CN107602556B - Intermediate of (1S,4S) -2, 5-diazabicyclo [2.2.2] octane derivative and preparation method thereof - Google Patents
Intermediate of (1S,4S) -2, 5-diazabicyclo [2.2.2] octane derivative and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an intermediate of (1S,4S) -2, 5-diazabicyclo [2.2.2] octane derivative and a preparation method thereof, wherein the preparation method comprises the following steps: taking a compound II as a raw material, protecting an amino group of the compound II through an amidation reaction to obtain a compound III; then carrying out reduction reaction with hydrogen in the presence of a catalyst to obtain a compound IV; then protecting nitrogen atoms on a piperidine ring through amidation reaction to obtain a compound V; then reacting with a reducing agent to obtain a compound VI; then reacting with a halogenating reagent to prepare a compound VII; the compound VII can also be subjected to ring closure reaction in the presence of alkali to obtain the compound I.
Description
Technical Field
The invention relates to the field of heterocyclic organic chemical synthesis, in particular to an intermediate of a (1S,4S) -2, 5-diazabicyclo [2.2.2] octane derivative and a preparation method thereof.
Background
Recently, it has been found that a compound which selectively activates/stimulates α -7 nicotinic receptors in mammals, has a significant effect in treating or preventing diseases caused by dysfunction of nicotinic acetylcholine receptor transmission in mammals, and in treating patients suffering from psychiatric diseases, neurodegenerative diseases involving dysfunction of the cholinergic system, and/or conditions of memory and/or cognitive disorders, mainly including schizophrenia, anxiety, mania, depression, manic depression, Tourette's syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, memory disorders, memory loss, cognitive impairment, attention deficit disorder, and the like, by linking a 2, 5-diazabicyclo [2.2.2] octane derivative to indole/1H-indole/1, 2-benzisoxazole/1, 2-benzisothiazole and the like.
Regarding the synthesis of (1S,4S) -2, 5-diazabicyclo [2.2.2] octane derivatives, CN106045999A reports the preparation method as follows:
reagents and yield: (a) pd (OH)2/C，H2Methanol, 65 ℃, 24h, 100%; (b) refluxing with thionyl chloride and methanol for 2h, 100%; (c) p-methylbenzenesulfonyl chloride, sodium carbonate, tetrahydrofuran/water, 25 ℃, 15h and 79 percent; (d/e) imidazole, tert-butyldimethylsilyl chloride, N, N-dimethylformamide, 25 ℃, 3h, 57%; (f) concentrated hydrochloric acid, methanol, room temperature, 3h, 90%; (g) methanesulfonyl chloride, triethylamine, dichloromethane, 10 ℃, 20min, 100%; (h) sodium azide and N, N-dimethylformamide at the temperature of 110-120 ℃ for 15h, 56%; (i) lithium aluminum hydride, tetrahydrofuran, room temperature, 15h, 100%; (j) (Boc)2O, triethylamine, methanol, 4h, 80%; (k) first of allSulfonyl chloride, triethylamine, dichloromethane, 100%; (l) Sodium hydrogen, N-dimethylformamide, 2h, 76%.
The method takes a compound ii as a raw material, and prepares the (1S,4S) -2, 5-diazabicyclo [2.2.2] octane derivative through reduction, esterification, Ts group adding, TBS group adding, column chromatography configuration purification, TBS group removing, Ms group adding, azido substitution, reductive amination, reduction ester, Boc group adding, Ms group adding and ring closing reaction in 12 steps in total, wherein the total yield is only 13.8 percent, and the method is not suitable for industrial production. The reason is mainly that:
1) the raw materials are expensive, the reaction steps are multiple, pyridine is reduced and taken to be a non-dominant configuration, and the total generated solid waste and liquid waste are more;
2) the general route needs three times of column chromatography, namely the preparation of a compound vi (the polarity difference of cis-trans configuration is small, the solubility of the product is poor, the purification of the column chromatography is difficult to realize, and the amplification production is not easy), the preparation of a compound ix (the column chromatography risk of the azide is high) and the preparation of a compound I;
3) preparation of compound x: sodium azide is required, and the compound is extremely toxic and explosive; the reaction temperature is high, which easily causes elimination of side reaction and reduction of yield;
4) preparation of compound xi: azide and ester need to be reduced simultaneously, and the consumption of lithium aluminum hydride is large;
5) preparation of compound ix and compound xiii: the use of methanesulfonyl chloride twice has strong toxicity and poor stability.
