CN121064203A - Methods for preparing carpacetinib, novel intermediates used therein, and their applications - Google Patents

Abstract

The invention provides a method for preparing capecitabine, a novel intermediate used in the method and application of the novel intermediate, and belongs to the field of medicine preparation. The invention provides a method for preparing capecitabine, which introduces a protecting group on an azaindole ring (pyrrolopyrimidine) which is a key starting material for the synthesis of the capecitabine, wherein the protecting group is selected from p-toluenesulfonyl (Tos), t-butoxycarbonyl (Boc) and (trimethylsilyl) ethoxymethyl (SEM), so that the reaction yield is improved, the total yield reaches 58.4%, and the material cost is reduced.

Description

Process for preparing capecitabine and novel intermediates used therein and uses thereof

Technical Field

The invention belongs to the field of medicine preparation, and in particular relates to a method for preparing capecitabine, a novel intermediate used in the method and application of the novel intermediate.

Background

Breast cancer is one of the most common malignant tumors in female patients worldwide, and despite some progress in existing treatment methods, there is still a disease progression in patients after receiving endocrine therapy, and new therapeutic drugs and methods are needed to improve prognosis of this part of patients.

Among the numerous breast cancer therapeutic targets, the AKT target has the unique advantage that the pathway is overactivated in various tumors, and is closely related to the growth, proliferation and survival of the tumors, and the PIK3CA/AKT1/PTEN gene variation is a common cause of abnormal activation of the AKT pathway. Thus, inhibition of AKT is a potential target for the treatment of tumors. Whereas capecitabine is able to target all three subtypes of AKT (AKT 1/2/3), blocking the growth and spread of cancer cells.

The uk cancer centre and AstraZeneca corporation cooperate to find 7-azaindoles as ATP-competitive ligands for AKT by fragment-based high throughput virtual screening. Researchers carry out a series of structural transformation and optimization, including replacing an azaindole ring with a pyrimidine ring, introducing a benzene ring as a connecting chain, carrying out substitution research on benzyl alpha position and the like, and finally obtaining the capecitabine.

The application for the marketing of capecitabine (structure shown as compound 1 below) was FDA accepted in the united states and granted priority for evaluation at month 6 of 2023. The medical evaluation Center (CDE) official network of the China national medical administration shows that the application of the Kapasitinib tablet on the market is accepted by 10 months of 2023. In 2023, 11 and 16, capecitabine was officially approved by the U.S. Food and Drug Administration (FDA) for the treatment of locally advanced or metastatic breast cancer patients with hr+/HER 2-who were tested for FDA approved trials for one or more PIK3CA/AKT1/PTEN gene changes and developed after the metastatic breast cancer patient received at least one endocrine treatment regimen, or developed a relapse at or within 12 months after completion of adjuvant therapy.

The general formula patent CN101861321a of the compound disclosed in 2008 of aslicon discloses that 3 routes can synthesize the target bulk drug:

Route 1:

Route 2:

Route 3:

The preparation of patent CN106661033a was disclosed in 2015 by aslicon, which discloses 1 route (route 4) with 3 steps, with open yields of 65%,84% and 80%, respectively, and total yield of 43.68%.

Route 4

The defects of the background technology are as follows:

Route 1. Expensive HATU condensing reagents are used, the intermediates are of lower purity, purification is difficult, and the overall yield is low and the material cost is high.

The method 2 has the advantages that the lithium aluminum tetrahydroide reducer is used for reducing methyl ester, the risk is high, the method is not suitable for mass production, the Boc protection reaction impurities are more in the last step, the yield is low, and the material cost is high.

Route 3, using expensive HATU condensing reagent, lower purity intermediate, more difficult purification, more impurities in the final Boc protection reaction, lower yield and serious corrosion of acid gas to equipment.

Route 4 although the material cost was optimized based on routes 1-3, the first step yield was only 65% and not high, the polarity of the intermediate was very high, the water solubility was strong, the purification difficulty loss by post-treatment was large, and there was room for further improvement in the overall yield of the route of 43%.

