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CN111087336A - Synthesis method of difluorine spiro-compound and intermediate thereof - Google Patents

Synthesis method of difluorine spiro-compound and intermediate thereof Download PDF

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CN111087336A
CN111087336A CN201811244818.2A CN201811244818A CN111087336A CN 111087336 A CN111087336 A CN 111087336A CN 201811244818 A CN201811244818 A CN 201811244818A CN 111087336 A CN111087336 A CN 111087336A
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张雷亮
李磊
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4ringchem Biopharmaceuticals Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/31—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C31/27—Polyhydroxylic alcohols containing saturated rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/06—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D331/00—Heterocyclic compounds containing rings of less than five members, having one sulfur atom as the only ring hetero atom
    • C07D331/04—Four-membered rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
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    • C07—ORGANIC CHEMISTRY
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract

The invention has provided a method for synthesizing and its midbody of compound of bis-fluoro spiro, is prepared from compound of formula II through fluorizating, reducing, and subsequent cyclization step, compared with existing technology that regard carbonyl as precursor to fluorinate directly, the invention has avoided the formation of cyclic internal olefin by-product, the operation of preparing and separating and purifying is simple, the process is stable; in addition, the starting materials are easy to obtain, and the production cost is saved.

Description

Synthesis method of difluorine spiro-compound and intermediate thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry synthesis, in particular to a synthetic method of a difluoride spiro ring.
Background
Spiro compounds have been widely used in the field of drug development as a relatively novel pharmaceutical intermediate, for example, in WO2011114271a1, 2, 7-diazaspiro [3.5] nonane may be used as part of the mother ring structure of a series of compounds having ghrelin antagonist activity:
Figure BDA0001840259210000011
fluorine atoms are often used for structural optimization of compounds due to their strong electronegativity, thereby improving the physicochemical properties of the compounds. Therefore, the fluorinated spiro compound has great potential as a drug development structure optimization intermediate.
Generally, the precursor for preparing the difluoride is a carbonyl group, which is fluorinated with a fluorinating agent to obtain the desired product. However, in the spiro compound containing six-membered ring, on one hand, the fluorination of the fluorinating agent tends to generate a large amount of byproducts which are eliminated as cyclic internal olefin, and the properties of the olefin and the fluoro product are very close, so that the separation and purification of the product are difficult; on the other hand, the carbonyl-substituted spiro compound as a precursor is not easily available, which greatly restricts the development and application of the fluorinated spiro product.
Disclosure of Invention
Aiming at the problems of difficult raw material obtaining and more byproducts existing in the preparation of the prior fluoro spiro compound, the invention provides a synthetic method of a difluoride spiro ring and an intermediate thereof.
In one aspect, the invention provides a compound of formula iv, as shown in the following structure:
Figure BDA0001840259210000012
wherein X is selected from C, N, O or S, and when X is N, it is substituted by an amino protecting group selected from tert-butoxycarbonyl or benzyloxycarbonyl;
r1 is selected from cyano or-CH2OH。
In another aspect, the present invention provides a process for the preparation of a compound of formula iv, which is prepared by the following route:
Figure BDA0001840259210000021
wherein X is selected from C, N, O or S, and when X is N, it is substituted by an amino protecting group selected from tert-butoxycarbonyl or benzyloxycarbonyl;
r1 is selected from cyano or-CH2OH；
R2 is selected from cyano or-COOR 4;
r3 is selected from methyl or ethyl;
r4 is selected from methyl, ethyl or isopropyl;
the fluorine-containing reagent is selected from ethyl difluorobromoacetate, methyl difluorobromoacetate or ethyl difluoroiodoacetate;
preferably, the compounds of formula II: fluorine-containing reagent: the molar ratio of zinc or copper is 1: 1-3, and more preferably 1:2: 2;
preferably, tetramethylethylenediamine and acetic acid are added in the reaction of the compounds shown in the formulas II to III;
preferably, the reducing agent is selected from sodium borohydride, potassium borohydride or lithium borohydride.
