(S)-3-aminobutyronitrile hydrochloride compound and preparation method thereof

Abstract

The invention discloses a preparation method of (S)-3-aminobutyronitrile hydrochloride compounds, which comprises the following steps: S1, chlorination reaction: adding thionyl chloride and a catalyst into a reaction solvent, controlling a certain temperature, dropwise adding a compound 1, reacting at a certain temperature after dropwise adding, and dropwise adding into water for quenching to obtain an aqueous solution of a compound 2; s2, cyaniding reaction: adding the compound 2 into a reaction solvent, adding a 30% sodium cyanide solution, controlling a certain temperature, reacting for a certain time, extracting and layering after the reaction is finished, washing an organic phase with a sodium chloride solution, and concentrating to obtain a compound 5; and S3, salt forming reaction: dropwise adding a solution of an HCl (gas) organic solvent into the organic solvent of the compound 5, controlling a certain temperature, reacting for a certain time, and after the reaction is finished, cooling, filtering and drying to obtain a target compound 6. The (S)-3-aminobutyronitrile hydrochloride is obtained with the mole yield of 68.5%, the cost is low, and the cost competitiveness is very high.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical synthesis preparation, in particular to (S)-3-aminobutyronitrile hydrochloride compounds and a preparation method thereof. Background Art

[0002] Orforglipron is an oral GLP-1 small molecule agonist developed by Eli Lilly and Company. It is used to treat obesity and type 2 diabetes. It is currently in Phase III clinical trials and is the fastest-progressing oral GLP-1 receptor agonist. (S)-3-aminobutyronitrile hydrochloride is an intermediate of the drug Orforglipron and has a huge market demand. However, the conventional synthesis method in the synthesis of (S)-3-aminobutyronitrile hydrochloride is complex in operation, high in cost, low in production capacity, and low in atomic utilization. In order to meet market demand, it is necessary to develop a new, efficient and concise synthesis method.

[0003] The published synthesis method of (S)-3-aminobutyronitrile hydrochloride can be found in patent CN116390926. In this route, compound 2-A is used as the starting material, and is substituted with MsCl and reacted with Boc to prepare compound 2-B. Compound 2-B is cyanated to obtain compound 2-C, and compound 2-C is then de-Boced to obtain the target product compound 2-D. The reaction route is as follows:

[0004]

[0005] The shortcomings of this route are as follows: the use of toxic reagents (MsCl), the reaction requires low temperature, the reaction process is highly exothermic, and the post-processing operation is cumbersome, the process cost is high, and the equipment utilization rate is low, resulting in low production capacity, which is not conducive to large-scale industrial production. Summary of the invention

[0006] In order to solve the defects in the prior art, the present invention provides a (S)-3-aminobutyronitrile hydrochloride compound and a preparation method thereof. The method has high conversion rate, high yield, simple operation, low cost and is suitable for industrial production.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] The preparation method of (S)-3-aminobutyronitrile hydrochloride compounds comprises the following steps:

[0009] S1 chlorination reaction: add thionyl chloride and a catalyst to a reaction solvent, control the temperature, dropwise add compound 1, react for a certain time at a certain temperature, and after the reaction is completed, dropwise add to water to quench, and obtain an aqueous solution of compound 2; the reaction formula is:

[0010]

[0011] S2 cyanation reaction: Compound 2 is added to a reaction solvent, 30% sodium cyanide solution is added, the temperature is controlled, the reaction is carried out for a certain time, after the reaction is completed, extraction and stratification are performed, the organic phase is washed with sodium chloride solution, and concentrated to obtain compound 5; the reaction formula is:

[0012]

[0013] S3 salt formation reaction: add the solution of HCl (gas) organic solvent dropwise to the organic solvent of compound 5, control the temperature to react for a certain time, and after the reaction is completed, cool down, filter, and dry to obtain the target compound 6; the reaction formula is:

[0014]

[0015] Wherein R1=Me, Et, OMe, OEt; R2=H, Boc.

