Dibromovinyl-containing heterocyclic alkane compound as well as preparation method and application thereof

Abstract

The invention discloses a heterocyclic alkane compound containing dibromovinyl as well as a preparation method and application of the heterocyclic alkane compound. The preparation method of the heterocyclic alkane compound containing the dibromovinyl group comprises the following steps: in the presence of triphenylphosphine, in a solvent, carrying out bromination reaction on a compound I and carbon tetrabromide to obtain a compound II. The preparation method has the advantages of good yield, chemical and chiral purity, good safety, low cost and good industrial application prospect. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a heterocycloalkane compound containing dibromovinyl groups, and a preparation method and application thereof. Background Art

[0002] (S)-2-ethynylmorpholine-4-carboxylic acid tert-butyl ester is an important intermediate for the synthesis of imidazopyridine P2X3 inhibitors. The Chinese patent CN105246888A-Imidazolopyridine compounds and their uses is disclosed on page 33 of the specification, and Example 7 discloses its preparation method. The specific synthesis route is as follows:

[0003]

[0004] However, this synthetic route is prone to produce nitrogen during the production process, which makes the production process have a greater safety risk. In addition, the raw material compound (1-diazo-2-oxopropyl) dimethyl phosphonate is expensive, has poor stability, is inconvenient to transport and store, and is easily restricted in production, making it unsuitable for industrial production.

[0005] However, when the nitrogen-containing heterocyclic aldehyde substrate is used to prepare the corresponding alkynyl product, the reaction yield of the nitrogen-containing heterocyclic aldehyde substrate is extremely low when it is converted into an olefin intermediate, and when the alkynyl product is generated from the olefin intermediate, the n-butyl lithium used therein still has certain safety hazards. Chinese patent application CN102336749A discloses the following method for preparing tert-butyl 3-ethynylpiperidine-1-carboxylate from 1-Boc-3-piperidinecarboxaldehyde, but the first step reaction yield is low, the yield is only 9%, and the second step reaction uses n-butyl lithium, the reaction conditions are relatively harsh, there are safety hazards, and it is not suitable for industrial production.

[0006]

[0007] In view of the importance of (S)-2-ethynylmorpholine-4-carboxylic acid tert-butyl ester, it is urgent to develop a preparation method suitable for industrial production with good yield, low cost and high safety. Summary of the invention

[0008] The technical problem to be solved by the present invention is that the existing (S)-2-ethynylmorpholine-4-carboxylic acid tert-butyl ester synthesis method has the defects of expensive materials, complex process, low safety, and unsuitability for industrial production. For this reason, the present invention provides a dibromovinyl-containing heterocycloalkane compound, its preparation method and application. The preparation method of the dibromovinyl-containing heterocycloalkane compound of the present invention has one or more of the following advantages: high yield, high chemical purity and high chiral purity. The present invention adopts alkali metal hydroxide as an alkaline reagent to synthesize compound III with the dibromovinyl-containing heterocycloalkane compound, achieving good conversion rate, yield and high chemical purity and chiral purity, and avoiding the use of expensive or dangerous reagents in the whole preparation route, reducing costs and improving safety, and is simple to operate and more suitable for industrial production.

[0009] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0010] The present invention provides a method for preparing a compound II, which comprises the following steps: in the presence of triphenylphosphine, in a solvent, subjecting a compound I to a bromination reaction with carbon tetrabromide to obtain a compound II;

[0011]

[0012] In the present invention, the conditions and operations of the bromination reaction are conventional conditions and operations of such reactions in the art. The present invention particularly prefers the following conditions and operations:

[0013] In the preparation method, the bromination reaction is preferably carried out in the presence of substance X, and the substance X is zinc powder and / or an organic base.

[0014] The organic base can be a nitrogen-containing organic base, such as an alkyl tertiary amine base (such as triethylamine or N,N-diisopropylethylamine), an alkyl secondary amine base (such as diethylamine), a nitrogen-containing heterocyclic aromatic hydrocarbon (such as pyrrole, pyridine or quinoline), or an aromatic amine (such as aniline or dimethylaniline).

[0015] In the present invention, the organic base is preferably pyridine and / or an alkyl tertiary amine base. The alkyl tertiary amine base is preferably triethylamine and / or N,N-diisopropylethylamine.

[0016] When the organic base is pyridine, the substance X is preferably zinc powder and pyridine.

[0017] When the organic base is an alkyl tertiary amine base, the substance X is preferably triethylamine.

[0018] In the preparation method, the molar ratio of the substance X to the compound I is preferably (2.0-16.0):1.0, more preferably (2.0-4.0):1.0, for example, 2.0:1.0, 2.5:1.0, 3.0:1.0, 3.5:1.0, 4.0:1.0.

[0019] When the substance X is zinc powder and an organic base, the molar ratio of the zinc powder to the organic base is preferably (0.5-1.0):1.0, more preferably (0.5-0.6):1.0, for example 0.5:1.0, 0.6:1.0.

[0020] In the preparation method, the solvent may be a halogenated hydrocarbon solvent.

[0021] The halogenated hydrocarbon solvent is preferably one or more of dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; more preferably dichloromethane.