In another aspect, the present invention provides a process for the preparation of a compound of formula I, as shown in the following structure, starting from a compound of formula V prepared by the process described above,
Figure BDA0001840259210000022
wherein X is selected from C, N, O or S, and when X is N, it is substituted by an amino protecting group selected from tert-butoxycarbonyl or benzyloxycarbonyl;
y is selected from O, S, substituted or unsubstituted N, and when Y is substituted N, the substituent is selected from benzyl, benzhydryl or p-toluenesulfonyl;
when Y is unsubstituted N, the compounds of formula I are prepared by the following scheme:
Figure BDA0001840259210000031
when Y is substituted N, the compounds of formula i are prepared by the following route:
Figure BDA0001840259210000032
when Y is S, the compounds of formula I are prepared by the following scheme:
Figure BDA0001840259210000033
when Y is O, the compounds of formula I are prepared by the following scheme:
Figure BDA0001840259210000034
r5 is selected from methanesulfonyl, p-toluenesulfonyl, or trifluoromethanesulfonyl;
the sulfonylation reagent is selected from methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonyl chloride;
the catalyst is selected from Raney nickel, Pd/C, Pd (OH)2C, red aluminum or lithium aluminum hydride;
the nitrogen-containing reagent is selected from benzylamine, benzhydrylamine or p-toluenesulfonamide;
the ring closing reagent is selected from triphenylphosphine, paratoluensulfonyl chloride or methanesulfonyl chloride;
when the ring closing reagent is triphenylphosphine, the alkaline reagent 4 is selected from diisopropyl azodicarboxylate or diethyl azodicarboxylate, and when the ring closing reagent is selected from paratoluensulfonyl chloride or methanesulfonyl chloride, the alkaline reagent 4 is selected from potassium tert-butoxide or n-butyllithium;
preferably, the basic agent 1 is selected from triethylamine, sodium hydroxide, pyridine, DBU, DMAP or DIPEA; the alkaline reagent 2 is selected from triethylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, DBU or DIPEA; the alkaline agent 3 is selected from potassium carbonate, cesium carbonate, DIPEA, DBU or pyridine;
preferably, when Y is unsubstituted N, the molar ratio of the compound shown in the formula IV to the sulfonylating agent to the basic agent 1 is 1: 1-2: 1-3, and the molar ratio of the compound shown in the formula V to the basic agent 2 is 1: 1-3;
when Y is substituted N, the molar ratio of the compound shown in the formula IV to the sulfonylating reagent to the basic reagent 1 is 1: 2-4: 2-5, and the molar ratio of the compound shown in the formula V to the nitrogen-containing reagent to the basic reagent 3 is 1: 1-2: 2-5;
when Y is S, the molar ratio of the compound shown in the formula IV to the sulfonylating reagent to the alkaline reagent 1 is 1: 2-4: 2-5;
when Y is O, the molar ratio of the compound shown in the formula IV to the ring closing reagent to the alkaline reagent 4 is 1: 1-2: 1-5;
preferably, X is N, substituted with an amino protecting group selected from t-butoxycarbonyl or benzyloxycarbonyl; y is unsubstituted N, and the compound of formula I is prepared by the following route:
Figure BDA0001840259210000041
the sulfonylation reagent is methanesulfonyl chloride, the alkaline reagent 1 is triethylamine, and the molar ratio of the compound shown in the formula IV to the sulfonylation reagent to the alkaline reagent 1 is 1: 1-2: 1-3;
r5 is methylsulfonyl, the catalyst is Raney nickel, the basic reagent 2 is triethylamine, and the molar ratio of the compound in the formula V to the basic reagent 2 is 1: 1-3.
Unless otherwise specified, the reagents and starting materials used in the present invention are commercially available.
