A kind of preparation method of triacetyl ganciclovir

Abstract

The invention relates to a method for preparing high-purity triacetylganciclovir, comprising the steps of mixing diacetylguanine, triacetylganciclovir N7 isomer, ganciclovir side chain and solvent I, adding a catalyst, heating to carry out a condensation reaction; vacuum concentrating the obtained product to concentrate solvent I to dryness; adding solvent II, heating and refluxing to dissolve, then slowly cooling to a predetermined temperature and keeping the temperature, so that triacetylganciclovir N7 isomer slowly precipitates, and centrifuging to obtain triacetylganciclovir N7 isomer and mother liquor I; concentrating mother liquor I to dry solvent II, and concentrating at normal pressure during the concentration process, and then concentrating under reduced pressure until no solvent II is distilled out; adding mixed solvent III to the obtained product, heating and refluxing, cooling and crystallizing, centrifuging to obtain triacetylganciclovir, and drying to obtain the finished product. The beneficial effects are as follows: the separation method is simple to operate, has a high safety factor, and a high separation efficiency, and triacetylganciclovir and its N7 isomer have high purity, both of which are ≥99%, and are suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of organic chemical drug synthesis, and in particular to a method for preparing triacetyl ganciclovir. Background Art

[0002] With the continuous development of the chemical synthesis pharmaceutical industry, the recycling and reuse of reaction media and raw materials produced in the pharmaceutical process has attracted special attention. Extensive production and unreasonable post-processing waste limited resources, increase manufacturing costs and have a great impact on environmental protection.

[0003] Ganciclovir is a nucleoside antiviral drug that competitively inhibits DNA polymerase and is incorporated into the DNA of viruses and host cells, thereby inhibiting DNA synthesis. The product was launched by Syntex Corporation in the United States and approved for marketing in 1988. It is the first choice for the treatment of cytomegalovirus infection. Abroad, ganciclovir is indicated for the induction and maintenance treatment of cytomegalovirus retinitis in immunodeficient patients (including AIDS patients). It can also be used to prevent cytomegalovirus serological test positive AIDS patients from developing cytomegalovirus disease. The product instructions of domestic ganciclovir generic drugs for injection specify the indications, in addition to the prevention and treatment of immunocompromised patients and cytomegalovirus retinitis, and are also suitable for various conditions such as hepatitis B, herpes zoster, and Epstein-Barr virus infection. The current marketed dosage forms in my country are mainly powder injections, and there are also a small number of oral preparations.

[0004] Ganciclovir condensate (also known as triacetyl ganciclovir) has the chemical name 9-(1.3-diacetyloxy-2-propoxymethyl)-N2-acetylguanine, which is an advanced intermediate of ganciclovir. Ganciclovir can be obtained by a one-step hydrolysis reaction. In addition, valganciclovir hydrochloride can also be prepared using ganciclovir condensate as a starting material.

[0005] In the published literature, there are few routes that are truly used for industrial production, and the main problems are as follows:

[0006] 1. Although the routes adopted in some literature are relatively short, there is no effective method to separate the intermediates, and the composition is relatively complex, resulting in the finished product requiring multiple refinements to meet the relevant standard requirements, resulting in low yields and high costs;

[0007] 2. The auxiliary materials used in some literature are not easy to obtain and recycle, which has a great impact on the environment and is not conducive to industrial production;

[0008] 3. Some literature uses column chromatography to separate isomers and impurities, which is inefficient and not suitable for industrial production.

[0009] In summary, it is necessary to obtain triacetylganciclovir, an important intermediate with high purity and high yield. We analyzed and compared the public literature and believed that the shortest, most effective and most applicable route is: diacetylguanine and the side chain (1,3-diacetoxy-2-acetoxymethoxypropane) undergo condensation reaction to obtain triacetylganciclovir, and then hydrolyze to obtain ganciclovir. This route has only two steps and is very short. However, the defect of this route is that in addition to generating triacetylganciclovir during the condensation reaction, a considerable amount of triacetylganciclovir N7 isomer product will also be produced. The methods for separating and purifying triacetylganciclovir that have been disclosed are relatively complicated, and the solvents used are relatively large, which is not conducive to industrial production. The separation efficiency and effect are not very ideal, and a monoacetylalkylguanine impurity will be produced during the separation process. The separation method of PCT international application W02004048380A1 is: after the reaction is completed, the solvent DMF is evaporated, and an alkanol solvent is first added to separate N7 triacetyl ganciclovir, and then another solvent or a mixed solvent (a solvent that is immiscible between alkanol and water) is used to separate triacetyl ganciclovir, and the separated triacetyl ganciclovir is then purified by crystallization. However, according to experiments, such separation of the N7 / N9 triacetyl ganciclovir mixture will produce a large monoacetyl alkyl guanine impurity in the triacetyl ganciclovir product, and it is difficult to remove. In the subsequent preparation of ganciclovir, an unknown impurity (impurity not listed in the pharmacopoeia) alkyl guanine (content>0.1%) will be produced, and it is difficult to remove in ganciclovir. Since N7 and N9 triacetyl ganciclovir are isomers with similar structures and properties, how to remove this impurity (N7 isomer) is a difficulty. Summary of the invention

