TW202222790A - Method for preparing 4-bromofuran-2- carboxylates - Google Patents

Method for preparing 4-bromofuran-2- carboxylates Download PDF

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TW202222790A
TW202222790A TW110136173A TW110136173A TW202222790A TW 202222790 A TW202222790 A TW 202222790A TW 110136173 A TW110136173 A TW 110136173A TW 110136173 A TW110136173 A TW 110136173A TW 202222790 A TW202222790 A TW 202222790A
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安德烈亞斯 倫比亞克
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德商拜耳廠股份有限公司
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    • C07D307/00Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
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    • C07D307/34Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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Abstract

The present invention relates to a method for preparing 4-bromofuran-2-carboxylates of the general formula ( I) and to the use thereof as important precursors for the synthesis of agrochemical and pharmaceutical active substances.

Description

製備4-溴呋喃-2-羧酸酯之方法Process for preparing 4-bromofuran-2-carboxylate

本發明係有關一用於製備通式( I)之4-溴呋喃-2-羧酸酯之方法及其作為用於合成農業化學與藥學活性物質之重要前驅物的用途。 The present invention relates to a method for preparing 4-bromofuran-2-carboxylate of general formula ( I ) and its use as an important precursor for synthesizing agrochemical and pharmaceutical active substances.

通式( I) 4-溴呋喃-2-羧酸酯(特別是R 1=COO甲基)為農業化學(參見WO 2018/228985)與藥學活性物質之重要前驅物(Craig et al., Bioorganic & Medicinal Chemistry Letters, 12(18), 2647-2650; 2002;F. Brucoli et al., Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012)。 4-Bromofuran-2-carboxylates of general formula ( I ) (especially R 1 =COO methyl) are important precursors for agrochemicals (see WO 2018/228985) and pharmaceutically active substances (Craig et al., Bioorganic & Medicinal Chemistry Letters, 12(18), 2647-2650; 2002 ; F. Brucoli et al., Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012 ).

通式( I) 4-溴呋喃-2-羧酸酯作為用於製備四氫與二氫呋喃羧酸與酯之起始材料(F. Brucoli et al., Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012)。 4-Bromofuran-2-carboxylates of general formula ( I ) were used as starting materials for the preparation of tetrahydro and dihydrofuran carboxylic acids and esters (F. Brucoli et al., Bioorganic & Medicinal Chemistry, 20(6) , 2019-2024; 2012 ).

針對4,5-二溴呋喃-2-羧酸甲酯之反應係描述於European Journal of Medicinal Chemistry, 2016, 117, 47、Journal of Agricultural and Food Chemistry, 2017, 65, 5397及CN105503832中。該反應使用2.2當量之氯化鋁。產率最大值為78%。然而,彼等條件導致形成相對大量(20-30%)之副產物,其無法移除或難以移除。此外,較低之反應溫度可導致反應器壁上實質結垢,且由於攪拌受阻而導致轉化不完全。 The reaction for methyl 4,5-dibromofuran-2-carboxylate is described in European Journal of Medicinal Chemistry, 2016 , 117 , 47, Journal of Agricultural and Food Chemistry, 2017 , 65 , 5397 and CN105503832. The reaction used 2.2 equivalents of aluminum chloride. The maximum yield was 78%. However, these conditions result in the formation of relatively large amounts (20-30%) of by-products that cannot be removed or are difficult to remove. In addition, lower reaction temperatures can result in substantial fouling of the reactor walls and incomplete conversion due to impeded agitation.