[0022] In the preparation method, the amount of the solvent may not be specifically limited, as long as it does not affect the reaction. In the preparation method, the volume-to-mass ratio of the solvent to the compound I is preferably 8-20 mL / g, more preferably 8-15 mL / g, for example 8 mL / g, 10 mL / g, 15 mL / g.

[0023] In the preparation method, the molar ratio of the carbon tetrabromide to the compound I is preferably (1.0-6.0):1.0, more preferably (1.0-3.0):1.0, for example, 1.0:1.0, 1.2:1.0, 1.3:1.0, 1.5:1.0, 2.0:1.0 or 3.0:1.0.

[0024] In the preparation method, the molar ratio of the triphenylphosphine to the compound I is preferably (1.0-6.0):1.0, more preferably (1.2-4.0):1.0, for example, 1.2:1.0, 1.35:1.0, 1.5:1.0, 1.65:1.0, 2.0:1.0, 2.4:1.0, 3.0:1.0, 4.0:1.0.

[0025] In the preparation method, the reaction temperature of the bromination reaction is a conventional temperature for such reactions in the art, preferably -5-30°C, more preferably -5-10°C, such as -5°C, -2.5-2.5°C, 10°C.

[0026] In the preparation method, the progress of the bromination reaction is monitored by conventional detection methods in the art (e.g., HPLC), and the disappearance or no-reaction of the compound I in the reaction solution is generally used as the reaction endpoint. The reaction time of the bromination reaction is preferably 8-18 hours, more preferably 12-16 hours, such as 12 hours, 16 hours.

[0027] In the preparation method, post-treatment may be included after the bromination reaction is completed.

[0028] The post-treatment steps preferably include filtration, extraction, concentration, beating (eg, beating with petroleum ether), filtration, concentration, and removal of triphenylphosphine.

[0029] In the extraction step, a citric acid solution (eg, a 5% by mass citric acid solution) is preferably used.

[0030] The concentration may also include washing (eg, washing with saturated brine) and drying (eg, with anhydrous sodium sulfate) steps.

[0031] The step of removing triphenylphosphine oxide preferably comprises mixing the concentrated solution and ZnCl2 (for example, in petroleum ether under the protection of an inert gas (nitrogen or argon)) (for example, stirring overnight at 20-25°C), filtering and concentrating to obtain compound II.

[0032] The present invention also provides a method for preparing compound III, which comprises the following steps:

[0033] Step 1: In the presence of triphenylphosphine, in a solvent, compound I and carbon tetrabromide are subjected to bromination reaction to obtain compound II;

[0034] Step 2: In the presence of an alkaline reagent, react the compound II obtained in step 1 in a solvent to obtain compound III;

[0035]

[0036] The conditions and operations in step 1 are preferably the same as those described in the preparation method of compound II.

[0037] In step 2, the reaction conditions and operations are conventional conditions and operations for such reactions in the art, and the present invention particularly prefers the following conditions and operations:

[0038] In step 2, the alkaline reagent is preferably an alkali metal hydroxide, n-butyl lithium (n-BuLi), lithium diisopropylamide (LDA) and (C 1-3 alkyl)MgBr, more preferably an alkali metal hydroxide.

[0039] The alkali metal hydroxide is preferably KOH.

[0040] In step 2, the molar ratio of the alkaline reagent to the compound II is preferably (3.0-15.0):1.0, most preferably (3.0-10.0):1.0, for example 3.0:1.0, 6.65:1.0, 10.0:1.0.

[0041] In step 2, the solvent is preferably one or more of a ketone solvent, an ether solvent, an aromatic hydrocarbon solvent, an alcohol solvent and an alkane solvent, and more preferably a ketone solvent.

[0042] Among them, the ketone solvent is preferably acetone. The ether solvent is preferably tetrahydrofuran. The aromatic hydrocarbon solvent is preferably toluene. The alcohol solvent is preferably ethanol. The alkane solvent is preferably n-heptane.

[0043] In the preparation method, the amount of the solvent may not be specifically limited, as long as it does not affect the reaction. In the preparation method, the volume-to-mass ratio of the solvent to the compound II is preferably 5-15 mL / g, more preferably 5-10 mL / g, such as 5 mL / g, 8 mL / g, 9 mL / g or 10 mL / g.

[0044] In step 2, the reaction temperature is a conventional temperature for such reactions in the art, preferably 25-40°C, more preferably 35-40°C, such as 35°C, 40°C.

[0045] In step 2, the reaction can also be carried out in the presence of a phase transfer catalyst. The phase transfer catalyst is preferably tetrabutylammonium bromide. The mass ratio of the phase transfer catalyst to the compound II is preferably (0.5-2):1, for example 0.5:1, 1:1, 2:1.

[0046] In step 2, the progress of the reaction is monitored by a conventional detection method in the art (e.g., HPLC), and preferably the disappearance or no reaction of the compound II and / or the monobrominated intermediate in the reaction solution is used as the reaction endpoint. The reaction time is preferably 16-30 h, such as 16 h, 26 h, 30 h.

[0047] In step 2, the reaction may include post-treatment after completion.

[0048] The post-treatment steps preferably include cooling, quenching, extraction, concentration and beating.

[0049] Among them, in the cooling step, the temperature is preferably lowered to below 5°C.