Compared with the prior art of direct fluorination by taking carbonyl as a precursor, the method avoids the generation of intra-annular olefin byproducts, and has simple preparation, separation and purification operations and stable process; in addition, the starting materials are easy to obtain, and the production cost is saved.
The following acronyms are used throughout the invention:
KHMDS: potassium bis (trimethylsilyl) amide;
NaHMDS: sodium bis (trimethylsilyl) amide;
LiHMDS: bis-trimethylsilyl amido lithium;
NaCl: sodium chloride;
DMSO, DMSO: dimethyl sulfoxide;
DBU: 1, 8-diazabicyclo [5.4.0] undec-7-ene;
DMAP: 4-dimethylaminopyridine;
DIPEA: n, N-diisopropylethylamine.
Detailed Description
Example 1
Preparation of Compounds of formula III
Figure BDA0001840259210000051
Wherein X is benzyloxycarbonyl substituted N, R2 is cyano, and R3 is ethyl.
Ethyl difluorobromoacetate (150.00g, 0.73mol, 1.8eq.) was dissolved in tetrahydrofuran (1L), and the compound of formula ii (93.00g, 0.41mol, 1.0eq.) was added, copper (54.00g, 0.86mol, 2.1eq.) was added, tetramethylethylenediamine (24.00g, 0.204mol, 0.5eq.) and acetic acid (22.00g, 0.366mol, 0.9eq.) were refluxed at 65 ℃ for 24h, 500mL of a saturated aqueous ammonium chloride solution was added for liquid separation, and the organic phase was washed with saturated brine, dried, concentrated, and subjected to column chromatography (petroleum ether/ethyl acetate) to obtain 118.00g of the compound of formula iii with a yield of 82%.
Preparation of Compounds of formula IV
Figure BDA0001840259210000052
Wherein X is benzyloxycarbonyl substituted N, R1 is cyano, R2 is cyano, R3 is ethyl.
Dissolving a compound (118.0g, 0.335mol, 1.0eq.) in ethanol (450mL), controlling the temperature to be lower than 5 ℃, adding sodium borohydride (12.70g, 0.335mol, 1.0eq.) in batches, stirring for 1h at room temperature after adding, adding water (100mL), concentrating, adding a saturated ammonium chloride aqueous solution (150mL), extracting with dichloromethane (100mL multiplied by 3), and concentrating an organic phase to obtain 93.5g of a compound (IV) with the yield of 90.0%. LCMS: CALD MS: 310.3 MS: [ M + H ]]+＝311.3。
Example 2
Preparation of Compounds of formula III
Figure BDA0001840259210000061
Wherein X is C, R2 is-COOCH3And R3 is methyl.
Methyl difluorobromoacetate (75.6g, 0.40mol, 1.0eq.) is dissolved in tetrahydrofuran (500mL), a compound of formula II (50.00g, 0.40mol, 1.0eq.) and zinc powder (26.2g, 0.40mol, 1.0eq.) are added, reflux is carried out at 65 ℃ for 15h, 250mL of saturated aqueous ammonium chloride solution is added for liquid separation, the organic phase is washed by saturated saline solution, and drying and concentration are carried out, so that 70.9g of a compound of formula III is obtained, and the yield is 75%.
Preparation of Compounds of formula IV
Figure BDA0001840259210000062
Wherein X is C, R1 is-CH2OH, R2 is-COOCH3And R3 is methyl.
Dissolving a compound (70.0g, 0.30mol, 1.0eq.) in a formula III in ethanol (450mL), controlling the temperature to be lower than 5 ℃, adding potassium borohydride (16.2g, 0.30mol, 1.0eq.) in batches, stirring for 2 hours at room temperature after adding, adding a saturated ammonium chloride aqueous solution (150mL), concentrating and evaporating ethanol, extracting dichloromethane (100mL × 3), and concentrating an organic phase to obtain 54.3g of a compound (IV) with the yield of 87.0%. LCMS: CALD MS: 180.2 MS: [ M + H ]]+＝181.2。
Example 3
Preparation of Compounds of formula III
Figure BDA0001840259210000071
Wherein X is O, R2 is cyano, and R3 is ethyl.