Regarding the synthesis of (1S,4S) -2, 5-diazabicyclo [2.2.2] octane derivatives, CN 106083862 a reports another preparation method as follows:
reagents and yield: (m) benzenesulfonyl chloride, N-diisopropylethylamine, acetonitrile, room temperature, 1 hour, 95.5%; (N) sodium azide, N, N-dimethylformamide, at 100 ℃ for 2 hours, 97.2%; (o) 87.5% of sodium borohydride, iodine and tetrahydrofuran at 25 ℃ for 10 hours; (p) tri-n-butylphosphine, diisopropyl azodicarboxylate, tetrahydrofuran, 22 ℃ for 10 hours, 83%.
The method takes a compound xiv as a raw material, and obtains the compound i-2 through 4 steps of reactions including O protection, azido substitution, reductive amination and ring closure, wherein the total yield is 67.4 percent, but the preparation needs to use sodium azide, the compound is extremely toxic and explosive, the cis-structure of the raw material xiv is difficult to separate, and the raw material is not easy to obtain; the compound xvii has high polarity and is difficult to separate, and the phosphine generated in the step p has more waste solid and waste liquid, is not environment-friendly and has high toxicity of tributyl phosphine.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to overcome the defects in the prior art and provides an intermediate of a (1S,4S) -2, 5-diazabicyclo [2.2.2] octane derivative and a preparation method thereof, wherein the method is simple and convenient to operate, has high yield and is suitable for large-scale preparation.
The technical scheme is as follows:
the present invention provides a compound of structural formula VII:
wherein:
R1is 4-toluenesulfonyl, 3-toluenesulfonyl, 4-nitrobenzenesulfonyl or 2-nitrobenzenesulfonyl;
R2is methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl or phenoxycarbonyl;
x is Cl, Br or I.
The corresponding structural formula and analytical data for compound VII are shown in table 1:
table 1:
a process for the preparation of the above compound VII, comprising:
wherein: r1、R2And X is as defined above.
Further, compound VII can be prepared by:
(1) starting from compounds II with R2Cl or (R)2)2O is subjected to amidation reaction to obtain a compound III,
(2) the compound III and hydrogen are subjected to reduction reaction in the presence of a catalyst to obtain a compound IV,
(3) compounds IV and R1Then performing amidation reaction on the Cl to obtain a compound V,
(4) reacting the compound V with a reducing agent to obtain a compound VI,
(5) reacting the compound VI with a halogenating reagent to prepare a compound VII;
wherein:
r is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, p-methylphenyl, o-methylphenyl, p-isopropylphenyl, o-isopropylphenyl, p-tert-butylphenyl, o-tert-butylphenyl, p-chlorophenyl or o-chlorophenyl;
R1and R2Is as defined above.
In the process of preparing compound IV from compound III, the catalyst is palladium carbon, palladium hydroxide carbon, rhodium palladium carbon or rhodium carbon.
In the process of preparing the compound VI from the compound V, the reducing agent is lithium aluminum hydride, sodium borohydride, lithium tri-tert-butoxyaluminum hydride, lithium borohydride, potassium borohydride/iodine or potassium borohydride/lithium chloride; the molar ratio of the compound V to the reducing agent is 1: 0.5-1: 10.
In the process of preparing the compound VII from the compound VI, the halogenating reagent is thionyl chloride, phosphorus trichloride, phosphorus tribromide, N-chlorosuccinimide/triphenylphosphine, N-bromosuccinimide/triphenylphosphine, N-iodosuccinimide/triphenylphosphine or iodine/triphenylphosphine.
In the process of preparing the compound VII from the compound VI, controlling the temperature to be-30 ℃, and adding a halogenating reagent into a reaction system; the molar ratio of the compound VI to the halogenating reagent is 1: 0.5-1: 10; the solvent is dichloromethane, 1, 2-dichloroethane, tetrahydrofuran or 1, 4-dioxane.
The present invention also provides a process for the preparation of a compound of formula I, comprising:
wherein: r1、R2And X is as defined above.
