroxy group by conversion of the V carbonyl group by reduction reactions known in the art, such as by sodium borohydride.

In a further aspect, the present application provides the use of a compound of formulae IV, V, VI as described above for the synthesis of suggestin of formula X as follows:

。

Compared with the prior art, the method for synthesizing the suggestin has the following advantages:

1. the raw materials are easy to obtain and low in price;

2. surprisingly, the inventor finds that after the cyclic protecting group is used for replacing propylidene, the intermediate and the product are easier to separate and purify, the extraction efficiency is greatly improved, and the sugelliflozin intermediate compound can be directly subjected to a series reaction to be used for preparing the sugelliflozin intermediate compound in the next step, so that the operation is simpler;

3. the extraction efficiency is improved, the use amount of the solvent is greatly reduced, and the method is more economical and environment-friendly;

4. compared with an acetone protecting group, the cyclic ketone protecting group has better stability in a process route and is not easy to remove to cause side reaction.

Detailed Description

Embodiments of the present application are described below by way of examples, and it should be appreciated by those skilled in the art that these specific examples merely illustrate selected embodiments for achieving the purposes of the present application and are not intended to limit the technical solutions. Modifications of the technical solutions of the present application in combination with the prior art are obvious from the teachings of the present application and fall within the protection scope of the present application.

The implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not noted are generally those in routine experiments.

Among them, the chemical agents used in the following examples are all commercially available chemical agents.

In the exemplary embodiments of the present invention, the skilled person can also make changes to the synthetic route, such as changing the specific reaction conditions or making adjustments to the synthetic route of one or more steps according to needs, etc., which are within the protection scope of the present application without departing from the essence of the present invention.

Example 01:

synthesis of Sot253

Under the protection of nitrogen, 60 mL of cyclohexanone and 10 g of L-xylose are added into a 250 mL three-neck round-bottom flask, the temperature is reduced to 0 to 5 ℃ by stirring, 1.5 mL of concentrated sulfuric acid is dripped, the temperature is raised to 20 to 30 ℃ after the dripping is finished, the reaction is carried out overnight (15 to 20 h), and the end point of the reaction (phosphomolybdic acid coloration) is monitored by TLC. After the reaction is finished, cooling the reaction liquid to 0-5 ℃, adding 6.15 g of sodium bicarbonate solid in batches, and then adjusting the pH of the system to be 6-7 by using 25% concentrated ammonia water. Filtering to remove insoluble solids, leaching a filter cake with a small amount of ethanol, collecting filtrate, concentrating the filtrate at 70 ℃ under reduced pressure until no obvious liquid is distilled off, adding 100 mL of absolute ethanol and 40 mL of water, cooling to 0-10 ℃, then turning to-20 ℃ overnight, performing suction filtration, leaching the filter cake with 30 mL of 60% ethanol (precooling to-20 ℃) to obtain 21.21 g of a Sot251 white solid wet product (ethyl acetate/n-heptane =1/9, rf is about 0.6, phosphomolybdic acid is developed), directly using the wet product for the next synthesis, drying the wet product to 13.36 g, and obtaining the yield on dry of 64.6%. ¹ H-NMR (DMSO-d6, 400 MHz) δ: 5.89 (d, J=3.8 Hz, 1 H), 4.47(d, J=3.8 Hz, 1H), 4.28(d, J=2.2 Hz, 1H), 4.06(dd, J=13.4, 2.4 Hz, 1H), 3.93(d, J=0.7 Hz, 1H), 3.81(d, J=13.4 Hz, 1H), 1.84-1.36(m, 20H)。

