A method for synthesizing diaminopyrimidine nitrogen oxide

Abstract

The invention discloses a method for synthesizing diaminopyrimidine nitrogen oxide, which comprises: performing a ring-closing reaction on ethoxymethylene cyanoacetoethyl ester and guanidine in a reaction solvent to obtain a pyrimidine skeleton intermediate, performing a decarboxylation reaction in a decarboxylation reagent and an organic solvent to obtain a diaminopyrimidine intermediate, and reacting with an oxidant to obtain diaminopyrimidine nitrogen oxide. The invention uses ethoxymethylene cyanoacetoethyl ester and guanidine as raw materials, sequentially undergoes a ring-closing reaction, a hydrolysis decarboxylation reaction and an oxidation reaction to obtain diaminopyrimidine nitrogen oxide in high yield. The synthetic route is novel, and a new synthetic method is provided for 2,4-diaminopyrimidine and 2,4-diaminopyrimidine nitrogen oxide. The raw materials are cheap and easy to obtain, the cost is low, and operations such as pressurization are not required, and a synthetic route with simple operation, short steps, high reaction selectivity and good safety is provided.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing diaminopyrimidine nitrogen oxide. Background Art

[0002] Diaminopyrimidine oxide is an effective anti-hair loss ingredient and a water-soluble hair growth enhancer. Its direct effects include: 1) preventing hair follicle blockage and strengthening hair roots to hair ends; 2) promoting keratin fiber formation and increasing hair density; 3) softening collagen fiber network and preventing hair loss; 4) extending hair growth cycle and accelerating hair growth; 5) making fine hair grow healthily and strengthening hair. Diaminopyrimidine oxide is now widely used in various hair growth products due to its excellent hair growth ability and is favored by consumers.

[0003] In the prior art, the synthesis of diaminopyrimidine oxide is rarely reported. For example, the preparation methods of aminopyrimidine derivatives reported in patents US3644364, US3382247, CN87104693, etc., the products are all derivatives of minoxidil, and no synthesis route of diaminopyrimidine oxide is proposed; patent CN114213340, etc. use chemical oxidation, microbial catalytic cyclization and other methods, which are complicated to operate, difficult to purify the product, and the solution leads to microbial residues, affecting the product quality. These synthetic routes all have certain limitations, and it is of great significance to propose an efficient chemical synthesis of diaminopyrimidine oxide.

[0004] The literature [Journal of the American Chemical Society, 1950, vol. 72, p. 2587-2593] reported a method for synthesizing the intermediate 2,6-diaminopyrimidine, and its synthesis route is as follows:

[0005]

[0006] It is synthesized by chemical synthesis, and cyanoacetaldehyde diethyl acetal and guanidine hydrochloride are refluxed in sodium metal and n-butanol to obtain 2,6-diaminopyrimidine sulfate, wherein the first step yield is about 80%, and the dissociation yield is unknown (the applicant uses sodium hydroxide to adjust to strong alkalinity for dissociation, and dichloromethane extraction, and the yield is repeated three times to 77-81%). This method uses active and explosive sodium metal, which has hidden dangers in production safety and has high requirements for equipment.

[0007] Patent document CN114213340A discloses a method for preparing 2,4-diaminopyrimidine oxide, and its synthesis route is as follows:

[0008]

[0009] It uses an enzymatic oxidation method to synthesize 3-oxopropionitrile, and synthesizes it with guanidine to obtain diaminopyrimidine oxide, but this method involves biological enzymes and there is a risk of biological residues. In addition, the entire engineering operation is cumbersome and difficult to be put into practical use. Patent document CN116143706B discloses a method for synthesizing diaminopyrimidine oxide, which uses 2-chloro-4-aminopyrimidine dissolved in a non-protonic solvent, reacts with sodium amide at 40-50°C to generate 2,4-diaminopyrimidine, and then oxidizes to generate diaminopyrimidine nitrogen oxide. Although this process has no microbial residues and the amination reaction process is simple to operate and has a high conversion rate, it requires the use of controlled liquid ammonia, and some processes require high-pressure operation, which also poses a great challenge to the treatment of ammonia nitrogen in the three wastes.