[0016] Preferably, step S11 is further included between step S1 and step S2:

[0017] Cyclization reaction: Add the aqueous solution of compound 2 dropwise to the aqueous solution of sodium hydroxide, control the temperature and react for a certain time. After the reaction is completed, an aqueous solution of compound 4 is obtained. Compound 4 is then reacted in step S2 to obtain compound 5. The overall reaction formula is as follows:

[0018]

[0019] Preferably, step S111 is further included between step S1 and step S11:

[0020] Substitution reaction: Compound 3 is obtained in step S11, di-tert-butyl dicarbonate is added to compound 3, the temperature is controlled to be certain, the reaction is carried out for a certain time, after the reaction is completed, extraction and stratification are performed, the organic phase is washed with a sodium chloride aqueous solution, and concentrated to obtain compound 4; the overall reaction formula is:

[0021]

[0022] Furthermore, the reaction solvent of step S1 is any one or more of solvents such as dichloromethane, tetrahydrofuran, methyltetrahydrofuran, chloroform, and dichloroethane.

[0023] Furthermore, the reaction temperature of step S1 is 20-80°C.

[0024] Furthermore, in step S1, the ratio of compound 1, thionyl chloride and reaction solvent is: 1W: 2.4W: 8W, wherein W refers to weight percentage, and the ratio value W appearing in this specification refers to weight percentage without specific explanation.

[0025] Furthermore, the reaction temperature of step S11 is 20-70°C.

[0026] Furthermore, in step S11, the ratio of compound 2, sodium hydroxide and water is: 1W: 1.08-3.6W: 2.52W.

[0027] Furthermore, in step S111, the ratio of compound 3, di-tert-butyl dicarbonate, and water is: 1W: 3.1W: 2.7W.

[0028] Furthermore, the extraction solvent for extracting and stratifying in step S111 is any one or more of solvents such as ethyl acetate and dichloromethane.

[0029] Furthermore, the reaction solvent of step S2 is any one or more of DMF, DMSO and tetrahydrofuran. DMF refers to N,N-dimethylformamide, and its chemical formula is CH3CON(CH3)2; DMSO refers to dimethyl sulfoxide, and its chemical formula is (CH3)2SO.

[0030] Furthermore, in step S2, the solvent weight is 3-10W.

[0031] Furthermore, the reaction temperature of step S2 is 20-80°C.

[0032] Furthermore, the organic solvent in step S3 is any one or more of solvents such as ethyl acetate, 1,4-dioxane solution, methanol, and ethanol.

[0033] Furthermore, the HCl(gas) organic solvent in step S3 is any one or more of HCl(gas) ethyl acetate solution, HCl(gas) 1,4-dioxane solution, HCl(gas) methanol solution, HCl(gas) ethanol solution and the like.

[0034] The invention also discloses a (S)-3-aminobutyronitrile hydrochloride compound prepared by a preparation method of the (S)-3-aminobutyronitrile hydrochloride compound.

[0035] The beneficial effects of the present invention are:

[0036] The synthetic route reported in the patent (CN116390926) requires the use of highly toxic MsCl for the protection of the hydroxyl group, which has the risk of introducing toxic impurities, and requires low-temperature equipment during workshop production, which is complex and costly. The present invention designs a completely new process route, through the steps of chlorination, cyclization, Boc protection, cyanidation, de-Boc salt formation, etc., to obtain (S)-3-aminobutyronitrile hydrochloride with a molar yield of 68.5%, which is low in cost and has strong cost competitiveness. At the same time, the reaction conditions are mild, the reaction is simple, the selectivity is good, it is easy to scale up, and it is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Attached Figure 1 The carbon spectrum of compound 2 obtained in Example 2 of the present invention;

[0038] Attached Figure 2 is the hydrogen spectrum of compound 2 obtained in Example 2 of the present invention;

[0039] Attached Figure 3 The carbon spectrum of compound 5 obtained in Example 4 of the present invention;

[0040] Attached Figure 4 is the hydrogen spectrum of compound 5 obtained in Example 4 of the present invention;

[0041] Attached Figure 5 The carbon spectrum of compound 6 obtained in Example 5 of the present invention;

[0042] Attached Figure 6 This is the hydrogen spectrum of compound 6 obtained in Example 5 of the present invention. DETAILED DESCRIPTION

[0043] In order to enable those skilled in the art to better understand the technical solution of the invention, the present invention is further described in detail below in conjunction with specific implementation methods.