In the process of preparing the compound I from the compound VII, the base is NaH, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, lithium 2,2,6, 6-tetramethylpiperidine, n-butyllithium, sodium hexamethyldisilazane, potassium hexamethyldisilazane or lithium hexamethyldisilazane; the molar ratio of the compound VII to the alkali is 1: 1-1: 3.
Further, compound I can be prepared by the following method:
wherein: r1、R2And X is as defined above, and the halogenating agent and the base are as defined above.
Further, the preparation method of the compound I is as follows:
(1) starting from compounds II with R2Cl or (R)2)2O is subjected to amidation reaction to obtain a compound III,
(2) the compound III and hydrogen are subjected to reduction reaction in the presence of a catalyst to obtain a compound IV,
(3) compounds IV and R1Then performing amidation reaction on the Cl to obtain a compound V,
(4) reacting the compound V with a reducing agent to obtain a compound VI,
(5) the compound VI reacts with a halogenating reagent to prepare a compound VII,
(6) and carrying out ring closing reaction on the compound VII in the presence of alkali to obtain a compound I.
Wherein: r, R1、R2And X is as defined above, and the halogenating agent and the base are as defined above.
Has the advantages that: the preparation method has the advantages of short route steps, mild conditions, simple and convenient operation and stable process, the total preparation route of the compound I is 6-step reaction, and the total yield can reach 73.6%. The yield of the two steps of preparing the compound VII and then preparing the compound I from the compound VI can reach 81.4%, the purification is convenient, the scale-up production is easy, and more prominent is that the highly toxic and explosive sodium azide used in the prior art is effectively avoided as a raw material, so that the whole synthesis process is safe and environment-friendly.
Detailed description of the preferred embodiments
The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1
Compound VI-1 preparation of Compound VII-1:
adding compound VI-1(180.5g, 0.527mol, 1.0e.q.) and dichloromethane (1.5L) into a reaction bottle, cooling to 0 ℃, dropwise adding thionyl chloride (627.0g, 5.270mol, 10.0e.q.) after dripping, heating to reflux for 2 hours, pouring the reaction mixture into a saturated sodium bicarbonate aqueous solution after TLC shows that the reaction is finished, carrying out layered liquid separation, washing an organic phase with water for 1 time, washing the organic phase with saturated saline water for 1 time, drying the organic phase with anhydrous sodium sulfate, and distilling under reduced pressure to remove the solvent to obtain compound VII-1 as a gray solid 177.30g, wherein the yield is: 93.2 percent.
Compound VII-1 preparation of compound I-1:
sodium methoxide (26.51g, 0.491mol, 1.0e.q.) and DMF (0.8L) were added into a reaction flask, a DMF (0.6L) solution of compound VII-1(177.30g, 0.491mol, 1.0e.q.) was added dropwise at 0 ℃, after completion of the addition, the mixture was heated to 95 ℃ for 1 hour, LC-MS showed that the reaction was complete, the temperature was lowered to 0 ℃, isopropanol (50mL) was added dropwise, the reaction mixture was poured into ice water (3.5L) after stirring for 12 hours, methyl tert-ether (2L) was added and stirred, the mixture was separated into layers, the aqueous phase was extracted with methyl tert-ether (1 lx2), the organic phase was combined, washed with water (2 lx3), washed with a saturated aqueous sodium chloride solution (2 lx1), dried over anhydrous sodium sulfate, sand was concentrated and column chromatography was performed (PE: DCM: EA ═ 10: 1: 0.5), so that 125.11g of compound I-1 white solid was obtained, yield: 78.5 percent.
Example 2
Compound VI-2 preparation of Compound VII-2:
adding compound VI-2(185.2g, 0.500mol, 1.0e.q.) and 1, 2-dichloroethane (1.5L) into a reaction flask, cooling to-30 ℃, dropwise adding phosphorus trichloride (68.7g, 0.500mol, 0.5e.q.) after finishing dripping, heating to reflux reaction for 1.5 hours, after TLC shows that the reaction is finished, pouring the reaction mixture into saturated sodium bicarbonate aqueous solution, carrying out layered liquid separation, washing an organic phase with water for 1 time, washing the organic phase with saturated saline water for 1 time, drying with anhydrous sodium sulfate, and distilling under reduced pressure to remove the solvent to obtain 185.5g of compound VII-2 as a gray solid, wherein the yield is as follows: 95.4 percent.