Disclosure of Invention

Aiming at the problem of low total yield of the synthesis of the capecitabine in the prior art, the invention provides a method for preparing the capecitabine, a novel intermediate used in the method and application of the novel intermediate. The method for preparing the capecitabine provided by the invention is to introduce a protecting group on an azaindole ring (pyrrolopyrimidine) which is a key starting material for the synthesis of the capecitabine, wherein the protecting group is selected from p-toluenesulfonyl (Tos), t-butoxycarbonyl (Boc) and (trimethylsilyl) ethoxymethyl (SEM).

In order to achieve the purpose, the invention provides the technical scheme that:

In one aspect, the present invention provides a process for preparing capecitabine, which comprises reacting a compound of formula (I) to remove the R ₁ group;

Wherein the R ₁ group is a protecting group, and the R ₁ group is selected from any one of tosyl, t-butoxycarbonyl and (trimethylsilyl) ethoxymethyl.

Preferably, when the R ₁ group is p-toluenesulfonyl, the reaction conditions are basic conditions, or

When the R ₁ group is tert-butoxycarbonyl, the reaction conditions are acidic conditions, or

When the R ₁ group is (trimethylsilyl) ethoxymethyl, the reaction conditions are acidic or fluorogenic.

Preferably, the base used in the alkaline conditions is selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium fluoride, cesium fluoride, lithium fluoride, triethylamine, DIPEA, ethylamine, methylamine, diethylamine, aniline and N, N-dimethylaniline;

the acid used in the acidic conditions is selected from the group consisting of hydrochloric acid, trifluoroacetic acid, acetic acid and hydrogen chloride-containing organic solutions, preferably trifluoroacetic acid;

The fluorine reagent used in the fluorine reagent conditions is selected from tetrabutylammonium fluoride, potassium fluoride, cesium fluoride, hydrofluoric acid and pyridine hydrofluoric acid complex, preferably tetrabutylammonium fluoride.

Preferably, the method further comprises:

Reacting a compound of formula (II) with a compound (III) in the presence of an activating reagent and under alkaline conditions to produce a compound of formula (I);

The activating reagent is selected from TFAA, triphosgene, CDI and phosphorus oxychloride, preferably TFAA, wherein the R ₂ group is a protecting group, the R ₂ group is selected from any one of tosyl, t-butoxycarbonyl and (trimethylsilyl) ethoxymethyl, and the alkali used in the alkaline condition is selected from potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably sodium bicarbonate or potassium bicarbonate.

Preferably, the process further comprises reacting the compound of formula (IV) with a compound of formula (V) under basic conditions to obtain a compound of formula (VI),

The compound of formula (VI) is produced into a compound (II) in the presence of a carboxyl activating agent, wherein the R ₃ group is a protecting group, and the R ₃ group is preferably tert-butoxycarbonyl.

Preferably, the base used in the alkaline conditions is potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably potassium carbonate, and the carboxyl activator is selected from TFAA, triphosgene, CDI and phosphorus oxychloride.

In another aspect, the present invention provides an intermediate for preparing capecitabine, the intermediate comprising a structure represented by formula (I) or formula (II), wherein the R ₁ group or R ₂ group is selected from any one of p-toluenesulfonyl, t-butoxycarbonyl and (trimethylsilyl) ethoxymethyl;

。

in some embodiments, the intermediate is of the structure shown in formula (I).

In some embodiments, the intermediate is of the structure shown in formula (II).

In another aspect, the invention provides the use of the above-described method or the above-described intermediate in the preparation of capecitabine.

The invention has the beneficial effects that:

The method for preparing the capecitabine improves the reaction yield, achieves the total yield of 58.4%, and reduces the material cost.

Detailed Description

The following specific examples are put forth so as to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

(1) Intermediate I for preparing capecitabine

On the one hand, the invention provides an intermediate for preparing the capecitabine, which introduces a protecting group at the azaindole position of the capecitabine intermediate, changes the polarity (smaller) of the intermediate in the synthesis step, has better solubility of an organic solvent of the intermediate, and is beneficial to post-treatment and purification.