[0044] The present invention relates to a preparation method and application of a (S)-3-aminobutyronitrile hydrochloride compound. The compound is mainly used for the preparation of a new drug Orforglipron, which is an oral GLP-1 small molecule agonist used to treat obesity and type II diabetes. It relates to the technical field of pharmaceutical synthesis preparation, including the following synthesis steps:

[0045] The present invention has three reaction routes for obtaining compound 6, and the following reaction route 1: (1) Compound 1 is used as a starting reaction material, and a chlorination reaction is performed to obtain compound 2; (2) Compound 2 is reacted under alkaline conditions to generate compound 3; (3) Compound 3 reacts with di-tert-butyl dicarbonate to generate compound 4; (4) Compound 4 is subjected to sodium cyanide ring opening to obtain compound 5; (5) Compound 5 is subjected to Boc removal to obtain a target compound 6;

[0046] Reaction route 2: (1) Compound 1 is used as the starting material to obtain compound 2 through chlorination reaction; (2) Compound 2 is subjected to ring opening with sodium cyanide to obtain compound 5; (3) Compound 5 is salted to obtain compound 6;

[0047] Reaction route 3: (1) Compound 1 is used as the starting material to obtain compound 2 through chlorination reaction; (2) Compound 2 is reacted under alkaline conditions to generate compound 4; (3) Compound 4 is subjected to sodium cyanide ring opening to obtain compound 5; (4) Compound 5 is salted to obtain compound 6;

[0048] The reaction formula is as follows:

[0049]

[0050] When R2 is H, the structural formula of compound 4 is consistent with that of compound 3.

[0051] The invention uses (S)-(+)-2-amino-1-propanol as a starting material, and has a total yield of 68.5% through five steps of reaction. The reaction is simple, the selectivity is good, the cost is low, and the invention is suitable for industrial production.

[0052] The above is the specific content of the present invention. The reaction steps will be further described below through specific examples.

[0053] Example 1 (Preparation of (2R)-1-chloropropane-2-amino hydrochloride)

[0054] Add chloroform (720.0 g, 8.0 W), N,N-dimethylformamide (1.75 g, 0.02 W), and thionyl chloride (213.8 g, 2.4 W) to the reaction flask; heat to 40-50 ° C, slowly add L-aminopropanol (compound 1) (90.0 g, 1.0 W) to the reaction flask, and keep warm for 24 hours; after the reaction, add the reaction solution dropwise to water (180.0 g, 2.0 W), stir and cool to 10-30 ° C to quench the reaction; extract and separate, retain the upper aqueous phase, add activated carbon (4.5 g, 0.05 W) for decolorization, filter, and rinse the filter cake with water (45 g, 0.5 W) to obtain compound 2, that is, (2R)-1-chloropropane-2-amino hydrochloride aqueous solution, which is directly fed to the next step; purity 96%, yield 98%.

[0055] Example 2 (Preparation of (S)-2-methylaziridine)

[0056] Add 30% liquid alkali (559.3g, 3.6W) to the reaction bottle, cool to 0-10°C, and dropwise add the entire batch of compound 2 (155.8, 1W) aqueous solution; after the addition is completed, control the temperature to 40-50°C, and keep the reaction for 1h. After the reaction is completed, cool to 20-30°C to obtain compound 3, i.e., (S)-2-methylaziridine aqueous solution, for standby use; purity: 99%, yield 98%.