[0010] Patent document CN114315738A discloses a method for preparing 2-4-diaminopyrimidine-3-oxide, which uses cytosine, isocytosine or uracil as raw materials, chlorinates the hydroxyl group with a chlorination agent, then reacts with an oxidizing agent to generate nitrogen oxides at the 3-N position, and then undergoes aminolysis with ammonia / methanol to obtain 2,4-diaminopyrimidine-3-oxide. This method also requires the use of controlled liquid ammonia, and some process steps require high-pressure operation, which poses safety risks and cumbersome post-processing. Summary of the invention

[0011] In view of the problems that the synthesis method of diaminopyrimidine nitrogen oxide in the prior art has limited technical routes, low economy, poor reaction selectivity and safety and environmental protection treatment risks, the purpose of the present invention is to provide a synthesis method of diaminopyrimidine nitrogen oxide, which is an ideal synthesis route with simple operation, short steps, high reaction selectivity and greater economy.

[0012] To achieve the above object, the present invention adopts the following technical solution:

[0013] The present invention provides a method for synthesizing diaminopyrimidine nitrogen oxide, and the synthesis route is shown as follows:

[0014]

[0015] The synthesis method comprises the following steps:

[0016] Step 1, ethoxymethylene cyanoacetoacetate (SM1) and guanidine (SM2) are subjected to a ring-closing reaction in a reaction solvent to obtain a pyrimidine skeleton intermediate (compound A);

[0017] Step 2, the pyrimidine skeleton intermediate undergoes a hydrolysis decarboxylation reaction in a decarboxylation reagent and an organic solvent to obtain a diaminopyrimidine intermediate (compound B);

[0018] Step 3: The diaminopyrimidine intermediate is subjected to an oxidation reaction with an oxidant to obtain diaminopyrimidine nitrogen oxide (compound C).

[0019] Preferably, in step 1, the molar ratio of ethoxymethylene cyanoacetoethyl ester to guanidine is 1:3-7.

[0020] More preferably, in step 1, the molar ratio of ethoxymethylene acetoacetate to guanidine is 1:3.5-5.5.

[0021] Preferably, in step 1, the guanidine is a compound generated in situ by a guanidine salt and a base in a reaction solvent, wherein the guanidine salt is selected from one or more of guanidine carbonate, guanidine hydrochloride, guanidine sulfate or guanidine phosphate; and / or the base is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, sodium methoxide; and / or the reaction solvent is selected from one or more of methanol, ethanol, propanol, butanol, tetrahydrofuran and water.

[0022] More preferably, in step 1, the method for preparing guanidine comprises: neutralizing the guanidine salt and the base in the reaction solvent at 30-60° C. for 1 hour, and cooling the temperature to 0-20° C.

[0023] Preferably, in step 1, the reaction temperature of the ring-closing reaction is -10 to 35°C, and the reaction time is 10 to 15 hours.

[0024] More preferably, in step 1, the ring-closing reaction temperature is 0-25° C., and the reaction time is 12 h.

[0025] Preferably, in step 2, the decarboxylation reagent is selected from concentrated sulfuric acid and / or lithium chloride, and the molar ratio of the decarboxylation reagent to the compound A is 2 to 5:1.

[0026] Preferably, in step 2, the reaction is carried out in the presence of a catalyst, wherein the catalyst is selected from cobalt porphyrin, copper tetraphenylporphyrin, sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate, and the molar ratio of the catalyst to the compound A is 0.01 to 0.03:1.

[0027] Preferably, in step 2, the organic solvent is selected from one or more of N-methylpyrrolidone (NMP), xylene, dimethyl sulfoxide (DMSO), and n-butanol.

[0028] Preferably, in step 2, the hydrolysis decarboxylation reaction temperature is 110-250° C., and the reaction time is 5-9 h.

[0029] Preferably, in step 3, the oxidant is 20-30% hydrogen peroxide, and the molar ratio of the oxidant to the compound B is 1.5-2.0:1, and the more preferred molar ratio is 1.7:1.

[0030] Preferably, in step 3, the oxidation reaction temperature is 40-60° C., and the reaction time is 10-20 h.