Compound VII-2 preparation of compound I-2:
adding potassium tert-butoxide (160.6g, 1.431mol, 3.0e.q.) and DMF (1.5L) into a reaction flask, dropwise adding a DMF (0.5L) solution of compound VII-2(185.5g, 0.477mol, 1.0e.q.) at 0-10 ℃, heating to 90 ℃ for reaction for 3 hours, after LC-MS shows that the reaction is finished, cooling to 0 ℃, dropwise adding isopropanol (60mL), stirring for 10 hours, pouring the reaction solution into ice water (6L), adding methyl tert-ether (3L), stirring, separating layers, extracting the aqueous phase with methyl tert-ether (2L × 2), combining the organic phases, washing with water (5L × 3), washing with a saturated chloride solution (5L × 1), drying with anhydrous sodium sulfate, concentrating and preparing sand, (PE: DCM: EA: 10: 1: 0.5) to obtain 124.6g of compound I-2 white solid, yield: 74.1 percent.
Example 3
Compound VI-3 preparation of Compound VII-3:
adding compound VI-3(146.1g, 0.380mol, 1.0e.q.) and dichloromethane (1.5L) into a reaction bottle, cooling to 10 ℃, adding N-chlorosuccinimide (60.9g, 0.456mol, 1.2e.q.) and triphenylphosphine (119.6g, 0.456mol, 1.2e.q.), heating to 30 ℃ after addition, reacting for 18 hours, pouring the reaction mixture into ice water, separating by layers, extracting the aqueous phase with dichloromethane (1L multiplied by 2), combining the organic phases, washing with water for 3 times, washing with saturated saline for 1 time, drying with anhydrous sodium sulfate, and distilling off the solvent under reduced pressure to obtain compound VII-3 as a gray solid 151.4g, wherein the yield is as follows: 98.9 percent.
Compound VII-3 preparation of compound I-3:
adding 60% NaH (18.0g, 0.451mol, 1.2e.q.) and DMF (1L) into a reaction bottle, dropwise adding a DMF (0.5L) solution of a compound VII-3(151.4g, 0.376mol, 1.0e.q.) at 0-10 ℃, heating to 95 ℃ for 1 hour after dropwise adding, cooling to 0 ℃ after LC-MS shows that the reaction is finished, dropwise adding isopropanol (50mL), pouring the reaction solution into ice water (4L) after stirring for 12 hours, adding methyl tert-ether (3L), stirring, separating layers, extracting an aqueous phase with methyl tert-ether (2L multiplied by 2), combining an organic phase, washing with water (5L multiplied by 3), washing with a saturated sodium chloride aqueous solution (5L multiplied by 1), drying with anhydrous sodium sulfate, concentrating and preparing sand, (PE: DCM: EA: 10: 1: 0.5) and carrying out column chromatography to obtain 113.3g of a compound I-3 white solid, wherein the yield is as follows: 82.3 percent.
Example 4
Compound VI-21 preparation of compound VII-21:
adding compound VI-21(108.9g, 0.250mol, 1.0e.q.) and THF (1.0L) into a reaction flask, cooling to 0 ℃, adding N-bromosuccinimide (66.7g, 0.375mol, 1.5e.q.) and triphenylphosphine (98.4g, 0.375mol, 1.5e.q.), after the addition, heating to 60 ℃ for reaction for 3 hours, pouring the reaction mixture into ice water, separating by layers, extracting the aqueous phase with ethyl acetate (0.5L multiplied by 2), combining the organic phases, washing with water for 3 times, washing with saturated saline water for 1 time, drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure to obtain compound VII-21 as a gray solid 110.5g, and obtaining the yield: 88.7 percent.