4-溴呋喃-2-羧酸甲酯之製備可另外藉由4,5-二溴呋喃-2-羧酸甲酯與異丙基氯化鎂之反應而達成。此反應係描述於European Journal of Medicinal Chemistry, 2016, 117, 47、CN105503832及WO 2008/98104中。缺點為產率相對較低、需要低的反應溫度及密集的廢水處理。此外,以工業規模處理異丙基氯化鎂具有挑戰性且成本高昂。 The preparation of methyl 4-bromofuran-2-carboxylate can additionally be achieved by the reaction of methyl 4,5-dibromofuran-2-carboxylate with isopropylmagnesium chloride. This reaction is described in European Journal of Medicinal Chemistry, 2016 , 117 , 47, CN105503832 and WO 2008/98104. Disadvantages are relatively low yields, the need for low reaction temperatures and intensive wastewater treatment. Furthermore, processing isopropylmagnesium chloride on an industrial scale is challenging and expensive.

作為替代,亦可能以三級丁基鋰合成4-溴呋喃-2-羧酸甲酯。此反應見於諸如EP1489077之文獻中。然而,已知丁基鋰 – 亦由於低溫 – 僅能在有限程度內進行大規模處理,且具有難度。As an alternative, it is also possible to synthesize methyl 4-bromofuran-2-carboxylate from tertiary butyllithium. This reaction is found in documents such as EP1489077. However, it is known that butyllithium - also due to the low temperature - can only be processed on a large scale to a limited extent and with difficulty.

進一步之選項為以氯化銨與鋅作為試劑合成4-溴呋喃-2-羧酸甲酯。此反應係描述於F. Brucoli et al., Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012及US 2016/0264544中,產率較低且需要大量的鹽。 A further option is to synthesize methyl 4-bromofuran-2-carboxylate using ammonium chloride and zinc as reagents. This reaction is described in F. Brucoli et al., Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012 and US 2016/0264544, with low yields and requiring large amounts of salt.

鑑於上述之先前技術,本發明之目的在於尋找一用於製備所稱之化合物的方法,使得以更高的產率、高的純度及環境上友善的方式取得通式( I)化合物,以在工業規模上生產用於製備活性物質之重要中間體。 In view of the above-mentioned prior art, the object of the present invention is to find a process for the preparation of the so-called compounds, so that the compounds of general formula ( I ) can be obtained in higher yields, in high purity and in an environmentally friendly manner, in Important intermediates for the preparation of active substances are produced on an industrial scale.

上述目的係藉由一用於製備通式( I)化合物之方法達成

Figure 02_image001
( I), 其中 R 1為COO(C 1-C 4)烷基, 其特徵在於通式( II)化合物
Figure 02_image003
( II), 其中 R 1係如上面之定義, 在1.0至1.8當量之氯化鋁 – 以通式( II)化合物為基準 – 與溴存在下反應以形成通式( III)化合物,
Figure 02_image005
( III) 其中 R 1係如上面之定義, 且係進一步與1.0至1.5當量之鋅和氯化銨反應以形成式( I)化合物。 The above objects are achieved by a method for the preparation of compounds of general formula ( I )
Figure 02_image001
( I ), wherein R 1 is COO(C 1 -C 4 ) alkyl, which is characterized by a compound of general formula ( II )
Figure 02_image003
( II ), wherein R1 is as defined above, and 1.0 to 1.8 equivalents of aluminum chloride - based on the compound of general formula ( II ) - is reacted with bromine to form the compound of general formula ( III ),
Figure 02_image005
( III ) wherein R1 is as defined above, and is further reacted with 1.0 to 1.5 equivalents of zinc and ammonium chloride to form compounds of formula ( I ).

通式( I)、( II)及( III)化合物中之基團的較佳定義如下: R 1為COOCH 3、COOC 2H 5Preferred definitions of the groups in the compounds of general formula ( I ), ( II ) and ( III ) are as follows: R 1 is COOCH 3 , COOC 2 H 5 .

通式( I)、( II)及( III)化合物中之基團的特別較佳定義如下: R 1為COOCH 3Particularly preferred definitions of the groups in the compounds of formula ( I ), ( II ) and ( III ) are as follows: R 1 is COOCH 3 .