[0031] More preferably, in step 3, the oxidation reaction temperature is 50° C. and the reaction time is 15 h.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] The present invention develops a method for synthesizing diaminopyrimidine nitrogen oxide, which uses ethoxymethylene cyanoacetoethyl ester and guanidine as raw materials, and sequentially undergoes ring-closing reaction, hydrolysis decarboxylation reaction and oxidation reaction to obtain diaminopyrimidine nitrogen oxide with high yield. The synthetic technology route is novel, provides a new idea for the synthesis of 2,4-diaminopyrimidine, and provides a new synthetic method for 2,4-diaminopyrimidine nitrogen oxide. In addition, the raw materials used in the present invention are cheap and easy to obtain, the cost is low, the process is reasonable, and no operations such as pressurization are required. It is an ideal synthetic route with simple operation, short steps, high reaction selectivity and good safety. DETAILED DESCRIPTION

[0034] In order to make the technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0035] The following example provides a method for synthesizing diaminopyrimidine nitrogen oxide, which is carried out according to the following synthetic route:

[0036]

[0037] Specifically, the steps include:

[0038] Step 1, ethoxymethylene cyanoacetoacetate (SM1) and guanidine (SM2) are subjected to a ring-closing reaction in a reaction solvent to obtain a pyrimidine skeleton intermediate (compound A);

[0039] Step 2, the pyrimidine skeleton intermediate undergoes a hydrolysis decarboxylation reaction in a decarboxylation reagent and an organic solvent to obtain a diaminopyrimidine intermediate (compound B);

[0040] Step 3: The diaminopyrimidine intermediate is subjected to oxidation reaction with an oxidant to obtain diaminopyrimidine nitrogen oxide (compound C).

[0041] In some embodiments, in step 1, the molar ratio of ethoxymethylene cyanoacetoacetate to guanidine is 1:3-7; guanidine is an in-situ compound neutralized by a guanidine salt and a base in a reaction solvent, wherein the guanidine salt can be selected from guanidine carbonate, guanidine hydrochloride, guanidine sulfate or guanidine phosphate; the base can be selected from potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, sodium methoxide; the reaction solvent can be selected from methanol, ethanol, propanol, butanol, tetrahydrofuran, water; the reaction temperature of the cyclization reaction is -10-35°C, and the reaction time is 10-15h.

[0042] In some embodiments, in step 1, the molar ratio of ethoxymethylene acetoacetate to guanidine is 1:3.5-5.5.

[0043] In some embodiments, in step 1, the guanidine salt and the base are neutralized and reacted in a reaction solvent at 30-60° C. for 1 h, and then the temperature is reduced to 0-20° C. to obtain guanidine.

[0044] In some embodiments, in step 1, the ring-closing reaction temperature is 0-25° C., and the reaction time is 12 h.

[0045] In some embodiments, in step 2, the decarboxylation reagent is selected from concentrated sulfuric acid and / or lithium chloride, and the molar ratio with compound A is 2 to 5:1. The organic solvent can be selected from NMP, xylene, DMSO, and n-butanol. The hydrolysis decarboxylation reaction temperature is 110 to 250° C., and the reaction time is 5 to 20 hours.

[0046] In some embodiments, in step 2, a catalyst is additionally added, and the catalyst is selected from porphyrin cobalt, tetraphenylporphyrin copper, and sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate, and the molar ratio of the catalyst to the compound A is 0.01 to 0.03:1.

[0047] In some embodiments, in step 3, the oxidant is 30% hydrogen peroxide, and the molar ratio of the oxidant to compound B is 1.5-2.0:1, and the molar ratio can also be 1.7:1; the oxidation reaction temperature is 40-60° C., and the reaction time is 10-20 h.

[0048] In some embodiments, in step 3, the oxidation reaction temperature is 40-50° C., and the reaction time is 15 h.

[0049] The present invention will be further described below by means of specific examples.

[0050] Example 1: Synthesis of Compound A

[0051]

[0052] Guanidine carbonate (31.6 g / 3.5 eq) and sodium ethoxide (23.9 g / 3.5 eq) were reacted in ethanol (200 mL) at 60°C for 1 h, cooled to 0-20°C, and ethoxymethylene cyanoacetoethyl ester (12.2 g / 1.0 eq) was added to the system, and the reaction was maintained at a reaction temperature of 15°C for 12 h. After the reaction was completed, the reaction liquid was filtered, rinsed with water and ethanol, and dried to obtain 16.8 g of the product with a yield of 92.2%.