Compound VII-21 preparation of compound I-21:
adding 1N LDA (330mL, 0.330mol, 1.5e.q.) into a reaction bottle, dropwise adding a THF (0.5L) solution of a compound VII-21(110g, 0.221mol, 1.0e.q.) at a temperature controlled between-20 ℃ and-10 ℃, heating to reflux for reaction for 3 hours after dropwise addition, cooling to 20 ℃ after LC-MS shows that the reaction is finished, pouring the reaction liquid into ice water (1L), adding methyl tert-ether (0.5L) for stirring, carrying out layered liquid separation, extracting an aqueous phase with methyl tert-ether (0.5L multiplied by 2), combining organic phases, washing with water (1L multiplied by 1), washing with a saturated sodium chloride aqueous solution (1L multiplied by 1), drying with anhydrous sodium sulfate, concentrating and preparing sand, (PE: DCM: EA is 10: 1: 0.5) and carrying out column chromatography to obtain 65.0g of a compound I-21 white solid, wherein the yield is as follows: 70.4 percent.
Example 5
Compound VI-30 preparation of compound VII-30:
adding a compound VI-30(207.7g, 0.500mol, 1.0e.q.) and 1, 4-dioxane (3.0L) into a reaction bottle, cooling to-15 ℃, adding iodine (114.2g, 0.900mol, 1.8e.q.) and triphenylphosphine (236.0g, 0.900mol, 1.8e.q.), heating to 80 ℃ after addition, reacting for 1 hour, TLC shows that the reaction is finished, performing suction filtration on a reaction mixture, concentrating a mother solution, pouring the mother solution into ice water, adding a layering liquid, extracting an aqueous phase with ethyl acetate (2L multiplied by 2), combining organic phases, washing for 3 times, washing with saturated saline water for 1 time, drying with anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain a compound VII-30 which is 146.3g of gray solid, wherein the yield is as follows: 73.6 percent.
Compound VII-30 preparation of compound I-30:
adding 1N NaHMDS (736mL, 0.736mol, 2.0e.q.) into a reaction bottle, dropwise adding a THF (1L) solution of a compound VII-30(146.3g, 0.368mol, 1.0e.q.) at a temperature controlled between-30 ℃ and-20 ℃, raising the temperature to room temperature for 5 hours after dropwise adding, after the reaction is finished, pouring the reaction liquid into ice water (1L), carrying out layer separation, extracting an aqueous phase with methyl tert-ether (0.5L multiplied by 2), combining organic phases, washing with water (2L multiplied by 1), washing with a saturated sodium chloride aqueous solution (2L multiplied by 1), drying with anhydrous sodium sulfate, concentrating and preparing sand, (PE: DCM: EA is 10: 1: 0.5) carrying out column chromatography to obtain 113.8g of a compound I-30 white solid, and obtaining the yield: 77.8 percent.
Example 6
Compound II-5 preparation of Compound III-5
Triethylamine (303.6g, 3.000mol, 3.0e.q.) and THF (500mL) were placed in a reaction flask, the temperature was reduced to-50 ℃, a THF (300mL) solution of compound II-5(138.1g, 1.000mol, 1.0e.q.) was added dropwise thereto, stirring was continued for 30 minutes while maintaining the temperature, ethyl chloroformate (162.8g, 1.500mol, 1.5e.q.) was added dropwise thereto, the reaction was continued for 1 hour while maintaining the temperature and slowly warmed to room temperature, LC-MS showed that the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution, the pH was adjusted to 5 with hydrochloric acid, extraction was performed with methyl t-butyl ether (800mL × 2), the organic phase was combined, washed with saturated brine (1L × 1), the organic phase was concentrated to obtain compound III-5 as a white-like solid 188.5g, yield: 89.7 percent.
Preparation of Compound III-5 Compound IV-5
Dissolving the compound III-5(188.5g, 0.897mol, 1.0e.q.) in ethanol (0.6L), placing in an autoclave, adding palladium hydroxide carbon (20g), replacing with hydrogen for 3 times, reacting at 45 ℃ and 4MPa for 3 days, LC-MS shows that the reaction is finished, filtering to remove the palladium hydroxide carbon, concentrating the mother liquor to obtain compound IV-5 as pale yellow oily substance 194.0g, and obtaining the yield: 100 percent.