方法與中間物之說明 流程圖 1

Figure 02_image007
Illustration of methods and intermediates Flowchart 1
Figure 02_image007

通式( II)化合物在1.0至1.8當量之氯化鋁 – 以通式( II)化合物為基準 – 與溴存在下反應以形成通式( III)化合物,其係進一步與1.0至1.5當量之鋅和氯化銨反應以形成式( I)化合物。 步驟 1 A compound of general formula ( II ) is reacted in the presence of 1.0 to 1.8 equivalents of aluminum chloride - based on the compound of general formula ( II ) - with bromine to form a compound of general formula ( III) which is further combined with 1.0 to 1.5 equivalents of zinc and ammonium chloride to form compounds of formula ( I ). Step 1

使用1.0至1.8當量之氯化鋁 – 以通式( II)化合物為基準,較佳地1.2至1.5當量,非常特別較佳地1.3至1.4當量。 1.0 to 1.8 equivalents of aluminium chloride are used - based on the compound of general formula ( II ), preferably 1.2 to 1.5 equivalents, very particularly preferably 1.3 to 1.4 equivalents.

使用1.8至3.0當量之溴 – 以通式( II)化合物為基準,較佳地1.9至2.2當量,非常特別較佳地2.0當量。 1.8 to 3.0 equivalents of bromine are used - based on the compound of general formula ( II ), preferably 1.9 to 2.2 equivalents, very particularly preferably 2.0 equivalents.

該反應通常在-10至30°C之溫度範圍內進行。該反應較佳地在0至30°C,非常特別較佳地在5至20°C之內進行。The reaction is usually carried out at a temperature ranging from -10 to 30°C. The reaction is preferably carried out at 0 to 30°C, very particularly preferably within 5 to 20°C.

該反應通常在氯化之溶劑,較佳地二氯甲烷或二氯乙烷,非常特別較佳地二氯甲烷之中進行。The reaction is generally carried out in a chlorinated solvent, preferably dichloromethane or dichloroethane, very particularly preferably dichloromethane.

減少所使用之氯化鋁之當量數 – 以通式( II)化合物為基準 – 相較於先前之技術(參見最大值78%),所得之( III)之產率增至> 85%。此外,所形成之副產物之量減至5至10%,使得通式( III)化合物之處理/分離變得更加容易。可藉由本領域具有通常知識者已知之方法完成分離,例如,萃取、溶劑之蒸餾及結晶。 然而,在本發明之上下文中,較佳為 – 在切換至步驟2中之較佳溶劑之後 – 進一步直接使用粗產物。 步驟 2 Reducing the number of equivalents of aluminium chloride used - based on the compound of general formula ( II ) - increased the yield of ( III ) obtained to > 85% compared to the previous technique (see max. 78%). Furthermore, the amount of by-products formed is reduced to 5 to 10%, making the handling/isolation of the compound of general formula ( III ) easier. Isolation can be accomplished by methods known to those of ordinary skill in the art, eg, extraction, distillation of solvent, and crystallization. However, in the context of the present invention it is preferred - after switching to the preferred solvent in step 2 - to further use the crude product directly. Step 2

使用1.0至1.5當量之鋅 – 以通式( II)化合物為基準,較佳地1.1至1.3當量,非常特別較佳地1.1至1.2當量。 1.0 to 1.5 equivalents of zinc are used - based on the compound of general formula ( II ), preferably 1.1 to 1.3 equivalents, very particularly preferably 1.1 to 1.2 equivalents.

使用2.0至4.0當量之氯化銨 – 以通式( II)化合物為基準,較佳地2.5至3.5當量,非常特別較佳地2.8至3.2當量。 2.0 to 4.0 equivalents of ammonium chloride are used - based on the compound of general formula ( II ), preferably 2.5 to 3.5 equivalents, very particularly preferably 2.8 to 3.2 equivalents.

該反應通常在-10至60°C之溫度範圍內進行。該反應較佳地在10至50°C,非常特別較佳地在30至50°C之內進行。The reaction is usually carried out in the temperature range of -10 to 60°C. The reaction is preferably carried out at 10 to 50°C, very particularly preferably within 30 to 50°C.