Ethyl difluorobromoacetate (322.8g, 1.59mol, 3.0eq.) was dissolved in tetrahydrofuran (3L), the compound of formula ii (50.00g, 0.53mol, 1.0eq.) and copper (101.8g, 1.59mol, 3.0eq.) were added, refluxing was carried out at 65 ℃ for 24h, 800mL of a saturated aqueous ammonium chloride solution was added for liquid separation, the organic phase was washed with saturated brine, dried and concentrated to obtain 94.1g of the compound of formula iii with a yield of 81%.
Preparation of Compounds of formula IV
Figure BDA0001840259210000072
Wherein X is O, R1 is cyano, R2 is cyano, and R3 is ethyl.
Dissolving a compound (94.0g, 0.43mol, 1.0eq.) in tetrahydrofuran (500mL), controlling the temperature at 0 ℃, adding lithium borohydride (14.2g, 0.65mol, 1.5eq.) in batches, stirring at room temperature for 3h, adding a saturated ammonium chloride aqueous solution (500mL), concentrating and evaporating tetrahydrofuran, adding dichloromethane (300mL) for extraction, and concentrating an organic phase to obtain 67.03g of a compound (V), wherein the yield is 88.0%. LCMS: CALD MS: 177.1 MS: [ M + H ]]+＝178.1。
Example 4
Preparation of Compounds of formula III
Figure BDA0001840259210000073
Wherein X is S and R2 is-COOC2H5And R3 is ethyl.
Ethyl difluorobromoacetate (205g, 1.01mol, 2.0eq.) was dissolved in tetrahydrofuran (2L), the compound of formula ii (80.00g, 0.51mol, 1.0eq.) and copper (64g, 1.01mol, 2.0eq.) were added, refluxing was carried out at 65 ℃ for 18h, 600mL of a saturated aqueous ammonium chloride solution was added for liquid separation, and the organic phase was washed with saturated brine, dried, and concentrated to obtain 118.1g of the compound of formula iii with a yield of 82%.
Preparation of Compounds of formula IV
Figure BDA0001840259210000081
Wherein X is S, R1 is-CH2OH, R2 being-COOC2H5And R3 is ethyl.
The compound of formula III (100.0g, 0.35mol, 1.0eq.) was dissolved in ethanol (300mL) and sodium borohydride (19.8g, 0.53mol, 1) was added in portions, with temperature controlled below 5 ℃.5eq.), stirring at room temperature for 3h after the addition, adding saturated ammonium chloride aqueous solution (400mL), concentrating and evaporating ethanol, adding dichloromethane (200mL) for extraction, and concentrating the organic phase to obtain 62.4g of the compound of the formula V with the yield of 90.0%. LCMS: CALD MS: 198.2 MS: [ M + H ]]+＝199.2。
Examples 5 to 10
Preparation of Compounds of formula IV by the methods of reference examples 1-4
TABLE-Structure of the Compound of formula IV of examples 5-10 and MS data
Figure BDA0001840259210000082
Figure BDA0001840259210000091
Example 11
Preparation of Compounds of formula V
Figure BDA0001840259210000092
Wherein X is benzyloxycarbonyl substituted N, R5 is methylsulfonyl, and the compound of formula IV is prepared by example 1.
Dissolving a compound (80.0g, 0.258mol, 1.0eq.) in dichloromethane (250mL), adding triethylamine (39g, 0.387mol, 1.5eq.), dropwise adding methanesulfonyl chloride (33g, 0.284mol, 1.1eq.) at the temperature of 0 ℃, preserving heat for 1h after dropwise adding, adding water (200mL) for separating liquid, and drying and concentrating an organic phase to obtain 93g of a yellow solid, namely the compound of the formula V, wherein the yield is 93%. Preparation of Compounds of formula I
Figure BDA0001840259210000093
Wherein X is N substituted by benzyloxycarbonyl, R5 is methylsulfonyl, and Y is N.