[0050] In the quenching step, preferably, a citric acid aqueous solution (eg, a 5% citric acid aqueous solution) is used. In the quenching step, the pH of the reaction solution is preferably 4 to 6 as the quenching end point.

[0051] Among them, n-heptane is preferably used in the extraction step.

[0052] Among them, in the pulping step, a mixed solvent of ethanol and water is preferably used.

[0053] Wherein, before the concentration step, washing (eg, washing with saturated brine) and drying (eg, with anhydrous sodium sulfate) may also be included.

[0054] The present invention also provides a method for preparing compound III, which comprises the following steps: reacting compound II in a solvent in the presence of an alkaline reagent to obtain compound III;

[0055] Wherein, the alkaline reagent is an alkali metal hydroxide; the solvent is a ketone solvent;

[0056]

[0057] Among them, the other conditions and operations in the preparation method of compound III are preferably the same as the conditions and operations described in step 2 of the preparation method of compound III.

[0058] The present invention provides a compound II having the following structure:

[0059]

[0060] The present invention also provides a method for preparing a P2X3 antagonist, which comprises the following scheme:

[0061] Scheme 1: It comprises the following steps: a method for preparing compound II;

[0062] and, a method for preparing a P2X3 antagonist by further preparing the compound II;

[0063] The preparation method of the compound II comprises the following steps: in the presence of triphenylphosphine, in a solvent, brominating the compound I with carbon tetrabromide to obtain the compound II;

[0064]

[0065] Scheme 2: It comprises the following steps: a method for preparing compound III;

[0066] and, a method for preparing a P2X3 antagonist by further preparing the compound III;

[0067] The preparation method of the compound III comprises the following steps: reacting the compound II in a solvent in the presence of an alkaline reagent to obtain the compound III;

[0068] The alkaline reagent is an alkali metal hydroxide; the solvent is a ketone solvent;

[0069]

[0070] Among them, other conditions and operations in the preparation methods of the compound II and the compound III are preferably the same as the conditions and operations described in the preparation methods of the compound II and the compound III.

[0071] The P2X3 antagonist is preferably as shown in Formula A:

[0072] In formula A, ring A is

[0073]

[0074] W is a single bond or -C(=O)-NH-;

[0075] Ring B is a benzene ring, a 5-6-membered heteroaromatic ring or a 5-6-membered heterocyclic ring, and the heteroatoms in the 5-6-membered heteroaromatic ring and the 5-6-membered heterocyclic ring are one or more of N, S or O, and the number is 1 or 2;

[0076] R 1 H, halogen, -OH, -CF3, -CN, -NH-C(=O)-R 1-1 , -C(=O)-R 1-2 、-OC(=O)-N(R 1-3 R 1 -4 )、-C(=O)-

[0077] N(R 1-5 R 1-6 )、-C(=NH)-N(R 1-7 R 1-8 )、-S(=O)2-N(R 1-9 R 1-10 )、-S(=O)-N(R 1-11 R 1-12 ),-OC(=O)-R 1-13 、-N(R 1-14 R 1-

[0078] 15 )、-NH-S(=O)2-R 1-16, unsubstituted or substituted C1~C6 alkyl, unsubstituted or substituted C1~C6 alkyl-O-, unsubstituted or substituted C2~C6 alkenyl, unsubstituted or substituted C2~C6 alkenyl-O-, unsubstituted or substituted C3~C 10 Cycloalkyl, unsubstituted or substituted C3-C9 heterocycloalkyl, unsubstituted or substituted C3-C9 heterocycloalkenyl, unsubstituted or substituted C6-C 10 Aryl, or unsubstituted or substituted 5-10 membered heteroaryl;

[0079] In the C3-C9 heterocycloalkyl, the C3-C9 heterocycloalkenyl and the 5-10 membered heteroaryl, the heteroatoms are independently one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is 1 to 3;

[0080] The substituted C1-C6 alkyl, the substituted C1-C6 alkyl-O-, the substituted C2-C6 alkenyl, the substituted C2-C6 alkenyl-O-, the substituted C3-C 10 Cycloalkyl, the substituted C6~C 10 In the aryl group, the substituted C3-C9 heterocycloalkyl group, the substituted C3-C9 heterocycloalkenyl group, or the substituted 5-10 membered heteroaryl group, the substitutions independently refer to one or more of the following substituents: halogen, -OH, -CF3, -CN, -COOH, -C(=O)NH2, =O (i.e., two geminal hydrogen atoms on the carbon atom are replaced by groups O), -N(R 1-21 R 1-22 )、-C(=O)-N(R 1-23 R 1-24 )、-S(=O)2-N(R 1-25 R 1-26 )、-C(=O)-OR 1-27 , or, unsubstituted or replaced by one or more R a Substituted: C1-C6 alkyl, C1-C6 alkyl-O- or C3-C6 cycloalkyl, R a When there are multiple, they are the same or different, R a is halogen, -OH, =O, -CF3, -CN, -COOH, -C(=O)NH2; when there are multiple substituents, the substituents are the same or different;