Preparation of Compound IV-5 Compound V-5
Adding compound IV-5(194.0g, 0.897mol, 1.0e.q.), triethylamine (208.8g, 2.063mol, 2.3e.q.) and dichloromethane (2L) into a reaction flask, adding 3-tosyl chloride (179.6g, 0.942mol, 1.05eq) in portions at about 10 ℃, reacting for 2h at 10 ℃, LC-MS indicating that the reaction of the raw materials is finished, adding acetic acid (60mL) into the reaction solution, stirring for 10 min, pouring the reaction solution into 1L of saturated ammonium chloride solution, separating the layers, washing the organic phase with water (1L × 1), washing with saturated sodium chloride aqueous solution (1L × 1), drying with anhydrous sodium sulfate, evaporating the solvent under reduced pressure to obtain compound V-5 as a light yellow oily substance 333.0g, and obtaining: 100 percent.
Preparation of Compound VI-5 from Compound V-5
Adding LiAlH into a reaction bottle4(17.04g，0.448mol, 0.5e.q.) and THF (3L) at-30 ℃ were added dropwise a solution of compound V-5(333.0g, 0.897mol, 1.0e.q.) in THF (1L) over 30 ℃ and the reaction was maintained at-30 ℃ for 30 minutes, and LC-MS showed completion of the reaction. Water (40mL), 15% NaOH solution (40mL) and water (120mL) were added dropwise in this order, and after completion of the addition, stirring was carried out at 15 ℃ for 1 hour, suction filtration was carried out, the cake was washed with THF (1.5L. times.1), and the solvent was distilled off under reduced pressure from the mother liquor to give compound VI-5 as a pale yellow oil 319.7g, yield: 100 percent.
Compound VI-5 preparation of compound VII-5:
adding compound VI-5(319.7g, 0.897mol, 1.0e.q.) and dichloromethane (1.5L) into a reaction bottle, cooling to 0 ℃, dropwise adding phosphorus trichloride (185.0g, 1.345mol, 1.5e.q.) after dropwise adding, heating to reflux for 3 hours, pouring the reaction mixture into a saturated sodium bicarbonate aqueous solution after TLC shows that the reaction is finished, carrying out layered liquid separation, washing an organic phase with water for 1 time, washing the organic phase with saturated saline water for 1 time, drying anhydrous sodium sulfate, and distilling under reduced pressure to remove the solvent to obtain compound VII-5 as a gray solid 305.0g, wherein the yield is: 90.7 percent.
Compound VII-5 preparation of compound I-5:
adding sodium tert-butoxide (117.3g, 1.220mol, 1.5e.q.) and DMF (3L) into a reaction flask, dropwise adding a DMF (1L) solution of compound VII-5(305.0g, 0.814mol, 1.0e.q.) at 0-10 ℃, heating to 90 ℃ for 4 hours after dropwise adding, cooling to 0 ℃ after LC-MS shows that the reaction is finished, dropwise adding isopropanol (100mL), stirring for 8 hours, pouring the reaction solution into ice water (12L), adding methyl tert-ether (6L), stirring, separating layers, extracting the aqueous phase with methyl tert-ether (4 Lx 2), combining the organic phase, washing with water (10 Lx 3), washing with a saturated sodium chloride aqueous solution (10 Lx 1), drying with anhydrous sodium sulfate, concentrating to prepare sand, and carrying out column chromatography (PE: DCM: EA: 10: 1: 0.5) to obtain 214.2g of compound I-5 white solid, wherein the yield is as follows: 77.8 percent.
Example 7
Preparation of Compound III-22 from Compound II-22
The reaction flask was charged with NaHMDS (821.25mL, 1.643mol, 2.5e.q.) and DMF (400mL),dropping II-22(100.00g, 0.657mol, 1.0e.q.) and (Boc) at-30-40 deg.C2Adding O (157.61g, 0.723mol, 1.1e.q.) in DMF (600mL) completely, wherein LC-MS shows that the raw materials are basically reacted completely, adding methyl tert-ether (1L) at 30 to-40 ℃, dropwise adding a mixed solution of acetic acid (200.00g) and methyl tert-ether (200mL), stirring for 30 minutes, pouring the reaction solution into saturated ammonium chloride aqueous solution (3.5L), carrying out layer separation, extracting an aqueous phase with methyl tert-butyl ether (1L multiplied by 2), combining organic phases, washing with water (500mL multiplied by 3), washing with saturated sodium chloride (500mL multiplied by 1), drying with anhydrous sodium sulfate, removing a solvent by organic phase under reduced pressure, adding petroleum ether (1L), pulping, carrying out suction filtration and drying to obtain a compound III-22 as an off-white solid 154.5g, and obtaining the yield: 93.2 percent.