The compound of formula V (74.0g, 0.191mol, 1.0eq.) and triethylamine (19.3g, 0.191mol, 1.0eq.) were dissolved in methanol (1L) and charged into an autoclave, Raney nickel (75.0g) was added, hydrogen was bubbled through, and the mixture was reacted at 40 deg.CAnd reacting for 30 hours, filtering the reaction solution, concentrating the filtrate, and performing column chromatography (petroleum ether/ethyl acetate) to obtain 23.2g of the compound shown in the formula I with the yield of 41%. LCMS: CALD MS: 296.3 MS: [ M + H ]]+＝297.3。
Example 12
Preparation of Compounds of formula V
Figure BDA0001840259210000101
Wherein X is tert-butoxycarbonyl substituted N and R5 is p-toluenesulfonyl, the compound of formula IV was prepared as in example 8.
Dissolving a compound (100.0g, 0.36mol, 1.0eq.) in dichloromethane (500mL), adding sodium hydroxide (14.4g, 0.36mol, 1.0eq.), dropwise adding a dichloromethane solution (300mL) of p-toluenesulfonyl chloride (205.8g, 1.08mol, 3.0eq.) at the temperature of 0 ℃, preserving the temperature for 1h after dropwise adding, adding water (400mL) for liquid separation, extracting the water phase with dichloromethane (500mL), combining the organic phases, drying and concentrating to obtain 193.2g of a compound (V), wherein the yield is 91%.
Preparation of Compounds of formula I
Figure BDA0001840259210000102
Wherein X is tert-butoxycarbonyl substituted N, R5 is p-toluenesulfonyl, and Y is benzyl substituted N.
Dissolving a compound (193.2g,0.33mol,1.0eq.) of the formula V in N, N-dimethylformamide (500mL), adding benzylamine (38.6g,0.36mol,1.1eq.), stirring, adding cesium carbonate (215.0g,0.66mol,2.0eq.), heating to 110 ℃ and 120 ℃ for reaction for 8h, cooling, adding water and ethyl acetate each 500mL, separating liquid, extracting an aqueous layer with ethyl acetate (2X 200mL), combining organic phases, washing with a saturated sodium chloride aqueous solution (2X 200mL), drying the organic phase with anhydrous sodium sulfate, and concentrating to obtain the compound I93.0 g with the yield of 80.0%. LCMS: CALD MS: 352.4 MS: [ M + H ]]+＝353.4。
Example 13
Preparation of Compounds of formula V
Figure BDA0001840259210000103
Wherein X is C and R5 is methanesulfonyl, and the compound of formula IV is prepared by example 2.
Dissolving the compound (80.0g, 0.44mol, 1.0eq.) in dichloromethane (400mL), adding DBU (267.5g, 1.76mol, 4.0eq.), dropwise adding methanesulfonyl chloride (100.8g, 0.88mol, 2.0eq.) at a controlled temperature of 0 ℃, preserving the temperature for 2 hours after dropwise adding, adding water (300mL) for separating liquid, extracting an aqueous phase with dichloromethane (2X 200mL), combining organic phases, drying and concentrating to obtain 140.7g of the compound (V), wherein the yield is 95.1%.
Preparation of Compounds of formula I
Figure BDA0001840259210000111
Wherein X is C, R5 is methylsulfonyl, and Y is S.