The chemical formula of the intermediate for preparing the capecitabine provided by the invention is shown as the formula (I):

wherein R ₁ is a protecting group selected from the group consisting of p-toluenesulfonyl (Tos), t-butoxycarbonyl (Boc) and (trimethylsilyl) ethoxymethyl (SEM).

In some embodiments, the intermediate is of the structure shown in formula (i.1):

in some embodiments, the intermediate is of the structure shown in formula (i.2):

In some embodiments, the intermediate is of the structure shown in formula (i.3):

(2) Intermediate II for preparing capecitabine

The invention also relates to an intermediate II for preparing the capecitabine, which has a structural formula shown in a formula (II):

Wherein R ₂ is a protecting group selected from the group consisting of p-toluenesulfonyl (Tos), t-butoxycarbonyl (Boc) and (trimethylsilyl) ethoxymethyl (SEM).

In some embodiments, intermediate II has the structure of formula (ii.1):

In some embodiments, intermediate II has the structure of formula (ii.2):

in some embodiments, intermediate II has the structure of formula (ii.3):

The intermediate II provided by the invention is used for preparing an intermediate I under certain reaction conditions, specifically, a compound of the formula (II) reacts with the following compound (III) under the existence of an activating reagent and alkaline conditions to generate the intermediate I,

;

In this preparation method, the activating reagent is selected from TFAA, triphosgene, CDI, phosphorus oxychloride, preferably TFAA, and the alkali under alkaline condition is selected from potassium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium bicarbonate or potassium bicarbonate.

(3) Method for preparing capecitabine

The preparation method of the capecitabine provided by the invention comprises the preparation method of the intermediate I or the intermediate II.

In one aspect, the invention relates to a method for preparing capecitabine by using the intermediate, which comprises the specific steps of removing a protecting group (R ₁) from the intermediate of the formula (I). The deprotection method for deprotecting the protecting group includes, for example, the method described in "Wuts P G M .Greene's Protective Groups in Organic Synthesis: Fifth Edition[J]. 2014.DOI:10.1002/9781118905074.".

In some embodiments, a method for preparing capecitabine is involved, wherein the reaction process is as follows:

In an embodiment of this preparation process, the reaction conditions are alkaline conditions, the alkaline conditions being selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium fluoride, cesium fluoride, lithium fluoride, triethylamine, DIPEA, ethylamine, methylamine, diethylamine, aniline, N-dimethylaniline, preferably the base is cesium carbonate. The amount of base used is in the range of 1.0 to 5.0 equivalents, preferably 2.0 equivalents.

As used herein, equivalents are molar ratios relative to the reaction principal substrate, i.e., molar ratios of all reagents to substrate, i.e., equivalent ratios

Alternatively, the preparation is carried out in a reaction solvent, wherein the reaction solvent may be a protic solvent or an aprotic solvent or a mixture of both, and for example, the reaction solvent may be methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, water, DMSO, DMF, acetonitrile, acetone, 2-butanone, preferably tetrahydrofuran, methanol. The reaction temperature of this preparation process is from-10 ℃ to 40 ℃, preferably 25 ℃.

In some embodiments, a method for preparing capecitabine is involved, wherein the reaction process is as follows:

in this embodiment of the process, the reaction conditions are acidic, wherein the acid under acidic conditions is selected from the group consisting of hydrochloric acid, organic solutions of hydrogen chloride, trifluoroacetic acid, acetic acid, preferably trifluoroacetic acid, and the reaction solvent is dichloromethane. The reaction temperature of this preparation process is from-10 ℃ to 40 ℃, preferably 25 ℃.

In some embodiments, a method for preparing capecitabine is involved, wherein the reaction process is as follows:

In an embodiment of this preparation process, the reaction conditions are acidic conditions selected from the group consisting of hydrochloric acid, organic solutions of hydrogen chloride, trifluoroacetic acid, acetic acid, preferably trifluoroacetic acid, or fluorogenic conditions selected from the group consisting of tetrabutylammonium fluoride, potassium fluoride, cesium fluoride, hydrofluoric acid, pyridine complex of hydrofluoric acid, preferably tetrabutylammonium fluoride. More preferably, the reaction conditions of this preparation method are tetrabutylammonium fluoride reagent conditions. The amount of the reagent used is in the range of 1.0 to 10 equivalents, preferably 4.0 equivalents, and the reaction temperature is in the range of-10 to 40 ℃, preferably 25 ℃.