[0057] Example 3 (Preparation of (S)-2-methylaziridine-1-carboxylic acid tert-butyl ester)

[0058] Add the aqueous solution of all the compound 3 ((S)-2-methylaziridine) (68.4 g, 1.0 W) from the previous batch to the reaction bottle, control the temperature at 25-35 ° C, add di-tert-butyl dicarbonate (209.2 g, 3.1 W) dropwise, keep the temperature for 2 hours, filter after the reaction, and wash the filter cake with ethyl acetate (287.3, 4.2 W)

[0059] The filtrate was washed and collected; the filtrate was separated into layers, and the organic phase was collected. The organic phase was washed with a 10% sodium chloride aqueous solution (205.2 g, 3.0 W), and the organic phase was separated and collected; the organic phase was concentrated under reduced pressure at a temperature of 40 to 50° C. and a vacuum degree of -0.085 to -0.095 MPa until no fraction was distilled out; the temperature was lowered to 20 to 30° C. to obtain compound 4, i.e., (S)-2-methylaziridine-1-carboxylic acid tert-butyl ester concentrate, a light yellow oil; purity: 99%, yield 80%;

[0060] Example 4 (Preparation of tert-butyl [(2S)-1-cyano-2-propyl]carbamate)

[0061] Compound 4 ((S)-2-methylaziridine-1-carboxylic acid tert-butyl ester) (130.0 g, 1.0 W) was added to the reaction bottle, N, N-dimethylamide (560.0 g, 4.3 W) was added, stirred to dissolve, 30% sodium cyanide (135.2 g, 1.04 W) aqueous solution was added, stirred and heated to 40-50 ° C, and the reaction was kept warm for 16 hours. After the reaction was completed, the temperature was lowered to 20-30 ° C, tap water (650.0 g, 5.0 W) and ethyl acetate (390.0 g, 3.0 W) were added, and the layers were extracted and separated. The organic phase was collected, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined; the organic phase was The mixture was washed with 10% sodium chloride (390.0 g, 3.0 W)*2 aqueous solution, and the organic phase was collected; the temperature was controlled at 40-50°C, the vacuum degree was -0.08-0.1 MPa, and the organic phase was concentrated under reduced pressure until a large amount of white solid appeared; n-heptane (650.0 g, 5.0 W) was slowly added dropwise, and the mixture was kept warm and stirred for 1 hour, and the temperature was slowly lowered to 0-10°C, and the mixture was kept warm and stirred for 2 hours. The filter cake was washed with 0-10°C n-heptane (65.0 g, 0.5 W) by pressure filtration, and the filter cake was collected to obtain compound 5 (tert-butyl [(2S)-1-cyano-2-propyl]carbamate) as a white solid; purity: 99%, yield 80%.

[0062] Example 5 (Preparation of (S)-3-aminobutyronitrile hydrochloride)

[0063] Compound 5 (tert-butyl [(2S)-1-cyano-2-propyl]carbamate) (110.0 g, 1.0 eq) and ethyl acetate (330.0 g, 3.0 eq) were added to the reaction flask at 25 ± 5 °C. 14.5-20% hydrogen chloride ethyl acetate solution (373.5 g, 2.5 eq) was added dropwise and stirred for 2 h ± 10 min. After the reaction was completed, the temperature was lowered to 0-10 °C.

[0064] Press filter, rinse with 0-10°C ethyl acetate (55.0 g, 0.5 W); obtain a crude product, add ethyl acetate (550.0 g, 5.0 W), cool to 0-10°C, and stir for 1 h; press filter, rinse the filter cake with 0-10°C ethyl acetate (55.0 g, 0.5 W); obtain compound 6 ((S)-3-aminobutyronitrile hydrochloride) as a white to off-white solid; purity: 99%, yield 95%.