該反應通常在溶劑之中進行,較佳之溶劑為甲醇。The reaction is usually carried out in a solvent, preferably methanol.

可依據較佳之反應條件由通式( III)化合物之分離材料轉化成通式( I)化合物。較佳的是, 步驟 1之通式( II)化合物,在溶劑蒸餾轉換後,直接用於 步驟 2中而無需中間物分離。溶劑交換係較佳地在20°C至100°C,最佳地30°C至60°C之溫度內進行。蒸餾可在標準條件下或減壓下,特別較佳地在50毫巴至1000毫巴,非常特別較佳地在200毫巴至550毫巴之下進行。 The isolated material of the compound of general formula ( III ) can be converted to the compound of general formula ( I ) according to the preferred reaction conditions. Preferably, the compound of general formula ( II ) in step 1 is directly used in step 2 without intermediate separation after solvent distillation conversion. Solvent exchange is preferably carried out at a temperature of 20°C to 100°C, most preferably 30°C to 60°C. The distillation can be carried out under standard conditions or under reduced pressure, particularly preferably at 50 mbar to 1000 mbar, very particularly preferably at 200 mbar to 550 mbar.

現在令人驚訝地發現,以次化學計量添加乾燥劑(如硫酸鈉)有利於減少鋅的量及高的產率。儘管系統中可容忍少量的水,但大量會導致所添加之鋅凝集。其結果為,不再達到足夠的反應性,意指完全轉化需要相當大量的鋅。其之進一步優勢為,不再需要步驟1與2之間費力的乾燥與蒸餾過程。It has now surprisingly been found that substoichiometric addition of a desiccant, such as sodium sulfate, is advantageous in reducing the amount of zinc and in high yields. Although small amounts of water can be tolerated in the system, large amounts can cause the added zinc to agglomerate. As a result, sufficient reactivity is no longer achieved, meaning that a considerable amount of zinc is required for complete conversion. A further advantage of this is that the laborious drying and distillation process between steps 1 and 2 is no longer required.

直接使用通式( III)化合物而無需中間物分離,以及減少起始材料,相較於先前之技術(參見最大值70%),兩個步驟內之總產率增至> 80%,伴隨高的純度。廢棄物體積亦顯著減少,從而改善該方法的環境衝擊。 實施例 Using the compound of general formula ( III ) directly without intermediate isolation, and reducing starting material, the overall yield in two steps increased to > 80% in two steps, with high purity. The waste volume is also significantly reduced, thereby improving the environmental impact of the method. Example

藉由下列實施例更詳盡闡述本發明,但本發明不侷限於此。 測量方法 The invention is illustrated in more detail by the following examples, but the invention is not limited thereto. Measurement methods

產物係藉由 1H NMR確認。 實施例 1 步驟 1 4,5- 二溴呋喃 -2- 羧酸甲酯 (III-1) The product was confirmed by 1 H NMR. Example 1 Step 1 : Methyl 4,5 -dibromofuran -2- carboxylate (III-1)