Will 2121 g of Sot251 wet product (13.36 g after drying) was added to 50 mL of acetonitrile, a previously prepared aqueous solution of phosphoric acid (12 mL of phosphoric acid dissolved in 120 mL of water) was added to form a white suspension, the system was heated to 55 ℃ to react until the system was clear, and the end point of the reaction was detected by TLC (phosphomolybdic acid coloration). After the reaction is finished, cooling to 20 to 30 ℃, extracting for 5 times by using 5 × 50 mL of dichloromethane, combining organic phases, washing the organic phases by using 40 mL of saturated sodium bicarbonate, separating, collecting the organic phases, concentrating and drying under reduced pressure at 45 ℃, and performing oil pump drying to obtain 10 g of crude Sot252 (ethyl acetate/n-heptane =1/1, rf is about 0.2, phosphomolybdic acid is developed) which is directly used for the synthesis of the next reaction. And purifying the crude Sot252 product by column chromatography to obtain a white solid pure Sot252 product (200-300 mesh silica gel, elution gradient: n-heptane/ethyl acetate =3/1 → 2/1, phosphomolybdic acid color development). ¹ H-NMR (DMSO-d6, 400 MHz) δ: 5.80(d, J=3.6 Hz, 1H), 5.09(d, J=5.2 Hz, 1H), 4.57(t, J=5.6 Hz, 1H), 4.36(d, J=4.0 Hz, 1H), 3.98(m, 2H), 3.61(m, 1H), 3.51(m, 1H), 1.60-1.33(m, 10H)。

Under the protection of nitrogen, 150 mL of acetone and 50 mL of water are added into a 250 mL three-neck flask, 10 g of Sot252 is added, 11 g of sodium bicarbonate and 0.91 g of sodium bromide are added, 200 mg of 2, 6-tetramethylpiperidine oxide (Tempo) is added, the temperature is controlled to be 0 to 10 ℃, 9.62 g of trichloroisocyanuric acid (TCCA) is added in batches, the reaction is carried out overnight at 20 to 25 ℃, and the reaction is monitored by TLC. And after the reaction is finished, performing suction filtration to remove insoluble solids, leaching with a small amount of acetone, concentrating under reduced pressure at 20 to 30 ℃ until no obvious liquid is distilled off, extracting the water phase with 120 mL ethyl acetate for 3 times, adjusting the pH of the water phase with phosphoric acid to be =2, extracting with 100 mL ethyl acetate for two times, combining the organic phases five times, drying with anhydrous sodium sulfate, filtering, leaching the filter cake with ethyl acetate, and concentrating under reduced pressure at 35 ℃ to obtain a crude product of Sot 253. The crude product was purified by column chromatography (200-300 mesh silica gel, elution gradient: n-heptane → n-heptane/ethyl acetate =4/1 → 3/1 → 1/1, color development of phosphomolybdic acid) to give 4.5 g of a white solid (Sot 253) in 27.7% yield (calculated from L-xylose). ¹ H-NMR (DMSO-d6, 400 MHz) δ: 12.55(brs, 1H), 5.92(d, J=3.6 Hz, 1H), 5.44(brs, 1H), 4.54(d, J=3.2 Hz, 1H), 4.41(d, J=3.2 Hz, 1H), 4.22(d, J=3.2 Hz, 1H), 1.61-1.24(m, 10H)。

Example 02:

synthesis of Sot254

Under the protection of nitrogen, 4.5 g of Sot253, 60 mL of tetrahydrofuran, 8.9 g of O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroboric acid (TBTU), 2.5 g of morpholine are added into a 100 mL three-neck flask, the mixture is stirred for 0.5 h at 20 to 30 ℃, 2.5 g of morpholine is added into the reaction system, the mixture is continuously stirred for 6 h at 20 to 30 ℃, and the reaction endpoint is detected by TLC (phosphomolybdic acid color development). After the reaction was completed, insoluble solids were removed by filtration, the filtrate was rinsed with tetrahydrofuran, collected, and concentrated to dryness at 40 ℃ under reduced pressure to give crude Sot254, which was purified by column chromatography (200-300 mesh silica gel, gradient elution polarity: n-heptane → n-heptane/ethyl acetate = 4/1) to give 2.6 g of a colorless oil (ethyl acetate/n-heptane =1/1, rf: about 0.3), yield: 45.1%. ¹ H-NMR (DMSO-d6, 400 MHz) δ: 5.97(d, J=4.0 Hz, 1H), 5.59(brs, 1H), 4.84(d, J=3.6 Hz, 1H), 4.44(d, J=3.6 Hz, 1H), 4.31(s, 1H), 3.46(m, 8H), 1.64-1.34(m, 10H)。