[0065] Example 6 (Preparation of (S)-3-aminobutyronitrile)

[0066] Compound 2 ((2R)-1-chloropropane-2-amino hydrochloride) (130.0 g, 1.0 W) was added to the reaction flask, N, N-dimethylamide (560.0 g, 4.3 W) was added, stirred to dissolve, 30% sodium cyanide (135.2 g, 1.04 W) aqueous solution was added, stirred and heated to 40-50 ° C, and the reaction was kept warm for 16 hours. After the reaction was completed, the temperature was lowered to 20-30 ° C, tap water (650.0 g, 5.0 W) and ethyl acetate (390.0 g, 3.0 W) were added, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate and the organic phases were combined; the organic phase was washed with 10% sodium chloride (390.0 g, 3.0 W) aqueous solution. The organic phase was collected; the temperature was controlled at 40-50°C, the vacuum degree was -0.08-0.1 MPa, and the organic phase was concentrated under reduced pressure until a large amount of white solid appeared; n-heptane (650.0 g, 5.0 W) was slowly added dropwise, and the mixture was kept warm and stirred for 1 hour, the temperature was slowly lowered to 0-10°C, and the mixture was kept warm and stirred for 2 hours, and the filter cake was washed with 0-10°C n-heptane (65.0 g, 0.5 W) by pressure filtration, and the filter cake was collected to obtain a crude product; ethyl acetate (260.0 g, 2.0 W) was added to the crude product, and the mixture was stirred to dissolve, and n-heptane (650.0 g, 5.0 W) was added dropwise at a temperature of 10-20°C, and the mixture was filtered to obtain compound 5 ((S)-3-aminobutyronitrile) as a white solid; purity: 99%, yield 65%.

[0067] Example 7 (Preparation of (S)-3-aminobutyronitrile)

[0068] Compound 4 ((S)-2-methylaziridine) (130.0 g, 1.0 W) was added to the reaction flask, N, N-dimethylamide (560.0 g, 4.3 W) was added, stirred to dissolve, 30% sodium cyanide (135.2 g, 1.04 W) aqueous solution was added, stirred and heated to 40-50 ° C, and the reaction was kept warm for 16 hours. After the reaction was completed, the temperature was lowered to 20-30 ° C, tap water (650.0 g, 5.0 W) and ethyl acetate (390.0 g, 3.0 W) were added, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate and the organic phases were combined; the organic phase was washed twice with 10% sodium chloride (390.0 g, 3.0 W) aqueous solution, and the mixture was collected. Organic phase; temperature controlled at 40-50°C, vacuum degree -0.08-0.1MPa, organic phase concentrated under reduced pressure until a large amount of white solid appears; n-heptane (650.0g, 5.0W) was slowly added dropwise, stirred at this temperature for 1h, slowly cooled to 0-10°C, stirred at this temperature for 2h, filter pressed and rinsed the filter cake with 0-10°C n-heptane (65.0g, 0.5W), collected the filter cake, and obtained a crude product; ethyl acetate (260.0g, 2.0W) was added to the crude product, stirred to dissolve, temperature controlled at 10-20°C, n-heptane (650.0g, 5.0W) was added dropwise, filtered to obtain compound 5 ((S)-3-aminobutyronitrile), a white solid; purity: 99%, yield 50%.

[0069] The NMR data of compound 2 are as follows:

[0070] 1HNMR (400MHz, D2O) δ3.87-3.92 (m, 1H), 3.71-3.78 (m, 2H), 1.38 (d, J=8.0Hz, 3H), 3.8 (d, J=12.0, 8.1Hz, 1H) ppm.

[0071] The NMR data of compound 5 are as follows:

[0072] 1HNMR (400MHz, CDCl3) δ4.77 (s, 1H), 3.94-4.00 (m, 1H), 2.76 (dd, J=16.5, 4.2Hz, 1H), 2.54 (dd, J=16.0, 4.0Hz, 1H), 1.46 (s, 9H), 1.33 (d, J=6.9Hz, 3H) ppm; MS: m / z=184 (GC).

[0073] The NMR data of compound 6 are as follows:

[0074] 1HNMR (400MHz, DMSO-d6) δ8.60 (s, 2H), 3.55 (m, 1H), 3.06 (dd, J=16.1, 16.1, 1 H), 2.94 (dd, J=16.1, 16.1, 1H), 1.34 (d, J=8.0Hz, 3H) ppm, MS: m / z=84 (GCMS).