[0053] Compound A: 1 H-NMR (400MHz, DMSO-d6)δ:8.10(s,1H),6.98(s,2H),6.56(s,2H),4.46-4.42(m,2H),1.54-1.50(m,3H).

[0054] Example 2: Synthesis of Compound A

[0055] Guanidine carbonate (36 g / 4.0 eq) and sodium tert-butoxide (38 g / 4.0 eq) were reacted in tetrahydrofuran (120 mL) at 60°C for 1 h, then cooled to 0-20°C, and ethoxymethylene cyanoacetoethyl ester (12.2 g / 1.0 eq) was added to the system, and the reaction was maintained at 10°C for 15 h. After the reaction was completed, the reaction solution was filtered, rinsed with water, and dried to obtain 17.2 g of the product with a yield of 94.4%.

[0056] Example 3: Synthesis of Compound A

[0057] Guanidine hydrochloride (34g / 3.6eq) and potassium hydroxide (20g / 3.6eq) were reacted in an ethanol / water mixed solvent (200mL, 2 / 1, V / V) at 30°C for 1h, cooled to 0-20°C, and ethoxymethylene cyanoacetoethyl ester (12.2g / 1.0eq) was added to the system, and the reaction was maintained at a reaction temperature of 25°C for 12h. After the reaction was completed, the reaction liquid was filtered, rinsed with water, and dried to obtain 17.5g of the product with a yield of 96%.

[0058] Example 4: Synthesis of Compound B

[0059]

[0060] Method 1: Compound A (3.6 g / 1 eq), lithium chloride (3.6 g / 4.3 eq), sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (0.5 g / 0.03 eq) and NMP (10 mL) were added to a reaction bottle, heated to 130 °C and reacted for 9 hours. TLC showed that the raw materials reacted completely, MTBE was added to precipitate solids, ethanol and activated carbon were added after filtration, the mixture was stirred for 30 min and filtered, and the filtrate was concentrated to obtain 2.04 g of brown solid with a yield of 93.7%.

[0061] Method 2: Compound A (3.6 g / 1 eq), lithium chloride (3.6 g / 4.3 eq) and NMP (10 mL) were added to a reaction bottle, heated to 190 °C and reacted for 14 hours. TLC showed that the raw material reacted completely. MTBE was added to precipitate a solid. After filtering, ethanol and activated carbon were added. The mixture was stirred for 30 min and then filtered. The filtrate was concentrated to obtain 2 g of a brown solid with a yield of 92%.

[0062] Compound B: 1 H-NMR(400MHz,CD3OD)δ:7.85(d,1H),5.97(d,1H).

[0063] Example 5: Synthesis of Compound B

[0064] Method 1: Add compound A (5.5 g / 1 eq), sulfuric acid (8.3 g / 2.8 eq), porphyrin cobalt (0.2 g / 0.01 eq) and n-butanol into a reaction flask, heat to 90 ° C and reflux for 1 hour. TLC shows that the raw materials are completely reacted. After cooling, add sodium hydroxide aqueous solution to adjust the pH value to 7-9, concentrate to dryness, add ethanol and activated carbon, stir at 40 ° C for 30 min, filter, and concentrate the filtrate to obtain 3.05 g of brown solid with a yield of 91.6%.

[0065] Method 2: Add compound A (5.5 g / 1 eq), sulfuric acid (8.3 g / 2.8 eq) and n-butanol into a reaction flask, heat to 150 ° C and reflux for 6 hours. TLC shows that the raw material reacts completely. After cooling, add sodium hydroxide aqueous solution to adjust the pH value to 7-9, concentrate to dryness, add ethanol and activated carbon, stir at 40 ° C for 30 min, filter, and concentrate the filtrate to obtain 2.8 g of brown solid with a yield of 84%.