The invention also relates to a method for preparing the capecitabine, which utilizes the intermediate II provided by the invention, namely the intermediate II to prepare the intermediate I under certain reaction conditions, specifically, the compound of the formula (II) reacts with the compound (III) to generate the intermediate I under the existence of an activating reagent and alkaline conditions,

In this preparation method, the activating reagent is selected from TFAA, triphosgene, CDI, phosphorus oxychloride, preferably TFAA, and the alkali under alkaline condition is selected from potassium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium bicarbonate or potassium bicarbonate.

In general, the invention utilizes intermediate I and intermediate II for preparing the capecitabine, and specifically, when the protecting group of the intermediate is p-toluenesulfonyl (Tos), the reaction scheme for preparing the capecitabine is as follows:

The invention also relates to a method for preparing the capecitabine, which comprises the steps of carrying out substitution reaction on a compound shown as a formula (IV) and a compound shown as a formula (V) under alkaline conditions to obtain a compound shown as a formula (VI), wherein a reaction solvent is a polar solvent, such as an ether solvent and an alcohol solvent, and is specifically selected from tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol and isopropanol, preferably tetrahydrofuran, and alkali in the alkaline conditions is potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably potassium carbonate, and the reaction temperature is 40 ℃ to the reflux temperature of the solvent;

a compound of formula IV: ,

A compound of formula V: ,

A compound of formula VI: 。

The compounds of formula (VI) form compound II (intermediate II) in the presence of a carboxyl activator selected from TFAA, triphosgene, CDI, phosphorus oxychloride, preferably TFAA. The carboxyl activator is used in an amount ranging from 1.0 to 3.0 equivalents, preferably 1.5 equivalents. The reactant is an aprotic solvent selected from acetonitrile, tetrahydrofuran, preferably acetonitrile. The reaction temperature is from-10 ℃ to 40 ℃, preferably 25 ℃.

Wherein the R ₃ group is t-butoxycarbonyl (Boc) and the R ₂ group is as defined above, i.e. selected from p-toluenesulfonyl (Tos), t-butoxycarbonyl (Boc) and (trimethylsilyl) ethoxymethyl (SEM).

In general, the invention relates to a method for preparing a carboplatin compound (1), which prepares the carboplatin compound by synthesizing an intermediate II and an intermediate I, wherein the synthetic flow of a specific preparation embodiment of the carboplatin compound is as follows:

except as specifically noted, the various materials and reagents of the invention were purchased from commercial suppliers and tested according to the instructions. Except for the special descriptions, the instruments, equipment, devices and the like are conventional instruments, equipment, devices and the like, and experiments are carried out according to the operation descriptions and the matched reagents.

The abbreviations and full names of the compounds referred to in the invention are shown in Table 1.

Table 1 abbreviations and full names of Compounds

The invention relates to a detection method which comprises the following steps:

(1) HPLC detection

Instrument HPLC (Shimadzu manufacturer type LC-2050C)

The specific method comprises the following steps:

the chromatographic column is ALPHASIL VC-C18.6X1250 mm, the chromatographic conditions are shown in Table 2.

TABLE 2

(2) LCMS detection

LCMS instrument (manufacturer: agilent model: agilent 1260 InfinityII+6125C)

The specific method is shown in Table 3:

TABLE 3 Table 3

(3) NMR detection

Instrument NMR (manufacturer: bruker model AVANCE NEO 400 MHz)

The acquisition parameters are shown in Table 4:

TABLE 4 Table 4

Example 1 preparation of intermediate I.1, intermediate II.1 and capecitabine

The reaction scheme of this example is as follows:

(1) Preparation of Compound 4

Adding 380mL of tetrahydrofuran into a three-port bottle, sequentially adding 2 (20.0 g, 81.G mmol), 3 (26.4 g, 85.8 mmol) and potassium carbonate (22.6 g, 164 mmol), heating the reaction solution to reflux, keeping the temperature for reaction for 12-16h, cooling to room temperature after the HPLC monitoring reaction is completed, adding 200 mL water and 200 mL ethyl acetate, stirring and adjusting the pH to 5-6 by 6N hydrochloric acid, extracting the water layer by 100 mL ethyl acetate once, washing the organic phase by 200 mL pure water for 2 times, concentrating the organic phase to solid, adding 200 mL ethyl acetate, stirring and dissolving the solid, dripping N-heptane, cooling to 0 ℃ for crystallization, filtering and drying to obtain 4 (40.26 g, 78.1 mmol) of the compound with the yield of 95%;

LCMS (M+1) +516.2, purity 99.5%;

¹H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 4.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.30 (br, 1H), 6.98 (d, J = 4.4 Hz, 1H), 4.21-4.24 (m, 2H), 3.46-3.50 (m, 2H), 2.36 (s, 3H), 2.00-2.05 (m, 2H), 1.83-1.90 (m, 2H), 1.38 (s, 9H) ppm.

(2) Preparation of Compound 6

Adding 300mL acetonitrile into a three-port bottle, adding compound 4 (20 g, 38.8 mmol), replacing the system with nitrogen, dropwise adding trifluoroacetic anhydride (11.7 g, 55.7 mmol) at the temperature of 25-30 ℃, keeping the temperature and stirring for 2 hours after the addition of 25-30 ℃, sequentially adding potassium bicarbonate (15.57 g, 155.5 mmol) and 80 mL acetonitrile after the detection reaction by HPLC, stirring for 1 hour, adding compound 5 (7.2 g, 38.7 mmol) and 40 mL water, keeping the temperature at 25-30 ℃ for stirring for 12-16 hours, adding 240 mL water and 400 mL dichloromethane after the detection reaction by HPLC is complete, separating an organic phase, washing for 1 time by 200 mL pure water, concentrating the organic phase to solid, adding 200 mL n-heptane into the solid, stirring for 12-16 hours for crystallization, and filtering to obtain compound 6 (17.06 g, 29.2 mmol) as a white solid, wherein the yield is 75%;

LCMS (M+1) + 583.2, purity 99.0%;

¹H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 7.6 Hz, 1H), 8.23 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 4.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.29-7.36 (m, 4H), 6.95 (d, J = 4.0 Hz, 1H), 4.85-4.87 (m, 1H), 4.28-4.35 (m, 2H), 3.53-3.55 (m, 2H), 3.34-3.37 (m, 2H), 2.15 (s, 3H), 2.10-2.18 (m, 2H), 1.79-1.92 (m, 4H) ppm.

(3) Preparation of capecitabine (Compound 1)

15ML of tetrahydrofuran and 15mL of methanol are added into a three-mouth bottle, compound 6 (intermediate I.1,10.0 g, 17.1 mmol) and cesium carbonate (16.8 g, 51.6 mmol) are sequentially added, the temperature is controlled to be 20-30 ℃ and the mixture is stirred for 8 hours, after the reaction is monitored by HPLC, 300 mL of water is added into the system, the mixture is extracted by 400 mL of dichloromethane, an organic phase is washed for 1 time by 200 mL of pure water, the organic phase is concentrated to oily matter, 200 mL of ethyl acetate is added, stirring is carried out for 12-16 hours at room temperature, and the mixture is filtered and dried to obtain white solid of capecitabine (6.01 g, 14.02 mmol) with the yield of 82%;

LCMS (M+1) +429.2, purity 99.8%;

¹H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 7.37-7.31 (m, 4H), 7.15-7.16 (m, 1H), 6.57 (m, 1H), 4.85-4.92 (m, 1H), 4.50-4.55 (m, 1H), 4.34-4.41 (m, 2H), 3.50-3.59 (m, 2H), 3.35-3.40 (m, 2H), 2.17 (s, 2H), 1.80-2.02 (m, 4H), 1.39-1.47 (m, 2H) ppm.

To sum up, total yield = 0.95 x 0.75 x 0.82 x 100% = 58.43%.