Preparation of Compound III-22 Compound IV-22
Dissolving the compound III-22(154.5g, 0.612mol, 1.0e.q.) in methanol (1L), placing the solution in an autoclave, adding palladium-rhodium-palladium-carbon hydride (20g), replacing the solution with hydrogen for 3 times, reacting at 50 ℃ and 3MPa for 2 days, and after the reaction is finished by LC-MS, filtering to remove the palladium-rhodium-palladium-carbon hydride, concentrating mother liquor to obtain a compound IV-22 which is 158.2g of light yellow oily matter, wherein the yield is as follows: 100 percent.
Preparation of Compound V-22 from Compound IV-22
Adding compound IV-22(158.2g, 0.612mol, 1.0e.q.) and triethylamine (80.6g, 0.796mol, 1.3e.q.) into a reaction flask, adding 2-nitrobenzenesulfonyl chloride (142.5g, 0.643mol, 1.05eq) in portions at about 10 ℃, reacting for 2 hours at 10 ℃, LC-MS (liquid chromatography-mass spectrometry) shows that the reaction of the raw materials is finished, adding acetic acid (40mL) into the reaction solution, stirring for 10 minutes, pouring the reaction solution into 0.8L of saturated ammonium chloride aqueous solution, separating layers, washing an organic phase (1L multiplied by 1), washing a saturated sodium chloride aqueous solution (1L multiplied by 1), drying anhydrous sodium sulfate, and distilling off the solvent under reduced pressure to obtain 270.5g of compound V-22 as a light yellow oily substance, wherein the yield is as follows: 99.6 percent.
Preparation of Compound VI-22 from Compound V-22
Adding NaBH into a reaction bottle4(230.7g, 6.100mol, 10.0e.q.) and THF (2L) A solution of compound V-5(270.5g, 0.610mol, 1.0e.q.) in THF (0.8L) was added dropwise at 30 ℃ and the reaction was maintained at-30 ℃ for 30 minutes, and LC-MS showed the reaction was complete. Water (300mL) and 15% N were added dropwise in this orderThe reaction mixture was stirred for 1 hour at 15 ℃ with the addition of the solution of aOH (300mL) and water (900mL), filtered, the filter cake was washed with THF (1L. times.1), the layers were separated, the organic phase was dried and filtered, and the solvent was distilled off under reduced pressure from the mother liquor to give compound VI-22 as a pale yellow oil 255.1g, yield: 100 percent.
Compound VI-22 preparation of compound VII-22:
adding compound VI-22(255.1g, 0.610mol, 1.0e.q.) and dichloromethane (1.5L) into a reaction bottle, cooling to 0 ℃, dropwise adding phosphorus tribromide (247.7g, 0.915mol, 1.5e.q.) after dropwise adding, heating to reflux for 3 hours, pouring the reaction mixture into a saturated sodium bicarbonate aqueous solution after TLC shows that the reaction is finished, carrying out layered liquid separation, washing an organic phase with water for 1 time, washing the organic phase with saturated saline water for 1 time, drying with anhydrous sodium sulfate, and distilling off the solvent under reduced pressure to obtain 272.8g of compound VII-22 as a gray solid, wherein the yield is as follows: 93.5 percent.
Compound VII-22 preparation of compound I-22:
adding 60% NaH (27.4g, 0.684mol, 1.2e.q.) and DMF (1.5L) into a reaction bottle, dropwise adding a DMF (1L) solution of a compound VII-22(272.8g, 0.570mol, 1.0e.q.) at 0-10 ℃, heating to 95 ℃ for 1 hour after dropwise adding, cooling to 0 ℃ after LC-MS shows that the reaction is finished, dropwise adding isopropanol (70mL), pouring the reaction liquid into ice water (6L), adding methyl tert-ether (5L), stirring, separating layers, extracting an aqueous phase with methyl tert-ether (3L multiplied by 2), combining organic phases, washing with water (8L multiplied by 3), washing with a saturated sodium chloride aqueous solution (8L multiplied by 1), drying with anhydrous sodium sulfate, concentrating and preparing sand, (PE: DCM: EA: 10: 1: 0.5) to obtain a white solid of a compound I-22 (192.2 g, yield: 84.8 percent.