[0081] R 1-1 , R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 , R1-10 , R 1-11 , R 1-12 , R 1-13 , R 1-14 , R 1-15 , R 1-16 , R 1-21 , R 1-22 , R 1-23 , R 1-24 , R 1-25 , R 1-26 and R 1-27 are independently H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C1-C6 alkyl-O-, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkenyl-O-, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C3-C 10 Cycloalkyl, unsubstituted or substituted C3-C9 heterocycloalkyl, unsubstituted or substituted C3-C9 heterocycloalkenyl, unsubstituted or substituted phenyl, or unsubstituted or substituted 5-10 membered heteroaryl;

[0082] In the C3-C9 heterocycloalkyl, the C3-C9 heterocycloalkenyl and the 5-10 membered heteroaryl, the heteroatoms are independently one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is 1 to 3;

[0083] The substituted C1-C6 alkyl, the substituted C1-C6 alkyl-O-, the substituted C2-C6 alkenyl, the substituted C2-C6 alkenyl-O-, the substituted C2-C6 alkynyl, the substituted C3-C 10 In the cycloalkyl, the substituted C3-C9 heterocycloalkyl, the substituted C3-C9 heterocycloalkenyl, the substituted phenyl, or the substituted 5-10 membered heteroaryl, the substitutions independently refer to one or more of the following substituents: halogen, -OH, -CF3, -CN, -COOH, -COOCH3, -NH2, =O (i.e., two geminal hydrogen atoms on the carbon atom are replaced by groups O), or unsubstituted or replaced by one or more R d Substituted: C1-C6 alkyl, C1-C6 alkyl-O- or C3-C6 cycloalkyl, R d When there are multiple, they are the same or different, R d are independently H, halogen, -OH, =O, -CF3, -CN, -COOH, -C(=O)NH2; when there are multiple substituents, the substituents are the same or different;

[0084] Or, R 1-3 and R 1-4 , R 1-5 and R 1-6, R 1-7 and R 1-8 , R 1-9 and R 1-10 , R 1-11 and R 1-12 , R 1-14 and R 1-15 , R 1-21 and R 1-22 , R 1-23 and R 1-24 , or, R 1-25 and R 1-26 They independently form together with the nitrogen to which they are directly connected an unsubstituted or substituted C3-C9 heterocycloalkyl, an unsubstituted or substituted C3-C9 heterocycloalkenyl, or an unsubstituted or substituted 5-10 membered heteroaryl; the C3-C9 heterocycloalkyl, except for the nitrogen, does not contain heteroatoms, or contains one or more of oxygen, sulfur and nitrogen, 1 to 2 heteroatoms; the C3-C9 heterocycloalkenyl, except for the nitrogen, does not contain heteroatoms, or contains one or more of oxygen, sulfur and nitrogen, 1 to 2 heteroatoms; the 5-10 membered heteroaryl In the substituted C3-C9 heterocycloalkyl, the substituted C3-C9 heterocycloalkenyl, or the substituted 5-10 membered heteroaryl, the substitutions independently refer to one or more of the following substituents: halogen, -OH, -CF3, -CN, C1-C6 alkyl, C1-C6 alkyl-O-, =O (i.e., two geminal hydrogen atoms on the carbon atom are replaced by groups O), or unsubstituted or replaced by one or more R b Substituted: C1-C6 alkyl, C1-C6 alkyl-O- or C3-C6 cycloalkyl, R b When there are multiple, they are the same or different, R b is halogen, -OH, =O, -CF3, -CN, -COOH or -C(=O)NH2;

[0085] R 2 and R 3 independently H, halogen, -OH, halogenated C1-C6 alkyl, -CN or C1-C6 alkyl; m and n are independently 1 or 2;

[0086] R 4 C(=O)R 4-1 , -C(NHCH3)=CH(NO2), 5-6 membered heteroaryl or 1 or more R 4-2 substituted 5-6 membered heteroaryl;

[0087] The 5-6 membered heteroaryl and the 4-2The heteroatoms in the substituted 5-6 membered heteroaryl group are independently one or more of oxygen, sulfur and nitrogen, 1 or 2 heteroatoms;

[0088] R 4-1 C1-C6 alkyl, C1-C6 alkyl substituted by one or more deuteriums, or -O-C1-C6 alkyl;

[0089] R 4-2 It is halogen, -CN, C1~C6 alkyl, C1~C6 alkoxy, -S(O)2C1~C6 alkyl, -C(O)CH3, -NHC2H3.

[0090] The P2X3 antagonist is preferably any of the following compounds:

[0091]

[0092]

[0093] Compounds numbered 1-192 disclosed in the patent specification of WO2020135771A1, which include a morpholine ring in their structures, and related intermediates;

[0094] Compounds 16-1, 16-2, 16-3, 16-4, 16-5, 16-6, 16-7, 16-8, 16-9, 16-10, 16-11, 16-12, 16-13, 16-14, 16-15, 16-16, 16-17, 16-18, 16-19, 16-20, 16-21, 16-22, 16-25, 16-33 disclosed in patent WO2014117274A1;

[0095] The compounds disclosed in the specification of patent CN115413279A [Paragraph 0166], specifically compounds numbered 1-13, 37-76 in sequence, and related intermediates thereof;

[0096] The compounds of Examples 2-4, 28-35, 40, 41, 44-86 disclosed in the specification of patent CN112409331A, and their related intermediates;

[0097] Compounds numbered 4-45, 47-51, 53-55, 58-60, 63-69, 76-89, 94 in sequence, and their related intermediates, disclosed in the specification