Example 03:

synthesis of Sot259

Under the protection of nitrogen, 3 g of Sot08 is added into a 50 mL three-neck flask, 12 mL of tetrahydrofuran is added, the temperature is reduced to minus 10 to minus 5 ℃ under stirring, 4.4 mL of isopropyl magnesium chloride (2.0M) is added dropwise, and the reaction solution A is obtained after the dropwise addition is finished and the stirring is continued at minus 10 to minus 5 ℃ (for later use).

Synchronously operating, under the protection of nitrogen, adding 2 g of Sot04 into another 50 mL three-neck flask, adding 11 mL of tetrahydrofuran, starting stirring, cooling the system to-30 to-20 ℃, dropwise adding 9 mL of tert-butyl magnesium chloride (1.0M), and continuously stirring for 1 h after dropwise adding to obtain a reaction liquid B. Controlling the temperature to be minus 30 to minus 20 ℃, slowly pressing the reaction liquid A into the reaction liquid B, and continuing to be minus 30 ℃ after the pressing is finishedStirring and reacting for 0.5 h at the temperature of minus 20 ℃, and detecting the reaction end point by HPLC. After the reaction, the reaction mixture was quenched by pressing it into 5 mL of 10% ammonium chloride. Then controlling the temperature to be 0-5 ℃, and dropwise adding 3 mL of 6N hydrochloric acid aqueous solution for neutralization reaction. The insoluble solids were removed by filtration, the filter cake was washed with ethyl acetate, the filtrate was collected, the aqueous phase was extracted once more with ethyl acetate, the organic phases were combined, the organic phase was washed 3 times with saturated sodium chloride and concentrated to dryness at not more than 40 ℃ under reduced pressure to give crude Sot259 (ethyl acetate/n-heptane =1/1, rf about 0.7, uv254 nm) which was purified by column chromatography (200-300 mesh silica gel, gradient elution polarity: n-heptane → n-heptane/ethyl acetate =5/1 → 3/1) to give 2.3 g Sot259 white solid in 76.2% yield. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 7.84(dd, J= 2.0, 8.4 Hz, 1H), 7.80(d, J= 2.0 Hz, 1H), 7.47(d, J= 8.4 Hz, 1H), 7.09(m, 2H), 6.83(m, 2H), 6.04(d, J= 3.6 Hz, 1H), 5.22(d, J= 2.4 Hz, 1H), 4.55(d, J= 3.6 Hz, 2H), 4.07(d, J= 4.4 Hz, 2H), 4.00 (q, 2H), 3.07(s, 1H), 1.70-1.57(m, 8H), 1.39(m, 2H), 1.40(t, J= 6.8 Hz, 3H). MS m/z: 473.2 [M+H] ⁺ , 495.1 [M+Na] ⁺ 。

Example 04:

synthesis of Sot263

To a 50 mL three-necked flask was added 2 g of Sot259, 20 mL of methanol was added, stirring was turned on, and 1.7 g of cerium chloride (CeCl) was added ₃ ▪7H ₂ O), then controlling the temperature to be 15-25 ℃, dropwise adding an alkali solution of sodium borohydride (68 mg of sodium borohydride is dissolved in 0.2 mL of 4% sodium hydroxide aqueous solution), continuing the reaction for 0.5 h, and monitoring the reaction end point (the isomer content is 8.7%) by HPLC. After the reaction is finished, adding 4 mL10% ammonium chloride aqueous solution to quench the reaction, concentrating under reduced pressure at 40 ℃ until no obvious liquid is distilled off, adding methyl tert-butyl ether and water, adjusting the pH of the system to be =2 by 6N hydrochloric acid, separating the liquid, collecting an organic phase, washing the organic phase once by using water, separating the liquid, temporarily storing the organic phase, combining aqueous phases, extracting the aqueous phase once by using methyl tert-butyl ether, combining the organic phasesThe phases, saturated sodium chloride, were backwashed once to the organic phase, the phases were separated and the organic phase was concentrated at 40 ℃ under reduced pressure to dryness to give 1.9 g of crude Sot263 (ethyl acetate/n-heptane =1/1, rf about 0.65, UV254 nm) with a yield of 95%. 1.5 g of crude Sot263 was purified by column chromatography (200-300 mesh silica gel, gradient elution polarity: n-heptane → n-heptane/ethyl acetate =10/1 → 8/1 → 5/1) to give 0.9 g of a white solid. ¹ H-NMR(CDCl ₃ , 400 MHz) δ: 7.37(d, J= 8.0 Hz, 1H), 7.25(dd, J= 2.4, 8.4 Hz, 1H), 7.19(d, J= 2.0 Hz, 1H), 7.08(m, 2H), 6.81(m, 2H), 5.98(d, J= 3.6 Hz, 1H), 5.12(d, J= 4.4 Hz, 1H), 4.45(d, J= 3.6 Hz, 1H), 4.11(m, 1H), 4.08(m, 1H), 4.03(d, J= 3.2 Hz, 2H), 4.00(q, 2H), 3.33(s, 1H), 1.63-1.47(m, 8H), 1.39(t, J= 6.8 Hz, 3H), 1.38(m, 2H)。

Example 05:

synthesis of Sot12

0.8 g of Sot263 and 5 mL of acetonitrile are added to a three-necked flask, stirring is started, 1.75 mL of 0.2 mol/L aqueous sulfuric acid solution is added, the temperature is raised to 80 ℃, stirring is carried out for 19 h, and the end point of the reaction is monitored by HPLC. After completion of the reaction, the temperature was lowered to 20 ℃ or lower, 1.8 mL of a saturated aqueous potassium carbonate solution was added to the reaction solution, 5 mL of methyl t-butyl ether was added thereto and stirred, liquid separation was carried out, the organic phase was collected, the aqueous phase was extracted 2 times with 2X 3 mL of methyl t-butyl ether, and the organic phases were combined. Washing the organic phase once with saturated sodium chloride, concentrating the organic phase, adding 5 mL of acetonitrile, and concentrating to 3 mL to obtain an acetonitrile solution of Sot10, which is directly used for the next step of Sot11 synthesis. MS M/z 412.1 [ M + NH ] ₄ ] ⁺ , 417.1 [M+Na] ⁺ 。

The temperature of the acetonitrile solution of Sot10 is reduced to 10 ℃, 12 mg of 4-Dimethylaminopyridine (DMAP) and 1.1 mL of acetic anhydride are added, 1.6 mL of triethylamine is added dropwise at the temperature controlled below 20 ℃, the reaction is carried out for 1 h at 20 ℃, and the reaction endpoint is monitored by HPLC. Adding 5 mL of methyl tert-butyl ether and 2.5 mL of water, stirring for 10 min, separating, extracting the aqueous phase with 3 mL of methyl tert-butyl ether, and mixingWashing the organic phase once with saturated potassium bicarbonate, washing the organic phase once with 1N sodium bisulfate, washing the organic phase once with saturated sodium chloride, and concentrating the organic phase to obtain the crude Sot11 product which is directly used for the next step of synthesis. MS M/z 580.2 [ M + NH ] ₄ ] ⁺ , 585.1 [M+Na] ⁺ 。