[0010] The technical problem to be solved by the present invention is to provide a method for preparing triacetyl ganciclovir to overcome the deficiencies in the prior art.

[0011] The technical solution of the present invention to solve the above technical problem is as follows: a method for preparing triacetyl ganciclovir, comprising the following steps:

[0012] S1, mixing diacetylguanine, triacetylganciclovir N7 isomer, ganciclovir side chain and solvent I, adding a catalyst, and heating to carry out a condensation reaction;

[0013] S2, vacuum concentrating the product obtained by the condensation reaction to concentrate the solvent I to dryness;

[0014] S3, adding solvent II, heating and refluxing to dissolve the clear solution, then slowly cooling to a predetermined temperature, and keeping the temperature, so that the triacetyl ganciclovir N7 isomer is slowly precipitated, and centrifuging to obtain the triacetyl ganciclovir N7 isomer and mother liquor I respectively;

[0015] S4, drying the triacetyl ganciclovir N7 isomer obtained in S3 to obtain a triacetyl ganciclovir N7 isomer finished product;

[0016] S5, concentrating the mother liquor I to dry the solvent II, and in the concentration process, first concentrating at normal pressure, at a temperature not exceeding 70° C., and then concentrating at reduced pressure, at a temperature not exceeding 70° C., until no solvent II is distilled out;

[0017] S6, adding mixed solvent III to the product obtained in S5, heating to reflux, cooling to crystallize, and centrifuging to obtain triacetylganciclovir;

[0018] S7, drying the triacetyl ganciclovir obtained in S6 to obtain a triacetyl ganciclovir finished product.

[0019] Based on the above technical solution, the present invention can also be improved as follows.

[0020] Furthermore, the side chain of ganciclovir is triacetylmethoxyglycerol, the solvent I is DMF (dimethylformamide) or toluene, and the catalyst is p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid.

[0021] Furthermore, the condensation reaction temperature was 100° C. and the time was 40 h.

[0022] Furthermore, during the condensation reaction, part of the solvent I was distilled every 10 hours, and then an equal amount of fresh solvent I was added to continue the reaction at the heat preservation. The distillation operation was carried out 3 times in total, and the part of the solvent distilled out was 0.3 times the amount of the solvent added to the feed.

[0023] Furthermore, solvent II is methanol or ethyl acetate.

[0024] Furthermore, the slow cooling is first cooling by circulating water and then cooling by frozen brine. After cooling, the insulation temperature is 23°C to 25°C for 1 hour.

[0025] Furthermore, the vacuum degree after the decompression in S5 is ≧0.09 MPa.

[0026] Furthermore, the mixed solvent III is a mixed solution of methanol and toluene, and the mass ratio of the mixed solvent is 1:4 to 1:8.

[0027] Furthermore, the centrifugation temperature in S6 is 10°C to 15°C.

[0028] Furthermore, the drying conditions are a hot air circulation oven at 80°C to 100°C for 10 hours to 12 hours.

[0029] The invention has the following beneficial effects: the separation method is simple to operate, has a high safety factor, and a high separation efficiency; the solvent involved is common and cheap; the obtained triacetyl ganciclovir and its N7 isomer are high in purity, both of which are ≥99%, are suitable for industrial production, and have great economic benefits and good social benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The liquid phase detection spectrum of triacetylganciclovir N7 isomer in Example 1 of the present invention;

[0031] Figure 2 The liquid phase detection spectrum of triacetyl ganciclovir of Example 1 of the present invention;

[0032] Figure 3 The liquid phase detection spectrum of triacetylganciclovir N7 isomer in Example 2 of the present invention;

[0033] Figure 4 The liquid phase detection spectrum of triacetyl ganciclovir of Example 2 of the present invention;

[0034] Figure 5 The liquid phase detection spectrum of triacetylganciclovir N7 isomer in Example 3 of the present invention;

[0035] Figure 6 The liquid phase detection spectrum of triacetyl ganciclovir of Example 3 of the present invention;

[0036] Figure 7 The process route diagram of the condensation reaction of the present invention. DETAILED DESCRIPTION

[0037] The principles and features of the present invention are described below in conjunction with the accompanying drawings. The examples given are only used to explain the present invention and are not used to limit the scope of the present invention.