[0116] of patent CN113549068A;

[0098] Compounds numbered 1-34, 37-57 in sequence, and their related intermediates disclosed in the specification [0153-0155] of patent CN113912601A;

[0099] The compounds shown in Examples 4 and 5 disclosed in the specification of patent WO2022117062A1;

[0100] Compounds numbered I-1 to I-13, I-16 to I-19, I-21, I-23 to I-39 disclosed in the patent specification of WO2021244634A1, and their related intermediates;

[0101] Compounds numbered Z-1 to Z-7, Z-15 to Z-36 disclosed in the patent specification WO2022161462A1, and their related intermediates;

[0102] The structure disclosed in the specification of patent CN115043836A [paragraphs 0108-0115] includes compounds containing morpholine rings, such as compounds numbered 1, 4, 7, 11, 14, 17, 21, 24, 27, 33, 36, 39, 40, 42, 46, 50, 53, 56, 60, 61, 64, 67, 70, 71, 74, 77, 81, 84, 87, 93, 96, 100, 103, 106, 110, 113, 120, 121-135, 139, 141-156, 159, 162-166 in sequence, and their related intermediates.

[0103] Preferably, the preparation methods of the compounds of formula A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15 and A16 are as follows:

[0104] The reaction route of the preparation method of the compound of formula A1 is as follows:

[0105]

[0106] The reaction route of the preparation method of the compound of formula A2 is as follows:

[0107]

[0108] The reaction route of the preparation method of the compound of formula A3 is as follows:

[0109]

[0110] The reaction route of the preparation method of the compound of formula A4 is as follows:

[0111]

[0112] The reaction route of the preparation method of the compound of formula A5 is as follows:

[0113] The reaction route of the preparation method of the compound of formula A6 is as follows:

[0114] The reaction schemes for the preparation of compounds of formula A7 and A8 are as follows:

[0115] The reaction route of the preparation method of the compound of formula A9 is as follows:

[0116] The reaction route of the preparation method of the compound of formula A10 is as follows:

[0117] The reaction schemes for the preparation of the compounds of formula A11 and A12 are as follows:

[0118] The reaction route of the preparation method of the compound of formula A13 is as follows:

[0119] The reaction schemes for the preparation of the compounds of formula A14 and A15 are as follows:

[0120] The reaction route of the preparation method of the compound of formula A16 is as follows:

[0121]

[0122] The present invention also provides a use of a compound II having the following structure as an intermediate in the preparation of a P2X3 antagonist:

[0123]

[0124] The definition of the P2X3 antagonist is preferably the same as the definition of the P2X3 antagonist described above.

[0125] The compound II is preferably used to prepare the P2X3 antagonist via compound III.

[0126] The reaction route for preparing the P2X3 antagonist is preferably the same as the reaction route in the above-mentioned method for preparing the P2X3 antagonist.

[0127] When using compound II or compound III to prepare the above-mentioned P2X3 antagonist, compound II, the stereoisomers of compound II, the mixture of compound II and its stereoisomers, compound III, the stereoisomers of compound III, and the mixture of compound III and its stereoisomers can all be used to prepare the above-mentioned P2X3 antagonist.

[0128] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0129] The reagents and raw materials used in the present invention, except compound I, are commercially available.

[0130] Compound I was synthesized by referring to the synthesis method on page 33 of the specification of Chinese patent CN105246888A, and was obtained by TEMPO oxidation of (R)-N-Boc-2-hydroxymethylmorpholine.

[0131] The positive and progressive effects of the present invention are: (1) the method for preparing the heterocyclic alkane compound containing dibromovinyl group of the present invention has one or more of the following advantages: high yield, high chemical purity and high chiral purity;

[0132] (2) The present invention uses alkali metal hydroxide as an alkaline reagent to synthesize compound III from a heterocycloalkane compound containing dibromovinyl groups, achieving good conversion rate and yield as well as high chemical purity and chiral purity. The entire preparation route avoids the use of expensive or dangerous reagents, thereby reducing costs and improving safety. The operation is simple and more suitable for industrial production. DETAILED DESCRIPTION

[0133] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0134] The following abbreviations, abbreviations or chemical formulae are used throughout the present invention:

[0135] PPh3 (triphenylphosphine), DCM (dichloromethane), CBr4 (carbon tetrabromide), TEA (triethylamine), KOH (potassium hydroxide), THF (tetrahydrofuran), tBuOK (potassium tert-butoxide), n-BuLi (n-butyllithium), LDA (lithium diisopropylamide), EtMgBr (ethylmagnesium bromide), DMSO (dimethyl sulfoxide).

[0136] The meaning of the characters used as units: g (gram), mg (milligram), mol (mole), h (hour), min (minute), mL (milliliter), ml (milliliter), eq (equivalent), M (mole per liter).

[0137] Overnight refers to 8-16 hours, preferably 12-16 hours, for example 12 hours; room temperature refers to 20°C to 30°C.

[0138] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated.

[0139] Detection instruments and methods

[0140] H NMR ( 1 H-NMR) detection instrument and method:

[0141] Instrument model: AVANCE III HD 300, equipped with autosampler (Sample Xpress 60).