To the above concentrated residue, 5 mL of dioxane was added, the organic phase was concentrated, 3 mL of dioxane was added, 0.28 g of thiourea and 0.6 mL of trimethylsilyl trifluoromethanesulfonate (TMSOTF) were added, the temperature was raised to 80 ℃ for 6 hours, and the end point of the reaction was monitored by HPLC (intermediate MS M/z: 579.1 [ M + H ] M + H] ⁺ ). After the reaction is finished, the temperature is reduced to 20 ℃, 0.2 mL of methyl iodide is added, the temperature is controlled to be not more than 20 ℃, 1.2 mL of N, N-Diisopropylethylamine (DIPEA) is added, the reaction is carried out for 24 h at 20 ℃, the reaction end point is detected by HPLC, 4 mL of water is added, 4 mL of methyl tert-butyl ether is added, the mixture is stirred and separated, the organic phase is washed twice by water, the crude product of Sot12 is obtained by decompression and concentration, the crude product of Sot12 is purified by column chromatography (200-300 meshes of silica gel, the gradient elution polarity is n-heptane → n-heptane/ethyl acetate = 5/1), 0.2 g of Sot12 white solid is obtained, and the yield is 21.5% (the yield is calculated from Sot 263). ¹ H-NMR (CDCl3, 400 MHz) δ: 7.37 (d, J=8.0 Hz, 1H), 7.19 (dd, J=2.0, 8.4 Hz, 1H), 7.07 (m, 3H), 6.84 (d, J=8.4 Hz, 2H), 5.32 (t, J=9.2 Hz, 1H), 5.20 (t, J=9.6 Hz, 1H), 5.05 (t, J=9.6 Hz, 1H), 4.51 (d, J=10.0 Hz, 1H), 4.38 (d, J=10.0 Hz, 1H), 4.03(m, 4H), 2.17 (s, 3H), 2.10 (s, 3H), 2.01 (s, 3H), 1.73 (s, 3H), 1.42 (t, J=7.2 Hz, 3H). MS m/z: 568.2 [M+NH ₄ ] ⁺ , 573.1 [M+Na] ⁺ 。

Example 06:

synthesis of Sot13

0.1 g of Sot12 is added into a 100 mL single-neck bottle, 2 mL of methanol is added, 0.25 mL of 25% sodium methoxide methanol solution is dropwise added at 15 to 20 ℃, the reaction is carried out for 2 h, and the reaction endpoint is monitored by HPLC. After the reaction is completed, the reaction solution is concentrated under reduced pressure at 40 ℃, and then5 mL of methyl tert-butyl ether and 2 mL of water are added and stirred, the organic phase is separated and collected, the organic phase is concentrated under reduced pressure at 40 ℃ to obtain crude Sot13, which is purified by column chromatography (200-300 mesh silica gel, gradient elution polarity: ethyl acetate) to obtain 60 mg of white solid with yield: 77.8 percent. ¹ H-NMR (DMSO-d6, 400 MHz) δ: 7.38 (d, J=8.4 Hz, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.21 (dd, J=2.0, 8.4 Hz, 1H), 7.10 (m, 2H), 6.83 (d, J=8.4 Hz, 2H), 5.24 (d, J=5.6 Hz, 1H), 5.16 (d, J=4.8 Hz, 1H), 4.97 (d, J=5.6 Hz, 1H), 4.35 (d, J=9.2 Hz, 1H), 4.09 (d, J=9.6 Hz, 1H), 3.96 (m, 4H), 3.21 (m, 3H), 2.03 (s, 3H), 1.30 (t, J=6.8 Hz, 3H). MS m/z: 442.2 [M+NH ₄ ] ⁺ , 447.1 [M+Na] ⁺ 。

Example 07:

synthesis of Sot257

Adding 180 mL of cyclopentanone and 30 g of xylose into a 500 mL three-neck round-bottom flask under the protection of nitrogen, stirring, cooling to 5 to 15 ℃, dropwise adding 4.5 mL of concentrated sulfuric acid, heating to 20 to 30 ℃ after dropwise adding, reacting for 15 to 20 hours, filtering to remove insoluble substances, cooling the filtrate to 0 to 10 ℃, adding 18.2 g of sodium bicarbonate solid in batches, and then adjusting the pH of the system to be =6-7 by using 25% ammonia water. Filtering to remove insoluble solids, collecting filtrate, concentrating the filtrate at 85 ℃ under reduced pressure until no obvious liquid is distilled off, adding 30 mL of ethanol into concentrated residual liquid, adding 30 mL of water, stirring to separate out solids, cooling to 0-10 ℃ in an ice water bath, stirring for 2-3 h at 0-10 ℃, filtering, rinsing the filter cake with 30 mL of ethanol/water =1/2 (v/v), and drying the wet product at 50 ℃ in vacuum to constant weight to obtain 9.4 g of Sot255 light brown solid (ethyl acetate/n-heptane =1/9, rf is about 0.6), wherein the yield is 16.7%. ¹ H -NMR(DMSO-d6, 400 MHz) δ: 5.88(d, J=3.6 Hz, 1H), 4.40(d, J=4.0 Hz, 1H), 4.27(d, J=2.0 Hz, 1H), 3.99(dd, J=2.4, 13.6 Hz, 1H), 3.91(m, 1H), 3.88(d, J=13.6 Hz, 1H), 1.98-1.51(m, 16H)。