[0038] The following is an example of carrying out condensation reaction in a 1500L reactor and feeding 100kg of diacetylguanine raw material to illustrate the specific implementation mode of the present invention, but it is not limited to the reactor of this volume and the feeding ratio of this ratio.

[0039] Example 1

[0040] Figure 1 , Figure 2 , Figure 7 , a method for preparing triacetyl ganciclovir, comprising the following steps:

[0041] Add 100.0 kg of diacetylguanine, 450 kg of DMF, 60.0 kg of N7 isomer, 110.0 kg of triacetylmethoxyglycerol, and 3.0 kg of p-toluenesulfonic acid into a 1500 L reactor, heat to 100° C., and carry out condensation reaction at this temperature for 40 hours;

[0042] During the condensation reaction, the vacuum degree was controlled to be ≥0.09 MPa, 135 kg of DMF was distilled out every 10 hours, and 135.0 kg of fresh DMF was added at the same time, and the distillation operation was repeated 3 times;

[0043] After the reaction is finished, the kettle temperature is maintained at 100°C and vacuum concentrated at a vacuum degree of ≥ 0.09 MPa until no DMF is distilled out;

[0044] After the temperature in the kettle drops to 80°C, add 500.0 kg of measured methanol, heat up, stir and reflux to dissolve for 1 hour, slowly cool down to 23-25°C for crystallization, slowly cool down by circulating water cooling and then cooling with frozen brine, then keep warm for 1 hour, centrifuge, and dry the filter cake in a hot air circulation oven at 80°C-100°C for 10 hours-12 hours to obtain 61.2 kg of triacetyl ganciclovir N7 isomer with a purity of 99.54%;

[0045] Transfer the centrifuged mother liquor to another concentration kettle, control the temperature at 60°C, concentrate at normal pressure first, and then concentrate at reduced pressure until no methanol is distilled out, and the vacuum degree is ≧0.09MPa;

[0046] After concentration, add 80.0 kg of methanol and 550.0 kg of toluene into the kettle, heat and reflux for 0.5 h, slowly cool to 10°C, centrifuge, and dry the filter cake in a hot air circulation oven at 80°C to 100°C for 10 h to 12 h to obtain 103.5 kg of triacetyl ganciclovir with a purity of 99.47%.

[0047] Table 1, Example 1 Triacetyl ganciclovir N7 isomer liquid phase detection data

[0048] DAD: Signal A, 260

[0049] n / m bandwidth: 4nm

[0050] result

[0051] Retention time area Area percentage Peak height Height Percent 4.173 46182 0.27 7227 0.32 4.547 17330429 99.54 2224650 99.53 5.093 177122 0.10 2092 0.09 7.280 16472 0.09 1177 0.05 total 17410792 100.00 2235146 100.00

[0052] Table 2, Example 1 Triacetyl ganciclovir liquid phase detection data

[0053] DAD: Signal A, 260

[0054] n / m bandwidth: 4nm

[0055] result

[0056]

[0057] Figure 1This is the liquid phase detection spectrum of the triacetylganciclovir N7 isomer in Example 1, wherein the purity of N7 is 99.54% and the purity of N9 is 0.27%, indicating that the N7 and N9 isomers are separated more thoroughly and N7 contains almost no N9.

[0058] Figure 2 This is the liquid phase detection spectrum of triacetylganciclovir in Example 1, wherein the purity of N9 is 99.47% and the purity of N7 is 0.17%, indicating that N7 is separated more thoroughly in Example 1 and N9 contains almost no N7.