[0142] HPLC detection instrument and method:

[0143] Shimadzu liquid chromatograph (LC20AD XR ), Agilent Eclipse XDB-C8 (4.6*150mm*3.5μm), 1mL / min, 30℃, 210nm, gradient elution see the table below.

[0144] Time (min) 0.1% phosphoric acid aqueous solution (%) Acetonitrile (%) 0 90 10 12 20 80 15 20 80 15.1 90 10 20 90 10

[0145] Chiral purity test instrument and HPLC method:

[0146] Shimadzu liquid chromatograph (LC20AT) CHIRALPAK CHIRALPAK AD-H (4.6*250mm*5μm), 2% ethanol / n-hexane, 1mL / min, 30℃, 210nm.

[0147] Example 1

[0148] Preparation route

[0149]

[0150] Procedure 1: Synthesis of Compound II

[0151] PPh3 (123.29 g) was dissolved in DCM (300 mL), replaced with N2 for protection, stirring was started, and the reaction solution was cooled to -5 to 0°C; CBr4 (138.57 g) was dissolved in DCM (300 mL) and added dropwise to the reaction solution; TEA (194 mL) was then added dropwise to the reaction system and stirred for 15 min; Compound I (85 g, content 88.18%) was dissolved in DCM (250 mL) and added dropwise to the reaction system; the temperature was controlled at -5 to 0°C during the addition of CBr4, TEA, and Compound I, and the temperature was maintained at -2.5 to 2.5°C after the addition of the materials was completed and the reaction was allowed to proceed overnight.

[0152] Post-treatment method for the synthesis of compound II

[0153] The reaction solution was filtered, the filter cake was rinsed with 200 mL DCM, the filtrate was extracted with 5% citric acid solution (2 L), and the aqueous phase was back-extracted with DCM (200 mL); the organic phases were combined and washed with saturated brine (300 mL), then dried with anhydrous sodium sulfate (85 g), filtered, and the filtrate was concentrated to obtain a crude product; the crude product was slurried with petroleum ether (20 V) for 5 to 10 hours, filtered, and the filter cake was rinsed with petroleum ether (5 V). The filtrate was collected and concentrated to obtain 114 g of a crude product, and the triphenylphosphine content in the crude product was calibrated to be 3.77%. The crude product was dissolved in petroleum ether (570 mL), and ZnCl2 (16 g) was added, and N2 was used for replacement protection. The mixture was stirred at 20-25°C overnight. The supernatant was filtered and sent to HPLC for inspection, which showed that triphenylphosphine accounted for 0.101%. The filtrate was filtered and concentrated to obtain 105 g of the final product. The final product was sampled and sent to HPLC for inspection, and the purity was 94.5%, the quantitative NMR content was 92%, and the yield was 74.76%.

[0154] Compound II: 1 H NMR (400MHz, DMSO-d6) δ6.64 (d, J=7.4Hz, 1H), 3.96 (ddd, J=10.2, 7.5, 2.9Hz, 1H), 3.79 (t, J= 14.1Hz,2H),3.66(d,J=13.3Hz,1H),3.43(td,J=11.4,2.8Hz,1H),2.91(s,2H),1.41(s,9H).

[0155] Procedure 2: Preparation of Compound III

[0156] Compound II (90 g, 94.5%) was dissolved in acetone (730 mL), replaced with N2, stirred, and the temperature was controlled to 20-25°C; KOH solution (200.5 mL, 3.43 M) was added dropwise, and the temperature was controlled to 25-30°C during the addition process; the temperature was raised to 35-40°C for reaction after the addition was completed, and the reaction was allowed to react for 26 hours. The reaction solution was cooled to below 5°C, and 5% citric acid (500 mL) was added dropwise to the reaction solution for quenching. The pH was 4-6 after the addition was completed.

[0157] Post-treatment method of compound III

[0158] 500 mL of water was added to the reaction system, extracted with 1.8 L of n-heptane, the aqueous phase was back-extracted with 300 mL of n-heptane, and the organic phases were combined and washed with 300 mL of saturated brine. The organic phase was concentrated to obtain 41 g of crude product with an HPLC purity of 82.971%; the crude product was slurried twice with 82 mL of ethanol / 205 mL of aqueous solution to obtain 40 g of crude product with an HPLC purity of 86%; 34 g of product was obtained by slurrying with 40 mL of ethanol / 160 mL of water, with a yield of 67.41%, a chemical purity of 96%, and a chiral purity of 99.98%.

[0159] Compound III:1 H NMR (400MHz, DMSO-d6) δ4.37–4.30(m,1H),3.83–3.75(m,1H),3.60–3.41(m,3H),3.33(s,1H),3.26(ddd,J=16.3,8.5,4.9Hz,2H),1.40(s,9H).

[0160] Example 2 Screening experiment of the type of base used in preparing compound II

[0161] Experimental process: CBr4 (corresponding to the equivalent), DCM, and PPh3 (corresponding to the equivalent) were mixed and protected with N2. Zn (corresponding to the equivalent) and the corresponding base were slowly added at 0-10°C. Compound I (1.0 eq) dissolved in DCM was then added dropwise to the reaction solution. The mixture was then reacted at -5 to 10°C. Treatment was started after 18 hours. MTBE was added to the reaction bottle and stirred for 1 hour to disperse. The mixture was filtered and the filtrate was concentrated by column chromatography using PE / EA=10 / 1.