Adding 8 g of Sot255 into 35 mL of acetonitrile, stirring for dissolving, adding a prepared phosphoric acid aqueous solution (4 mL of phosphoric acid is dissolved in 80 mL of water) to form a white suspension, heating the system to 20-30 ℃, reacting until the system is clear, and detecting the reaction end point by TLC (phosphomolybdic acid color development). After the reaction, the reaction solution was extracted once with 20 mL of n-heptane, the aqueous phase was retained, then the aqueous phase was extracted 3 times with 3 × 40 mL of ethyl acetate, the organic phases were combined, the organic phase was back-washed once with 20 mL of saturated sodium bicarbonate, the liquid was separated, the organic phase was collected, and the organic phase was concentrated under reduced pressure at a temperature of not more than 45 ℃ until no significant liquid was distilled off, to obtain 7.1 g of crude Sot252 (ethyl acetate/n-heptane =1/1, rf about 0.2) which was directly used in the next reaction synthesis. A small amount of crude Sot256 was taken and subjected to column chromatography to give Sot256 as a white solid (200-300 mesh silica gel, eluent: n-heptane/ethyl acetate =3/1 → 2/1, phosphomolybdic acid developed). ¹ H-NMR (DMSO-d6, 400 MHz) δ: 5.78(d, J= 3.6 Hz, 1H), 5.13(brs, 1H), 4.60(brs, 1H), 4.30(d, J=3.6 Hz, 1H), 4.00(m, 2H), 3.60(m, 1H), 3.50(m, 1H), 1.85-1.54(m, 8H)。

Under the protection of nitrogen, 7.1 g of the crude Sot256 is added into a 500 mL three-neck flask, 25 mL of acetonitrile, 25 mL of water, 5.7 g of dipotassium hydrogen phosphate and 2.3 g of monopotassium phosphate are added, stirring is started, 408 mg of 2, 6-tetramethylpiperidine oxide (Tempo) is added, meanwhile, an aqueous sodium chlorite solution (5.7 g of sodium chlorite dissolved in 13 mL of water) and 5.0 g of an aqueous sodium hypochlorite solution are added dropwise, the reaction is carried out overnight at 15 to 25 ℃, and the end point of the reaction is monitored by TLC (phosphomolybdic acid color development). After the reaction is finished, the temperature of the reaction is reduced to 0 to 10 ℃, the reaction is quenched by 30 mL of 15% sodium sulfite aqueous solution, 60 mL of acetonitrile is added, then the pH of a phosphoric acid adjusting system is used for =3-4, liquid separation is carried out, an organic phase is collected, an aqueous phase is extracted by 3 × 50 mL of ethyl acetate for three times, the organic phases are combined and concentrated to dryness under reduced pressure at 30 ℃, so 257 crude product of Sot is obtained, and the crude product is purified by column chromatography (200-300 mesh silica gel, elution gradient: n-heptane → ethyl acetate/n-heptane =3/1 → ethyl acetate/n-heptane =1.7/1, phosphomolybdic acid is developed to obtain 5.0 g of white solid (Sot 253) with the yield of 76.7% (the yield is calculated from Sot 255). ¹ H-NMR (DMSO-d6, 400 MHz) δ: 12.58(brs, 1H), 5.91(d, J= 3.6 Hz, 1H), 5.67(brs, 1H), 4.54(d, J= 3.2 Hz, 1H), 4.36(d, J= 3.6 Hz, 1H), 4.24(d, J= 3.2 Hz, 1H), 1.85-1.53(m, 8H)。