[0066] Example 6: Synthesis of Compound C

[0067]

[0068] Compound B (15 g / 1 eq) and acetic acid (80 mL) were added to a reaction flask, 30% hydrogen peroxide (27 g / 1.7 eq) was slowly added dropwise under ice-water bath conditions, and the reaction was maintained at 50°C for 15 hours. The reaction was complete by TLC. The temperature was lowered, water was added, and the mixture was concentrated under reduced pressure to remove a large amount of acetic acid. After repeating 2 to 3 times, a small amount of volume remained. The temperature was lowered and stirred for crystallization, and an off-white solid was obtained by filtration. The solid was further crystallized with ethanol to obtain 15.1 g of compound C as a white solid with a yield of 88%.

[0069] Compound C: 1H-NMR(400MHz,DMSO-d6)δ:7.42(d,1H),7.33(s,2H),7.20(s,2H),6.10(d,1H).

[0070] The above is a preferred embodiment of the present invention, but the present invention should not be limited to the contents disclosed in the embodiment. Therefore, any equivalent or modification completed without departing from the spirit disclosed in the present invention shall fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing diaminopyrimidine nitrogen oxide, characterized in that: The synthetic route is as follows: The synthesis method comprises the following steps: Step 1, ethoxymethylene cyanoacetoethyl ester SM1 and guanidine SM2 are subjected to a ring-closing reaction in a reaction solvent to obtain a pyrimidine skeleton intermediate A; Step 2, the pyrimidine skeleton intermediate A is subjected to a hydrolysis decarboxylation reaction in a decarboxylation agent and an organic solvent to obtain a diaminopyrimidine intermediate B; the decarboxylation agent is selected from lithium chloride, and the molar ratio to the intermediate A is 2-5: 1; the organic solvent is selected from N-methylpyrrolidone; the reaction is carried out under a catalyst, and the catalyst is selected from sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate, and the molar ratio to the intermediate A is 0.01-0.03: 1; the hydrolysis decarboxylation reaction temperature is 110-250°C, and the reaction time is 5-9h; Step 3: The diaminopyrimidine intermediate is subjected to an oxidation reaction with an oxidant to obtain diaminopyrimidine nitrogen oxide C.

2. The method for synthesizing diaminopyrimidine nitrogen oxide according to claim 1, characterized in that: In step 1, the molar ratio of ethoxymethylene acetoacetate to guanidine is 1: 3-7.

3. The method for synthesizing diaminopyrimidine nitrogen oxide according to claim 1, characterized in that: In step 1, the guanidine is a compound generated in situ by a guanidine salt and a base in a reaction solvent, wherein: the guanidine salt is selected from one or more of guanidine carbonate, guanidine hydrochloride, guanidine sulfate or guanidine phosphate; and / or the base is selected from one or more of potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium ethoxide, sodium methoxide; and / or the reaction solvent is selected from one or more of methanol, ethanol, propanol, butanol, tetrahydrofuran and water.

4. The method for synthesizing diaminopyrimidine nitrogen oxide according to claim 3, characterized in that: In step 1, the guanidine preparation method comprises: neutralizing a guanidine salt and a base in a reaction solvent at 30-60° C. for 1 hour, and cooling the mixture to 0-20° C.

5. The method for synthesizing diaminopyrimidine nitrogen oxide according to claim 1, characterized in that: In step 1, the ring-closing reaction temperature is -10°C to 35°C, and the reaction time is 10-15h.

6. The method for synthesizing diaminopyrimidine nitrogen oxide according to claim 5, characterized in that: In step 1, the molar ratio of ethoxymethylene acetoacetate to guanidine is 1: 3.5-5.5; and / or the ring-closing reaction temperature is 0-25° C., and the reaction time is 12 h.

7. The method for synthesizing diaminopyrimidine nitrogen oxide according to claim 1, characterized in that: In step 3, the oxidant is 20-30% hydrogen peroxide, and the molar ratio of the oxidant to the intermediate B is 1.5-2.0: 1; and / or the oxidation reaction temperature is 40-60° C., and the reaction time is 10-20 h.

8. The method for synthesizing diaminopyrimidine nitrogen oxide according to claim 7, characterized in that: In step 3, the oxidation reaction temperature is 40-50°C and the reaction time is 15h.

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