在氬氣下將1100毫升之二氯甲烷裝載至配備機械攪拌器之2升夾套反應器中,並將296.0克(1.4當量)之三氯化鋁懸浮其中。將懸浮液冷卻,並在< 5°C下之45分鐘期間內計量添加200.0克(1.0當量)之2-呋喃羧酸甲酯。在計量添加結束時,將反應混合物升溫至22°C,並在此溫度下攪拌60分鐘。再次冷卻至14至15°C之後,在此溫度下之2.5小時期間內計量添加499.2克(2.0當量)之溴,同時使酸性氣體通過鹼性氣體洗滌器。在計量添加結束時,反應混合物在此溫度下另外攪拌1.5小時,隨後在< 10°C下之2小時期間內,計量添加含有32.5克(0.1當量)之偏二亞硫酸鈉的1500毫升之水溶液。在添加結束時,將混合物升溫至22°C,分開各相,並以300毫升之水洗滌有機相。再次以230毫升之飽和碳酸氫鈉溶液洗滌有機相,在減壓下移除溶劑,並將殘餘物溶於2400毫升之甲醇中,且不經進一步純化直接用於第二步驟:轉化率為97面積% (HPLC)。A 2-liter jacketed reactor equipped with a mechanical stirrer was charged with 1100 mL of dichloromethane under argon, and 296.0 g (1.4 equiv.) of aluminum trichloride was suspended therein. The suspension was cooled and 200.0 g (1.0 equiv.) of methyl 2-furancarboxylate were metered in over a period of 45 minutes at <5°C. At the end of the metered addition, the reaction mixture was warmed to 22° C. and stirred at this temperature for 60 minutes. After cooling to 14 to 15°C again, 499.2 g (2.0 equiv.) of bromine are metered in over a period of 2.5 hours at this temperature, while the acid gas is passed through the alkaline gas scrubber. At the end of the metered addition, the reaction mixture was stirred for a further 1.5 hours at this temperature, and then 1500 ml of an aqueous solution containing 32.5 g (0.1 eq) of sodium metabisulfite was metered in over a period of 2 hours at <10°C. At the end of the addition, the mixture was warmed to 22°C, the phases were separated and the organic phase was washed with 300 mL of water. The organic phase was washed again with 230 mL of saturated sodium bicarbonate solution, the solvent was removed under reduced pressure, and the residue was dissolved in 2400 mL of methanol and used directly in the second step without further purification: conversion 97 Area % (HPLC).

在藉由蒸餾移除溶劑而分離並在30°C之減壓下乾燥固體之後,取得純的化合物之分析樣本。Analytical samples of pure compounds were taken after isolation by distillative removal of the solvent and drying of the solids under reduced pressure at 30°C.

1H NMR (400 MHz, CDCl 3):δ = 3.90 (s, 3H)、7.46 (s, 1H) ppm。 步驟 2 5- 溴呋喃 -2- 羧酸甲酯 (I-1) 1 H NMR (400 MHz, CDCl 3 ): δ = 3.90 (s, 3H), 7.46 (s, 1H) ppm. Step 2 : Methyl 5- bromofuran -2- carboxylate (I-1)