Example 08:

synthesis of Sot258

Under the protection of nitrogen, 5 g of Sot257, 100 mL of tetrahydrofuran, 10.7 g of O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate (TBTU), 2.9 g of morpholine are added into a 250 mL three-neck flask, the mixture is stirred for 1 h at 20-30 ℃, 3.0 g of morpholine is added into the reaction system, the mixture is continuously stirred for overnight (about 12 h) at 20-30 ℃, and the end point of the reaction is detected by TLC (phosphomolybdic acid is developed). After the reaction was completed, insoluble solid was removed by filtration, rinsed with tetrahydrofuran, the filtrate was collected, and concentrated to dryness under reduced pressure at 40 ℃ to obtain crude Sot254, which was purified by column chromatography (200-300 mesh silica gel, gradient elution polarity: n-heptane → n-heptane/ethyl acetate = 4/1) to obtain 4.32 g of white solid (ethyl acetate/n-heptane =1/1, rf: about 0.3), yield: 67.4%. ¹ H-NMR (DMSO-d6, 400 MHz) δ: 5.96(d, J= 4.0 Hz, 1H), 5.61(d, J= 5.2 Hz, 1H), 4.87(d, J= 3.6 Hz, 1H), 4.38(m, 1H), 4.32(m, 1H), 3.46(m, 8H), 1.88-1.53(m, 8H)。

Example 09:

synthesis of Sot262

Under the protection of nitrogen, 6 g of Sot08 is added into a 50 mL three-neck flask, 22 mL of tetrahydrofuran is added, the temperature is reduced to minus 10 to 0 ℃ under stirring, 9 mL of isopropyl magnesium chloride (2.0M) is added dropwise, and the reaction solution A is obtained after the dropwise addition at minus 10 to 0 ℃ is continued to be stirred.

Synchronously operating, adding 4 g of Sot258 into another 50 mL three-neck flask under the protection of nitrogen, adding 16 mL of tetrahydrofuran, starting stirring, cooling the system to-30 to-20 ℃, dropwise adding 16 mL of tert-butyl magnesium chloride (1.0M), and continuously stirring for 1 h after dropwise adding to obtain the magnesium chloride-aluminum alloy materialAnd (C) reaction liquid B. Controlling the temperature to be minus 30 to minus 20 ℃, slowly pressing the reaction liquid A into the reaction liquid B, continuously stirring and reacting for 1 h at the temperature of minus 30 to minus 20 ℃ after the pressure is finished, and detecting the reaction end point by TLC. After the reaction, the reaction mixture was quenched by pouring it into 30 mL of 10% ammonium chloride. Then controlling the temperature to be-5 to 5 ℃, dropwise adding 8 mL of 6N hydrochloric acid for neutralization reaction, separating liquid, washing an organic phase by saturated sodium chloride, concentrating the organic phase at 45 ℃ under reduced pressure and drying to obtain a crude Sot262 product (ethyl acetate/N-heptane =1/1, rf is about 0.7), and purifying the crude product by column chromatography (200-300 meshes silica gel, gradient elution polarity: N-heptane → N-heptane/ethyl acetate = 10/1) to obtain 3.9 g of Sot262 white solid with the yield of 63.6%. ¹ H-NMR(CDCl ₃ , 400 MHz) δ: 7.85(dd, J= 2.4, 8.4Hz, 1H), 7.79(d, J= 2.4 Hz, 1H), 7.47(d, J= 8.4 Hz, 1H), 7.09(d, J= 8.4 Hz, 2H), 6.83(m, 2H),6.02(d, J= 4.0 Hz, 1H), 5.22(d, J= 2.8 Hz, 1H), 4.54(m, 1H), 4.49(d, J= 3.6 Hz, 1H), 4.08(d, J= 3.6 Hz, 2H), 4.00(q, 2H), 2.99(d, J= 4.4 Hz, 1H), 2.02-1.65(m, 8H), 1.40(t, J= 6.8 Hz, 1H). MS m/z: 459.2 [M+H] ⁺ , 481.1[M+Na] ⁺ , 497.1[M+K] ⁺ 。