Dissolving the compound of formula V (140.7g,0.42mol,1.0eq.) in ethanol (500mL), adding anhydrous sodium sulfide (149.1g,1.05mol,2.5eq.), stirring, heating to 75-80 deg.C for 5h, cooling, concentrating to remove ethanol, adding water and ethyl acetate (300mL each), separating, extracting the water layer with ethyl acetate (2X 200mL), combining the organic phases, washing with saturated aqueous sodium chloride solution (2X 200mL), drying with anhydrous sodium sulfate, and concentrating to obtain compound I, 62.7g, with a yield of 83.7%. LCMS: CALD MS: 178.2 MS: [ M + H ]]+＝179.2。
Example 14
Preparation of Compounds of formula I
Figure BDA0001840259210000112
Wherein X is O and Y is O, the compound of formula IV is prepared by example 9.
Dissolving the compound of formula IV (80.0g, 0.44mol, 1.0eq.) in tetrahydrofuran (400mL), adding 2.5M n-butyllithium hexane solution (528mL, 1.32mol, 3.0eq.) dropwise at a temperature below 0 deg.C, reacting at 0 deg.C for 1h, and adding p-toluenesulfonyl chloride (167.8g, 0eq.) dropwise at a temperature below 0 deg.C88mol, 2.0eq.) tetrahydrofuran solution (600mL) is added, the mixture is naturally raised to room temperature, and after the mixture is heated to 60 ℃ for reaction for 1h, the system is cooled to 40 ℃, water (400mL) is added into the reaction liquid, ethyl acetate (300mL multiplied by 2) is used for extraction, organic phases are combined, the organic phases are dried and spin-dried, and column chromatography (petroleum ether/ethyl acetate) is carried out, so that the compound of the formula I is obtained, the total amount is 40.0g, and the yield is 54%. LCMS: CALD MS: 164.1 MS: [ M + H ]]+＝165.1。
Example 15
Preparation of Compounds of formula I
Figure BDA0001840259210000121
Wherein X is S and Y is O, are prepared as described in example 4.
The compound of formula IV (40.0g, 0.2mol, 1.0eq.) was dissolved in toluene (300mL), triphenylphosphine (104.9g, 0.4mol, 2.0eq.) was added, diethyl azodicarboxylate (69.7g, 0.4mol, 2.0eq.) was added dropwise, and the reaction was carried out at room temperature for 5h, in a manner referred to the post-treatment of this step in example 14, to give 22.0g of the compound of formula I in a yield of 61%. LCMS: CALDMS: 180.2 MS: [ M + H ]]+＝181.2。

Claims (9)

1. A compound of formula IV represented by the following structure:
Figure FDA0001840259200000011
wherein X is selected from C, N, O or S, and when X is N, it is substituted by an amino protecting group selected from tert-butoxycarbonyl or benzyloxycarbonyl;
r1 is selected from cyano or-CH2OH。
2. A process for the preparation of a compound of formula iv, characterized in that it is prepared by the following route:
Figure FDA0001840259200000012
wherein X is selected from C, N, O or S, and when X is N, it is substituted by an amino protecting group selected from tert-butoxycarbonyl or benzyloxycarbonyl;
r1 is selected from cyano or-CH2OH；
R2 is selected from cyano or-COOR 4;
r3 is selected from methyl or ethyl;
r4 is selected from methyl, ethyl or isopropyl;
the fluorine-containing reagent is selected from ethyl difluorobromoacetate, methyl difluorobromoacetate or ethyl difluoroiodoacetate.
3. The method of claim 2, wherein: the compound of formula II: fluorine-containing reagent: the molar ratio of zinc or copper is 1: 1-3, preferably 1:2: 2.
4. The production method according to claim 2 or 3, characterized in that: adding tetramethylethylenediamine and acetic acid in the reaction of the compounds shown in the formulas II to III.
5. The method of claim 2, wherein: the reducing agent is selected from sodium borohydride, potassium borohydride or lithium borohydride.