[0059] Example 2

[0060] Figure 3 , Figure 4 , Figure 7 , a method for preparing triacetyl ganciclovir, comprising the following steps:

[0061] Add 100.0 kg of diacetylguanine, 450 kg of DMF, 61.0 kg of N7 isomer, 108.9 kg of triacetylmethoxyglycerol, and 3.1 kg of p-toluenesulfonic acid into a 1500 L reactor, heat to 100° C., and carry out condensation reaction at this temperature for 40 hours;

[0062] During the condensation reaction, the vacuum degree was controlled to be ≥0.09 MPa, 135 kg of DMF was distilled out every 10 hours, and 135.0 kg of fresh DMF was added at the same time, and the distillation operation was repeated 3 times;

[0063] After the reaction is finished, the kettle temperature is maintained at 100°C and vacuum concentrated at a vacuum degree of ≥ 0.09 MPa until no DMF is distilled out;

[0064] After the temperature in the kettle drops to 80°C, add 502.4 kg of measured methanol to raise the temperature, stir and reflux to dissolve for 1 hour, slowly cool to 23°C to 25°C for crystallization, slowly cool by circulating water cooling and then cooling with frozen brine, then keep warm for 1 hour, centrifuge, and dry the filter cake in a hot air circulation oven at 80°C to 100°C for 10 hours to 12 hours to obtain 59.4 kg of triacetyl ganciclovir N7 isomer with a purity of 99.33%;

[0065] Transfer the centrifuged mother liquor to another concentration kettle, control the temperature at 60°C, concentrate at normal pressure first, and then concentrate at reduced pressure until no methanol is distilled out, and the vacuum degree is ≧0.09MPa;

[0066] After concentration, add 78.7 kg of methanol and 561.0 kg of toluene into the kettle, heat and reflux for 0.5 h, slowly cool to 10°C, centrifuge, and dry the filter cake in a hot air circulation oven at 80°C to 100°C for 10 h to 12 h to obtain 102.6 kg of triacetyl ganciclovir with a purity of 99.66%.

[0067] Table 3, Example 2 Triacetyl ganciclovir N7 isomer liquid phase detection data

[0068] DAD: Signal A, 260

[0069] n / m bandwidth: 4nm

[0070] result

[0071] Retention time area Area percentage Peak height Height Percent 4.087 59122 0.34 10142 0.44 4.407 17211685 99.33 2277702 99.34 4.907 15054 0.09 1968 0.09 6.873 17432 0.10 1546 0.07 10.540 11296 0.07 570 0.02 17.280 13558 0.08 830 0.04 total 17328147 100.00 2292758 100.00

[0072] Table 4, Example 2 Triacetyl Ganciclovir Liquid Phase Detection Data

[0073] DAD: Signal A, 260

[0074] n / m bandwidth: 4nm

[0075] result

[0076]

[0077] Figure 3 This is the liquid phase detection spectrum of the triacetylganciclovir N7 isomer of Example 2, wherein the purity of N7 is 99.33% and the purity of N9 is 0.34%, indicating that the N7 and N9 isomers are separated more thoroughly and N7 contains almost no N9.

[0078] Figure 4 This is the liquid phase detection spectrum of triacetylganciclovir in Example 2, wherein the purity of N9 is 99.66% and the purity of N9 is 0.12%, indicating that N7 is separated more thoroughly in Example 2 and N9 contains almost no N7.

[0079] Example 3

[0080] Figure 5 , Figure 6 , Figure 7 , a method for preparing triacetyl ganciclovir, comprising the following steps:

[0081] Add 100.0 kg of diacetylguanine, 450 kg of DMF, 59.2 kg of N7 isomer, 111.2 kg of triacetylmethoxyglycerol, and 3.0 kg of p-toluenesulfonic acid into a 1500 L reactor, heat to 100° C., and keep the reaction at this temperature for 40 hours;

[0082] During the condensation reaction, the vacuum degree was controlled to be ≥0.09 MPa, 135 kg of DMF was distilled out every 10 hours, and 135.0 kg of fresh DMF was added at the same time, and the distillation operation was repeated 3 times;

[0083] After the reaction is finished, the kettle temperature is maintained at 100°C and vacuum concentrated at a vacuum degree of ≥ 0.09 MPa until no DMF is distilled out;

[0084] After the temperature in the kettle drops to 80°C, add 501.1 kg of measured methanol to raise the temperature, stir and reflux to dissolve for 1 hour, slowly cool to 23°C to 25°C for crystallization, slowly cool by circulating water cooling and then cooling with frozen brine, then keep warm for 1 hour, centrifuge, and dry the filter cake in a hot air circulation oven at 80°C to 100°C for 10 hours to 12 hours to obtain 60.8 kg of triacetyl ganciclovir N7 isomer with a purity of 99.38%;