Example 2 preparation of intermediate I.2, intermediate II.2 and capecitabine

The reaction procedure of this example is as follows:

(1) Preparation of Compound 8

Adding 310 mL ethanol into a three-mouth bottle, sequentially adding 2 (48.86 g, 200 mmol), 7 (50.1 g, 200 mmol) and potassium carbonate (111 g, 800 mmol), heating the reaction liquid to reflux, stirring and preserving heat for reaction for 12-16h, cooling to room temperature after the HPLC monitoring reaction is completed, adding 600 mL water and 600 mL ethyl acetate, stirring and adjusting pH to 5-6 with 6N hydrochloric acid, separating an organic phase, extracting a water layer with 400 mL ethyl acetate, merging the organic phases, washing with 300 mL pure water, concentrating the organic phase to be solid, adding 400 mL ethyl acetate for dissolution, dropwise adding 200 mL N-heptane, cooling to 0 ℃ for crystallization, filtering and drying to obtain a pure compound 8 (76.6 g, 166 mmol), and obtaining the yield of 83%;

LCMS (M+1) +462.2, purity 99.0%;

¹H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.60 (d, J = 4.0 Hz, 1H), 7.15 (br, 1H), 6.82 (d, J = 4.0 Hz, 1H), 4.01-4.19 (m, 2H), 3.35-3.45 (m, 2H), 2.02-2.08 (m, 2H), 1.79-1.82 (m, 2H), 1.65 (s, 9H), 1.33 (s, 9H) ppm.

(2) Preparation of Compound 9

400 ML acetonitrile is added into a three-mouth bottle, compound 8 (10.0 g, 22.0 mmol) is added, the system is replaced by nitrogen, trifluoroacetic anhydride (5.66 g, 28.0 mmol) is dropwise added at the temperature of 25-30 ℃, the temperature is kept and stirred for 2 hours until the reaction is complete after the reaction is completed, sodium bicarbonate (4.6 g, 54.0 mmol) and 40mL acetonitrile are sequentially added after the reaction is completed by HPLC detection, compound 5 (6.0 g, 33.0 mmol) and 20mL water are added after the reaction is stirred for 1 hour, the reaction is stirred for 12-16 hours at the temperature of 25-30 ℃, 200mL water is added after the reaction is completed by HPLC monitoring, and 300 mL dichloromethane is added into the system, and an organic phase is separated. The organic phase is washed by 100mL pure water, the organic phase is concentrated to solid, the solid is added with 200mL ethyl acetate for dissolution, 100mL n-heptane is added dropwise for stirring for 12-16 hours for crystallization, filtration and drying are carried out, thus obtaining white solid compound 9 (intermediate I.2) (8.03 g, 15.2 mmol) with the yield of 69%;

LCMS (M+1) +529.2, purity 99.1%;

¹H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 7.32-7.37 (m, 4H), 7.13-7.17 (m, 1H), 6.45-6.52 (m, 1H), 4.80-4.87 (m, 1H), 4.44-4.49 (m, 1H), 4.30-4.38 (m, 2H), 3.46-3.50 (m, 2H), 3.28-3.32 (m, 2H), 2.13 (s, 2H), 1.72-2.79 (m, 4H), 1.65 (s, 9H), 1.33-1.39 (m, 2H) ppm.

(3) Preparation of capecitabine (Compound 1)

15 ML methylene chloride was added to a three-necked flask, compound 9 (5.00 g, 9.5 mmol), trifluoroacetic acid (3.42 g,30.0 mmol) and a temperature control of 20-30 ℃ were sequentially added, stirred until the reaction was completed by HPLC, 100mL water was added to the system, and the pH was adjusted to 7-8 with a saturated aqueous solution of sodium carbonate, and an organic phase was separated. The aqueous phase was extracted with 200 mL dichloromethane, the organic phases were combined and washed with 200 mL pure water, and the organic phase was concentrated to an oil. The crude oil is stirred for 12 to 16 hours at room temperature with 20 mL ethyl acetate for crystallization, filtered and dried to obtain the white solid of capecitabine (1.83 g, 4.3 mmol) with the yield of 45 percent;

LCMS (M+1) +429.2, purity 99.6%;

To sum up, total yield = 0.83 x 0.69 x 0.45 x 100% = 25.77%.