6. A process for the preparation of a compound of formula I as shown in the following structure starting from a compound of formula IV as prepared according to any one of claims 2, 3 or 5,
Figure FDA0001840259200000021
wherein X is selected from C, N, O or S, and when X is N, it is substituted by an amino protecting group selected from tert-butoxycarbonyl or benzyloxycarbonyl;
y is selected from O, S, substituted or unsubstituted N, and when Y is substituted N, the substituent is selected from benzyl, benzhydryl or p-toluenesulfonyl;
when Y is unsubstituted N, the compounds of formula I are prepared by the following scheme:
Figure FDA0001840259200000022
when Y is substituted N, the compounds of formula i are prepared by the following route:
Figure FDA0001840259200000023
when Y is S, the compounds of formula I are prepared by the following scheme:
Figure FDA0001840259200000024
when Y is O, the compounds of formula I are prepared by the following scheme:
Figure FDA0001840259200000031
r5 is selected from methanesulfonyl, p-toluenesulfonyl, or trifluoromethanesulfonyl;
the sulfonylation reagent is selected from methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonyl chloride;
the catalyst is selected from Raney nickel, Pd/C, Pd (OH)2C, red aluminum or lithium aluminum hydride;
the nitrogen-containing reagent is selected from benzylamine, benzhydrylamine or p-toluenesulfonamide;
the ring closing reagent is selected from triphenylphosphine, paratoluensulfonyl chloride or methanesulfonyl chloride;
when the ring closing reagent is triphenylphosphine, the basic reagent 4 is selected from diisopropyl azodicarboxylate or diethyl azodicarboxylate, and when the ring closing reagent is selected from paratoluensulfonyl chloride or methanesulfonyl chloride, the basic reagent 4 is selected from potassium tert-butoxide or n-butyllithium.
7. A process for the preparation of a compound of formula i according to claim 6, characterized in that: the alkaline reagent 1 is selected from triethylamine, sodium hydroxide, pyridine, DBU, DMAP or DIPEA; the alkaline reagent 2 is selected from triethylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, DBU or DIPEA; the alkaline agent 3 is selected from potassium carbonate, cesium carbonate, DIPEA, DBU or pyridine.
8. A process for the preparation of a compound of formula i according to claim 6, characterized in that:
when Y is unsubstituted N, the molar ratio of the compound shown in the formula IV to the sulfonylating reagent to the basic reagent 1 is 1: 1-2: 1-3, and the molar ratio of the compound shown in the formula V to the basic reagent 2 is 1: 1-3;
when Y is substituted N, the molar ratio of the compound shown in the formula IV to the sulfonylating reagent to the basic reagent 1 is 1: 2-4: 2-5, and the molar ratio of the compound shown in the formula V to the nitrogen-containing reagent to the basic reagent 3 is 1: 1-2: 2-5;
when Y is S, the molar ratio of the compound shown in the formula IV to the sulfonylating reagent to the alkaline reagent 1 is 1: 2-4: 2-5;
when Y is O, the molar ratio of the compound shown in the formula IV to the ring closing reagent to the alkaline reagent 4 is 1: 1-2: 1-5.
9. A process for the preparation of a compound of formula i according to any one of claims 6 to 8, characterized in that:
x is N, substituted with an amino protecting group selected from tert-butoxycarbonyl or benzyloxycarbonyl;
y is unsubstituted N, and the compound of formula I is prepared by the following route:
Figure FDA0001840259200000041
the sulfonylation reagent is methanesulfonyl chloride, the alkaline reagent 1 is triethylamine, and the molar ratio of the compound shown in the formula IV to the sulfonylation reagent to the alkaline reagent 1 is 1: 1-2: 1-3;
r5 is methylsulfonyl, the catalyst is Raney nickel, the basic reagent 2 is triethylamine, and the molar ratio of the compound in the formula V to the basic reagent 2 is 1: 1-3.
CN201811244818.2A 2018-10-24 2018-10-24 Synthesis method of difluorine spiro-compound and intermediate thereof Pending CN111087336A (en)

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