[0162] Table 1 Statistical table of the screening experiment results of the base used to prepare compound II

[0163]

[0164]

[0165] The yield of the post-processed product shows that when no base is added, the yield is only 41%, 48% and 69%, when zinc powder is used alone, the yield is only 59%, and when pyridine is used alone, the yield is only 49%; when zinc powder and pyridine are used in combination, the yield is more than 88%; and when triethylamine is used as a base, the yield can reach 88% regardless of whether zinc powder is added. Therefore, adding triethylamine or a combination of zinc powder and pyridine in the preparation of compound II can effectively improve the yield of the product. When triethylamine is added alone, post-processing is more convenient and the cost is lower.

[0166] Example 3 Step 2 Effect of adding base type on the reaction

[0167] Experimental process:

[0168] a: After dissolving compound II in the corresponding solvent, add base (corresponding to the amount) at 20-30°C, raise the temperature to 35-40°C and react for 26 hours; (No. 1-2 in Table 2);

[0169] b: After dissolving compound II in THF, cool down to a predetermined temperature, slowly drop the corresponding alkaline solution into the reaction system, and keep the temperature for 26 hours; (No. 3-7 in Table 2).

[0170] Table 2

[0171]

[0172]

[0173] According to the results of the central control HPLC, when potassium hydroxide was used as the base, neither the raw material nor the monobrominated intermediate was detected, and the reaction was complete; when n-butyl lithium was used as the base, both the raw material and the monobrominated intermediate remained; under other conditions, both the raw material and the monobrominated intermediate remained in large quantities.

[0174] Example 4 Effect of the Type of Solvent in Step 2 on the Reaction

[0175] Experimental process: Compound II was dissolved in the corresponding solvent, a phase transfer catalyst (corresponding to the equivalent) was added, KOH solution (corresponding to the equivalent) was added dropwise at 20-30°C, and after the addition was completed, the temperature was raised to 35-40°C and reacted for 26 hours.

[0176] Table 3

[0177]

[0178] According to the HPLC test results of the reaction liquid, when acetone was used as the solvent, compound II and the monobrominated intermediate were completely reacted. After using other solvents, most of the reaction remained in the monobrominated intermediate state, and basically no product was generated. Acetone as a reaction solvent can achieve a higher conversion rate.

Claims

1. A method for preparing compound II, characterized in that: It includes the following steps: In the presence of triphenylphosphine, in a solvent, compound I and carbon tetrabromide are subjected to bromination reaction to obtain compound II; 2. The method for preparing compound II according to claim 1, characterized in that: The bromination reaction is also carried out in the presence of substance X, wherein substance X is zinc powder and / or an organic base; The organic base is preferably pyridine and / or an alkyl tertiary amine base; The alkyl tertiary amine base is preferably triethylamine and / or N,N-diisopropylethylamine.

3. The method for preparing compound II according to claim 2, characterized in that: The amount ratio of the substance X to the compound I is (2.0-16.0):1.0; preferably (2.0-4.0):1.0, for example, 2.0:1.0, 2.5:1.0, 3.0:1.0, 3.5:1.0, 4.0:1.0; and / or, when the organic base is pyridine, the substance X is zinc powder and pyridine; when the organic base is an alkyl tertiary amine base, the substance X is triethylamine; When the substance X is zinc powder and an organic base, the molar ratio of the zinc powder to the organic base is preferably (0.5-1):1; more preferably (0.5-0.6):1, such as 0.5:1, 0.6:

1.

4. The method for preparing compound II according to any one of claims 1 to 3, characterized in that: It meets one or more of the following conditions: (1) The solvent is a halogenated hydrocarbon solvent; The halogenated hydrocarbon solvent is preferably one or more of dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; more preferably dichloromethane; (2) The volume-to-mass ratio of the solvent to the compound I is 8-20 mL / g; preferably 8-15 mL / g, such as 10 mL / g, 15 mL / g; (3) The molar ratio of the carbon tetrabromide to the compound I is (1.0-6.0):1.0; preferably (1.0-3.0):1.0, for example, 1.0:1.0, 1.2:1.0, 1.3:1.0, 1.5:1.0, 2.0:1.0 or 3.0:1.0; (4) The molar ratio of the triphenylphosphine to the compound I is (1.0-6.0):1.0; preferably (1.2-4.0):1.0, for example, 1.2:1.0, 1.35:1.0, 1.5:1.0, 1.65:1.0, 2.0:1.0, 2.4:1.0, 3.0:1.0, 4.0:1.0; (5) The reaction temperature of the bromination reaction is -5-30°C; preferably -5-10°C, for example -5°C, -2.5-2.5°C, 10°C; (6) The reaction time of the bromination reaction is 8-18 h; preferably 12-16 h, for example 12 h, 16 h; and (7) after the bromination reaction is completed, post-treatment is included; the post-treatment steps include filtering, extracting, concentrating, beating, filtering, concentrating and removing triphenylphosphine oxide; Wherein, in the extraction step, citric acid solution is preferably used; The concentration may also include washing and drying steps; Wherein, the step of removing triphenylphosphine oxide preferably comprises mixing the concentrated solution with ZnCl2, filtering and concentrating to obtain compound II.