Claims (10)
1. A process for the preparation of a compound of formula (VII) comprising:
wherein:
R1is 4-toluenesulfonyl, 3-toluenesulfonyl, 4-nitrobenzenesulfonyl or 2-nitrobenzenesulfonyl;
R2is methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl or phenoxycarbonyl;
x is Cl, Br or I;
formula VI is prepared in the following manner:
(1) starting from compounds II with R2Cl or (R)2)2O is subjected to amidation reaction to obtain a compound III,
(2) the compound III and hydrogen are subjected to reduction reaction in the presence of a catalyst to obtain a compound IV,
(3) compounds IV and R1Then performing amidation reaction on the Cl to obtain a compound V,
(4) reacting the compound V with a reducing agent to obtain a compound VI,
(5) reacting the compound VI with a halogenating reagent to prepare a compound VII;
wherein:
r is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, p-methylphenyl, o-methylphenyl, p-isopropylphenyl, o-isopropylphenyl, p-tert-butylphenyl, o-tert-butylphenyl, p-chlorophenyl or o-chlorophenyl.
2. The method of claim 1, wherein: in the process of preparing the compound VII from the compound VI, the halogenating reagent is thionyl chloride, phosphorus trichloride, phosphorus tribromide, N-chlorosuccinimide/triphenylphosphine, N-bromosuccinimide/triphenylphosphine, N-iodosuccinimide/triphenylphosphine or iodine/triphenylphosphine.
3. The method of claim 2, wherein: in the process of preparing the compound VII from the compound VI, controlling the temperature to be-30 ℃, and adding a halogenating reagent into a reaction system; the molar ratio of the compound VI to the halogenating agent is 1: 0.5-1: 10.
4. The production method according to claim 3, characterized in that: the solvent is dichloromethane, 1, 2-dichloroethane, tetrahydrofuran or 1, 4-dioxane.
5. The method of claim 1, wherein: in the process of preparing compound IV from compound III, the catalyst is palladium carbon, palladium hydroxide carbon, rhodium palladium carbon or rhodium carbon.
6. The method of claim 1, wherein: in the process of preparing the compound VI from the compound V, the reducing agent is lithium aluminum hydride, sodium borohydride, lithium tri-tert-butoxyaluminum hydride, lithium borohydride, potassium borohydride/iodine or potassium borohydride/lithium chloride.
7. The method of claim 6, wherein: the molar ratio of the compound V to the reducing agent is 1: 0.5-1: 10.
8. A process for the preparation of a compound of formula (I) comprising:
wherein:
R1is 4-toluenesulfonyl, 3-tolueneSulfonyl, 4-nitrobenzenesulfonyl or 2-nitrobenzenesulfonyl;
R2is methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl or phenoxycarbonyl;
x is Cl, Br or I;
further comprising the step of preparing a compound of formula (VII) by the preparation process according to any one of claims 1 to 7.
9. The method of claim 8, wherein: the alkali is NaH, potassium tert-butoxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, lithium 2,2,6, 6-tetramethylpiperidine, n-butyllithium, sodium hexamethyldisilazane, potassium hexamethyldisilazane or lithium hexamethyldisilazane.
10. The production method according to claim 8 or 9, characterized in that: the molar ratio of the compound VII to the alkali is 1: 1-1: 3.
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| CN106083862A (en) * | 2016-06-08 | 2016-11-09 | 南京富润凯德生物医药有限公司 | One prepares (1S, 4S) 2,5 diazabicylo [2.2.1] heptane or the method for [2.2.2] Octane derivatives |
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| MX2016012648A (en) * | 2014-03-29 | 2017-01-11 | Wockhardt Ltd | A process for preparation of sodium (2s, 5r)-6-(benzyloxy)-7-oxo- 1,6-diazabicyclo[3.2.1]octane-2-carboxylate. |
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| CN106083862A (en) * | 2016-06-08 | 2016-11-09 | 南京富润凯德生物医药有限公司 | One prepares (1S, 4S) 2,5 diazabicylo [2.2.1] heptane or the method for [2.2.2] Octane derivatives |
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