[0085] Transfer the centrifuged mother liquor to another concentration kettle, control the temperature at 60°C, concentrate at normal pressure first, and then concentrate at reduced pressure until no methanol is distilled out, and the vacuum degree is ≧0.09MPa;

[0086] After concentration, add 80.2 kg of methanol and 557.6 kg of toluene into the kettle, heat and reflux for 0.5 h, slowly cool to 10°C, centrifuge, and dry the filter cake in a hot air circulation oven at 80°C to 100°C for 10 h to 12 h to obtain 101.9 kg of triacetyl ganciclovir with a purity of 99.58%.

[0087] Table 5, Example 3 Triacetyl ganciclovir N7 isomer liquid phase detection data

[0088] DAD: Signal A, 260

[0089] n / m bandwidth: 4nm

[0090] result

[0091]

[0092]

[0093] Table 6, Example 3 Triacetyl Ganciclovir Liquid Phase Detection Data

[0094] DAD: Signal A, 260

[0095] n / m bandwidth: 4nm

[0096] result

[0097]

[0098] Figure 5 This is the liquid phase detection spectrum of the triacetylganciclovir N7 isomer in Example 3, wherein the purity of N7 is 99.38% and the purity of N9 is 0.34%, indicating that the N7 and N9 isomers are separated more thoroughly and N7 contains almost no N9.

[0099] Figure 6 This is the liquid phase detection spectrum of triacetylganciclovir in Example 3, wherein the purity of N9 is 99.36% and the purity of N9 is 0.17%, indicating that N7 is separated more thoroughly in Example 3 and N9 contains almost no N7.

[0100] The raw materials listed in the present invention, as well as the upper and lower limits and interval values ​​of the raw materials of the present invention, and the upper and lower limits and interval values ​​of the process parameters (such as temperature, time, etc.) can all realize the present invention, and the embodiments are not listed one by one here.

[0101] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A method for preparing triacetyl ganciclovir, characterized in that: The steps include: S1. Mix diacetylguanine, triacetylganciclovir N7 isomer, ganciclovir side chain and solvent I, add a catalyst, and heat to carry out a condensation reaction. The temperature of the condensation reaction is 100°C and the time is 40 hours. The ganciclovir side chain is triacetylmethoxyglycerol. During the condensation reaction, part of the solvent I is distilled every 10 hours, and then an equal amount of fresh solvent I is added to continue the heat preservation reaction. The distillation operation is carried out 3 times in total, and the part of the solvent distilled out is 0.3 times the mass of the solvent added to the material; S2, vacuum concentrating the product obtained by the condensation reaction to concentrate the solvent I to dryness; S3, adding solvent II, heating and refluxing to dissolve the clear solution, then slowly cooling to a predetermined temperature, and keeping the temperature, so that the triacetyl ganciclovir N7 isomer is slowly precipitated, centrifuging, and obtaining the triacetyl ganciclovir N7 isomer and mother liquor I respectively, the slow cooling is first cooling with circulating water and then cooling with frozen brine, and the insulation temperature after cooling is 23°C to 25°C, and the time is 1h; S4, drying the triacetyl ganciclovir N7 isomer obtained in S3 to obtain a triacetyl ganciclovir N7 isomer finished product; S5. Concentrate the mother liquor I and evaporate the solvent II. During the concentration process, first concentrate at normal pressure, then at 70°C or less, and then reduce the pressure. The vacuum degree after the reduction is ≥ 0.09 MPa. Concentrate at 70°C or less until no solvent II is distilled out. Solvent II is methanol. S6, adding mixed solvent III to the product obtained in S5, heating to 80°C for reflux, then slowly cooling to 10°C for crystallization, and centrifuging to obtain triacetyl ganciclovir, wherein the mixed solvent III is a mixture of methanol and toluene, and the mass ratio of the mixed solvent is 1:4 to 1:8; S7, drying the triacetyl ganciclovir obtained in S6 to obtain a triacetyl ganciclovir finished product; The solvent I is DMF, and the catalyst is p-toluenesulfonic acid.

2. A method for preparing triacetyl ganciclovir according to claim 1, characterized in that, The centrifugation temperature in S6 is 10°C to 15°C.

3. A method for preparing triacetyl ganciclovir according to claim 1, characterized in that: The drying conditions are hot air circulation oven at 80℃~100℃ and time of 10h~12h.

Images