[0075] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention, and the protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing a (S)-3-aminobutyronitrile hydrochloride compound, characterized in that: The steps include: S1 chlorination reaction: add thionyl chloride and a catalyst to a reaction solvent, control the temperature, dropwise add compound 1, react at a certain temperature for a certain time, and after the addition is complete, dropwise add to water to quench, and obtain an aqueous solution of compound 2; the reaction formula is: S2 cyanation reaction: Compound 2 is added to a reaction solvent, 30% sodium cyanide solution is added, the temperature is controlled, the reaction is carried out for a certain time, after the reaction is completed, extraction and stratification are performed, the organic phase is washed with sodium chloride solution, and concentrated to obtain compound 5; the reaction formula is: S3 salt formation reaction: add the solution of HCl (gas) organic solvent dropwise to the organic solvent of compound 5, control the temperature to react for a certain time, and after the reaction is completed, cool down, filter, and dry to obtain the target compound 6; the reaction formula is: Wherein R1=Me, Et, OMe, OEt; R2=H, Boc.

2. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 1, characterized in that: Also included between step S1 and step S2 is step S11: Cyclization reaction: Add the aqueous solution of compound 2 dropwise to the aqueous solution of sodium hydroxide, control the temperature and react for a certain time. After the reaction is completed, an aqueous solution of compound 4 is obtained. Compound 4 is then reacted in step S2 to obtain compound 5. The overall reaction formula is as follows:

3. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 2, wherein: Also included between step S1 and step S11 is step S111: Substitution reaction: Compound 3 is obtained in step S11, di-tert-butyl dicarbonate is added to compound 3, the temperature is controlled to be certain, the reaction is carried out for a certain time, after the reaction is completed, extraction and stratification are performed, the organic phase is washed with a sodium chloride aqueous solution, and concentrated to obtain compound 4; the overall reaction formula is:

4. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 1, characterized in that: The reaction solvent of step S1 is any one or more of solvents such as dichloromethane, tetrahydrofuran, methyltetrahydrofuran, chloroform, and dichloroethane.

5. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 1, characterized in that: The reaction temperature of step S1 is 20-80°C.

6. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 1, characterized in that: In step S1, the ratio of compound 1, thionyl chloride and reaction solvent is 1W: 2.4W: 8W.

7. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 2, characterized in that: The reaction temperature of step S11 is 20-70°C.

8. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 2, characterized in that: In step S11, the ratio of compound 2, sodium hydroxide and water is: 1W: 1.08-3.6W: 2.52W.

9. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 3, characterized in that: In step S111, the ratio of compound 3, di-tert-butyl dicarbonate, and water is 1W: 3.1W: 2.7W.

10. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 3, characterized in that: The extraction solvent for extracting and stratifying in step S111 is any one or more of solvents such as ethyl acetate and dichloromethane.

11. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 1, characterized in that: The reaction solvent of step S2 is any one or more of DMF, DMSO and tetrahydrofuran.

12. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 1, characterized in that: The solvent weight in step S2 is 3-10W.

13. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 1, characterized in that: The reaction temperature of step S2 is 20-80°C.

14. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 1, characterized in that: The organic solvent in step S3 is any one or more of solvents such as ethyl acetate, 1,4-dioxane solution, methanol, and ethanol.

15. The method for preparing the (S)-3-aminobutyronitrile hydrochloride compound according to claim 1, characterized in that: The HCl(gas) organic solvent in step S3 is any one or more of HCl(gas) in ethyl acetate, HCl(gas) in 1,4-dioxane, HCl(gas) in methanol, HCl(gas) in ethanol, and the like.

16. A (S)-3-aminobutyronitrile hydrochloride compound prepared according to the method for preparing a (S)-3-aminobutyronitrile hydrochloride compound according to any one of claims 1 to 15.

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