Example 10:

synthesis of Sot261

To a 50 mL three-necked flask was added 0.5 g Sot262, 6 mL methanol, stirring was turned on, and 0.43 g cerium chloride (CeCl) was added ₃ ▪7H ₂ O), controlling the temperature to be 15-25 ℃, adding 25 mg of sodium borohydride solid, reacting for 0.5 h, adding an alkali solution of sodium borohydride (10 mg of sodium borohydride is dissolved in 0.05 mL of 4% sodium hydroxide aqueous solution), reacting for about 0.5 h continuously, and monitoring the reaction end point by TLC. After the reaction is finished, adding 2 mL of 10% ammonium chloride aqueous solution to quench the reaction, concentrating under reduced pressure at 40 ℃ until no obvious liquid is distilled off, adding 5 mL of methyl tert-butyl ether and 3 mL of water, adjusting the pH of the system to be =2 by using 6N hydrochloric acid, separating, collecting an organic phase, extracting an aqueous phase once by using the methyl tert-butyl ether, combining the organic phases, washing the organic phase by using saturated sodium chloride, and performing liquid separation on the organic phaseThe phases, the organic phase was concentrated under reduced pressure at 45 ℃ to give 408 mg of crude Sot261, and 300 mg of crude was purified by column chromatography (200-300 mesh silica gel, polarity of gradient elution: n-heptane → n-heptane/ethyl acetate =10/1 → 8/1 → 4/1) to give 100 mg of a white solid. ¹ H-NMR (CDCl ₃ , 400 MHz) δ: MS m/z: 7.37(d, J= 8.4 Hz, 1H), 7.24(dd, J=2.0, 8.4 Hz, 1H), 7.19(d, J=1.6 Hz, 1H), 7.08 (m, 2H), 6.81(m, 2H), 5.95(d, J= 4.0 Hz, 1H), 5.10(d, J= 4.4 Hz, 1H), 4.39(d, J= 3.6 Hz, 1H), 4.11(m, 2H), 4.03(d, J= 4.4 Hz, 2H), 3.99(q, 2H), 1.95-1.63(m, 8H), 1.39(t, J= 6.8 Hz, 3H). MS m/z: 478.2 [M+NH ₄ ] ⁺ , 483.2 [M+Na] ⁺ 。

Example 11:

sot253& Sot03 extraction efficiency study:

2 g of Sot253-A was dissolved in 12 mL of water, pH =2 was adjusted with phosphoric acid, divided into four portions by mass, extracted with solvents in the following table, and the aqueous phase was checked for substantial absence of Sot253 by TLC.

Sot03-A repeats the above operations and data are collected as follows:

according to the experimental data, compared with Sot03, sot253 has better extraction efficiency, greatly reduces the solvent consumption, reduces the generation of three wastes, simplifies the production process, and is a more environment-friendly process with higher economical efficiency.

This application is intended to cover any variations, equivalents, and modifications falling within the spirit of the invention.

Claims

1. A compound having the structure of formula IV-a:

wherein n =1 or 2.

2. A compound having the structure of formula V-a:

wherein n =1 or 2.

3. A compound having the structure of formula VI-a:

wherein n =1 or 2.

4. A process for preparing a compound of claim 1, compound IV-a is prepared from compound III-a by dehydration reaction with morpholine, comprising the steps of:

wherein n =1 or 2.

5. A process for the preparation of a compound as claimed in claim 2, compound IX is reacted with compound IV-a to prepare compound V-a, said process comprising the steps of:

wherein n =1 or 2,X is Br or I.

6. A process for the preparation of a compound as claimed in claim 3, compound V-a being reduced to compound VI-a, which process comprises the steps of:

wherein n =1 or 2.

7. Use of a compound according to any one of claims 1 to 3 for the synthesis of suggestin.