Example 3 preparation of intermediate I.3, intermediate II.3 and capecitabine

The reaction procedure of this example is as follows:

(1) Preparation of Compound 11

Adding 310 mL ethanol into a three-mouth bottle, sequentially adding 2 (12.22 g, 50.0 mmol), 10 (14.2 g, 50.0 mmol) and potassium carbonate (27.6 g, 200 mmol), heating the reaction solution to reflux, keeping the temperature for reaction for 12-16h, cooling to room temperature after the HPLC monitoring reaction is completed, adding 300 mL water and 300 mL ethyl acetate, stirring and adjusting the pH to 5-6 by 6N hydrochloric acid, extracting the water layer by 200 mL ethyl acetate, washing the organic phase by 300 mL pure water, concentrating the organic phase to solid, adding 200 mL ethyl acetate for dissolution, dropwise adding 100 mL N-heptane, cooling to 0 ℃ for crystallization, filtering, and vacuum drying for 8h to obtain 11 (22.9 g, 46.5 mmol) compound with 93 yield;

LCMS (M+1) +492.3, purity 98.9%;

¹H NMR (400 MHz, DMSO-d6) δ 12.43 (br, 1H), 8.21 (s, 1H), 7.36 (d, J = 4.0 Hz, 2H), 6.72 (d, J = 3.6 Hz, 1H), 5.52 (s, 2H), 4.30-4.34 (m, 2H), 3.48-3.52 (m, 4H), 1.91-1.94 (m, 4H), 1.40 (s, 9H), 0.82 (t, J = 8.0 Hz, 2H), 0.05 (s, 9H) ppm.

(2) Preparation of Compound 12

Adding 400 g acetonitrile into a three-mouth bottle, adding 11 (11.0 g, 22.0 mmol) compound, replacing the system with nitrogen, dropwise adding trifluoroacetic anhydride (5.85 g, 29.0 mmol) at the temperature of 25-30 ℃, keeping the temperature and stirring for 2 hours at 25-30 ℃ after the completion of the addition, sequentially adding sodium bicarbonate (4.7 g, 56.0 mmol) and 40 mL acetonitrile after the completion of the HPLC detection reaction, stirring for 1 hour, adding 5 (5.0 g, 27.0 mmol) compound and 20mL water, stirring for 12-16 hours at the temperature of 25-30 ℃, adding 200 mL water and 300 mL dichloromethane after the completion of the HPLC monitoring reaction, separating out an organic phase, washing the organic phase with 100 mL pure water, concentrating the organic phase to be solid, adding 200 3836 ethyl acetate into the crude product for dissolution, dropwise adding 100 mL n-heptane for stirring for 12-16 hours for crystallization, filtering, and drying to obtain a white solid compound 12 (intermediate I.3) (8.86, 6753, 15.8) and obtaining the white solid compound 12 after the drying;

LCMS (M+1) + 559.3, purity 98.5%;

¹H NMR (400 MHz, DMSO-d6) δ 8.39 (br, 1H), 7.27 (s, 2H), 7.26 (s, 1H), 7.11-7.16 (m, 4H), 6.96 (d, J = 3.2 Hz, 1H), 6.95 (d, J = 2.8 Hz, 1H), 5.48 (s, 2H), 4.13-4.15 (m, 1H), 4.05-4.07 (m, 2H), 3.45-3.49 (m, 4H), 2.00-2.02 (m, 4H), 1.75-1.80 (m, 2H), 1.60-1.65 (m, 2H), 1.11 (t, J = 8.0 Hz, 2H), 0.08 (s, 9H) ppm.