5. A method for preparing a compound represented by formula III, characterized in that: It includes the following steps: Step 1: In the presence of triphenylphosphine, in a solvent, compound I and carbon tetrabromide are subjected to bromination reaction to obtain compound II; Step 2: In the presence of an alkaline reagent, react the compound II obtained in step 1 in a solvent to obtain compound III; 6. The method for preparing the compound of formula III as claimed in claim 5, characterized in that: It meets one or more of the following conditions: (1) The conditions and operations in step 1 are the same as those described in any one of claims 2 to 4; (2) In step 2, the alkaline reagent is an alkali metal hydroxide, n-butyl lithium, lithium diisopropylamide and (C 1-3 alkyl)MgBr; preferably an alkali metal hydroxide; more preferably KOH; (3) In step 2, the molar ratio of the alkaline reagent to the compound II is (3.0-15.0):1.0; preferably (3.0-10.0):1.0, for example 3.0:1.0, 6.65:1.0, 10.0:1.0; (4) In step 2, the solvent is one or more of a ketone solvent, an ether solvent, an aromatic hydrocarbon solvent, an alcohol solvent and an alkane solvent; preferably a ketone solvent; The ketone solvent is preferably acetone; The ether solvent is preferably tetrahydrofuran; The aromatic hydrocarbon solvent is preferably toluene; The alcohol solvent is preferably ethanol; The alkane solvent is preferably n-heptane; (5) In step 2, the volume-to-mass ratio of the solvent to the compound II is 5-15 mL / g; preferably 5-10 mL / g, such as 5 mL / g, 8 mL / g, 9 mL / g, 10 mL / g; (6) In step 2, the reaction temperature is 25-40°C; preferably 35-40°C, for example 35°C or 40°C; (7) In step 2, the reaction is also carried out in the presence of a phase transfer catalyst; the phase transfer catalyst is preferably tetrabutylammonium bromide; The mass ratio of the phase transfer catalyst to the compound II is preferably (0.5-2):1.0, for example 0.5:1.0, 1.0:1.0, 2.0:1.0; (8) In step 2, the reaction time is 16-30 h, for example 16 h, 26 h, 30 h; and (9) in step 2, after the reaction is completed, post-treatment is further included; the post-treatment step preferably includes cooling, quenching, extraction, concentration and pulping; Wherein, in the cooling step, the temperature is preferably lowered to below 5°C; Wherein, in the quenching step, a citric acid aqueous solution is preferably used; in the quenching step, the pH of the reaction solution is preferably 4 to 6 as the quenching end point; Wherein, n-heptane is preferably used in the extraction step; Wherein, in the pulping step, a mixed solvent of ethanol and water is preferably used; Washing and drying may also be included before the concentration step.

7. A method for preparing a compound represented by formula III, characterized in that: It includes the following steps: In the presence of a basic reagent, compound II is reacted in a solvent to obtain compound III; Wherein, the alkaline reagent is an alkali metal hydroxide; the solvent is a ketone solvent; The other conditions and operations in the method for preparing the compound represented by formula III are preferably the same as those described in claim 6.

8. A compound II having the following structure:

9. A method for preparing a P2X3 antagonist, characterized in that: It is the following scheme 1 or 2: Scheme 1: It comprises the following steps: a method for preparing compound II; and, a method for preparing a P2X3 antagonist by further preparing the compound II; The preparation method of the compound II comprises the following steps: in the presence of triphenylphosphine, in a solvent, subjecting the compound I to a bromination reaction with carbon tetrabromide to obtain the compound II; Scheme 2: It comprises the following steps: a method for preparing compound III; and, a method for preparing a P2X3 antagonist by further preparing the compound III; The preparation method of the compound III comprises the following steps: reacting the compound II in a solvent in the presence of an alkaline reagent to obtain the compound III; The alkaline reagent is an alkali metal hydroxide; the solvent is a ketone solvent; Among them, the other conditions and operations in the preparation method of compound II are preferably the same as those described in any one of claims 2-4; the other conditions and operations in the preparation method of compound III are preferably the same as those described in claim 7.

10. The method for preparing a P2X3 antagonist according to claim 9, characterized in that: The P2X3 antagonist is any of the following compounds: Preferably, the preparation methods of the compounds of formula A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15 and A16 are as follows: The reaction route of the preparation method of the compound of formula A1 is as follows: The reaction route of the preparation method of the compound of formula A2 is as follows: The reaction route of the preparation method of the compound of formula A3 is as follows: The reaction route of the preparation method of the compound of formula A4 is as follows: The reaction route of the preparation method of the compound of formula A5 is as follows: The reaction route of the preparation method of the compound of formula A6 is as follows: The reaction schemes for the preparation of compounds of formula A7 and A8 are as follows: The reaction route of the preparation method of the compound of formula A9 is as follows: The reaction route of the preparation method of the compound of formula A10 is as follows: The reaction schemes for the preparation of the compounds of formula A11 and A12 are as follows: The reaction route of the preparation method of the compound of formula A13 is as follows: The reaction schemes for the preparation of the compounds of formula A14 and A15 are as follows: The reaction route of the preparation method of the compound of formula A16 is as follows:

11. Use of a compound II having the following structure as an intermediate in the preparation of a P2X3 antagonist as claimed in claim 9 or 10;

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