(3) Preparation of capecitabine (Compound 1)

15ML of tetrahydrofuran was added to a three-necked flask, compound 12 (5.59 g, 10.0 mmol), tetrabutylammonium fluoride (10.5 g,40.0 mmol) and controlled temperature 20-30℃were sequentially added, and after stirring until the reaction was completed by HPLC monitoring, 100mL water and 200 mL methylene chloride were added to the system, and the organic phase was separated and washed with 200 mL pure water. The organic phase was concentrated to an oil and the crude oil was stirred with 50 mL ethyl acetate at room temperature for 12-16h to crystallize, filtered and dried to give capecitabine (2.19 g, 5.1 mmol) as a white solid in 51% yield.

LCMS (M+1) +429.2, purity 99.7%;

To sum up, total yield=0.93×0.72×0.51×100% =34.15%.

Summarizing scheme 4 in the background and the fractional yields and overall yields of inventive examples 1-3 are shown in table 5.

TABLE 5 fractional yields and Total yields for different technical schemes

The intermediate I and the intermediate II with protecting groups have proper polarities, are favorable for the purification of the subsequent synthetic process, and are different from the intermediate compound in the route 4, which has stronger polarities and stronger water solubility and is not easy to purify.

Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.

Claims (10)

1. A process for the preparation of capecitabine, which comprises the reaction of a compound of formula (I) to remove the R ₁ group;

Wherein the R ₁ group is a protecting group selected from any one of p-toluenesulfonyl, t-butoxycarbonyl and (trimethylsilicon) ethoxymethyl.

2. The method of claim 1, wherein the step of determining the position of the substrate comprises,

When the R ₁ group is p-toluenesulfonyl, the reaction conditions are basic conditions, or

When the R ₁ group is tert-butoxycarbonyl, the reaction conditions are acidic conditions, or

When the R ₁ group is (trimethylsilyl) ethoxymethyl, the reaction conditions are acidic or fluorogenic.

3. The method of claim 2, wherein the step of determining the position of the substrate comprises,

The base used in the alkaline conditions is selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium bicarbonate, potassium fluoride, cesium fluoride, lithium fluoride, triethylamine, DIPEA, ethylamine, methylamine, diethylamine, aniline and N, N-dimethylaniline;

the acid used in the acidic conditions is selected from the group consisting of hydrochloric acid, trifluoroacetic acid, acetic acid and hydrogen chloride-containing organic solutions, preferably trifluoroacetic acid;

The fluorine reagent used in the fluorine reagent conditions is selected from tetrabutylammonium fluoride, potassium fluoride, cesium fluoride, hydrofluoric acid and pyridine hydrofluoric acid complex, preferably tetrabutylammonium fluoride.

4. The method according to any one of claims 1 to 3, wherein the method further comprises reacting the compound of formula (II) with the compound (III) in the presence of an activating reagent and under basic conditions to produce the compound of formula (I);

the activating reagent is selected from TFAA, triphosgene, CDI and phosphorus oxychloride, preferably TFAA;

Wherein the R ₂ group is a protecting group selected from any one of p-toluenesulfonyl, t-butoxycarbonyl and (trimethylsilyl) ethoxymethyl;

the base used in the alkaline conditions is selected from potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably sodium bicarbonate or potassium bicarbonate.

5. The method according to claim 4, wherein the method further comprises:

Reacting a compound of formula (IV) with a compound of formula (V) under basic conditions to obtain a compound of formula (VI);

The compound of formula (VI) is produced into compound (II) in the presence of carboxyl activating agent, wherein R ₃ group is protecting group.

6. The process according to claim 5, wherein the base used in the alkaline conditions is potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably potassium carbonate, and the carboxyl activating agent is selected from TFAA, triphosgene, CDI and phosphorus oxychloride, preferably TFAA.

7. An intermediate for preparing capecitabine, which is characterized in that the intermediate comprises a structure shown in a formula (I) or a formula (II), wherein the R ₁ group or the R ₂ group is selected from any one of tosyl, t-butoxycarbonyl and (trimethylsilyl) ethoxymethyl;

。

8. An intermediate according to claim 7, wherein the intermediate has the structure of formula (I).

9. An intermediate according to claim 7, wherein the intermediate has the structure of formula (II).

10. Use of the process of any one of claims 1-6 or the intermediate of any one of claims 7-9 in the preparation of capecitabine.