將含有源自步驟1 (實施例1,(III-1))之4,5-二溴呋喃-2-羧酸甲酯(1.0當量)的2400毫升之甲醇溶液裝載至配備機械攪拌器之4升夾套反應器中, 並添加232.8克(3.0當量)之氯化銨。將懸浮液升溫至30°C,並在添加51.5克(0.25當量)之硫酸鈉後,在此溫度下攪拌45分鐘。隨後,在2小時內以6份添加106.4克(1.1當量)之鋅粉。在添加結束時,將混合物加熱至45°C,並在此溫度下攪拌30分鐘。一旦反應完成(藉由HPLC監控),將懸浮液冷卻至< 10°C,經過濾,並以300毫升之冰冷甲醇洗滌濾餅。在200毫巴與35°C下將合併之濾液濃縮,並在35°C下將殘餘物溶於1000毫升之正庚烷中。在移除殘留之甲醇並共沸乾燥有機相後,將175毫升之三級丁基甲基醚添加至有機相中,並在40°C下以兩份300毫升之10% (以重量計) HCl洗滌。在重新共沸乾燥有機相並在40°C之減壓下部分移除溶劑後,將有機相冷卻至30°C,且產物在25°C至30°C下結晶。可在30°C下任意地進行播晶種。隨後,在6小時期間內冷卻至0°C,並在過濾及以兩份75毫升之冷的正庚烷洗滌濾餅後,取得產物,為無色至淡米色固體:產率為248克(在2個步驟內為理論值之83%,> 99重量%)。A solution of 4,5-dibromofuran-2-carboxylate (1.0 equiv) in methanol containing 2400 mL of methyl 4,5-dibromofuran-2-carboxylate (1.0 equiv) from step 1 (Example 1, (III-1)) was loaded into 4 equipped with a mechanical stirrer. A jacketed reactor was added and 232.8 grams (3.0 equiv.) of ammonium chloride was added. The suspension was warmed to 30°C and, after adding 51.5 g (0.25 equiv) of sodium sulfate, was stirred at this temperature for 45 minutes. Subsequently, 106.4 grams (1.1 equiv) of zinc powder was added in 6 portions over 2 hours. At the end of the addition, the mixture was heated to 45°C and stirred at this temperature for 30 minutes. Once the reaction was complete (monitored by HPLC), the suspension was cooled to <10°C, filtered, and the filter cake was washed with 300 mL of ice-cold methanol. The combined filtrates were concentrated at 200 mbar and 35°C, and the residue was dissolved in 1000 ml of n-heptane at 35°C. After removal of residual methanol and azeotropic drying of the organic phase, 175 mL of tert-butyl methyl ether was added to the organic phase and washed with two 300 mL portions of 10% (by weight) HCl at 40°C . After re-azeotropic drying of the organic phase and partial removal of the solvent under reduced pressure at 40°C, the organic phase was cooled to 30°C and the product crystallized at 25°C to 30°C. Seeding can be optionally performed at 30°C. Subsequently, cooling to 0°C over a period of 6 hours, and after filtration and washing of the filter cake with two 75 ml portions of cold n-heptane, the product was obtained as a colourless to pale beige solid: yield 248 g (in 83% of theory in 2 steps, > 99% by weight).

1H NMR (400 MHz, CDCl 3):δ = 3.90 (s, 3H)、7.18 (s, 1H)、7.57 (s, 1H) ppm。 具有 2.2 當量之 AlCl 3 的比較例 1 H NMR (400 MHz, CDCl 3 ): δ = 3.90 (s, 3H), 7.18 (s, 1H), 7.57 (s, 1H) ppm. Comparative example with 2.2 equivalents of AlCl

在氬氣下將50毫升之二氯甲烷裝載至250毫升之4-頸圓底燒瓶中,添加10.0克(1.0當量)之2-呋喃羧酸甲酯,並將溶液冷卻至< 5°C。在此溫度下逐份添加23.0克(2.2當量)之三氯化鋁,並將懸浮液攪拌15分鐘。隨後,在相同溫度下之30分鐘期間內計量添加25.0克(2.0當量)之溴,並在計量添加結束時,將反應混合物升溫至20至22°C,在此溫度下攪拌1小時,並在氬氣下儲存過夜。隨後,將反應混合物逐份添加至60克之冰、10克之水及10毫升之飽和亞硫酸鈉溶液的混合物中。分開各相,以100毫升之乙酸乙酯稀釋有機相,並以50毫升之水洗滌有機相。在30°C之減壓下將溶劑移除,以取得產物,為暗橙色固體:產率為17.4克。A 250 mL 4-neck round bottom flask was charged with 50 mL of dichloromethane under argon, 10.0 g (1.0 equiv) of methyl 2-furancarboxylate was added, and the solution was cooled to <5°C. 23.0 g (2.2 equiv.) of aluminium trichloride were added portionwise at this temperature and the suspension was stirred for 15 minutes. Subsequently, 25.0 g (2.0 equiv.) of bromine are metered in over a period of 30 minutes at the same temperature, and at the end of the metered addition, the reaction mixture is warmed to 20 to 22° C., stirred at this temperature for 1 hour, and heated at this temperature for 1 hour. Store under argon overnight. Subsequently, the reaction mixture was added portionwise to a mixture of 60 g of ice, 10 g of water and 10 ml of saturated sodium sulfite solution. The phases were separated, the organic phase was diluted with 100 mL of ethyl acetate and washed with 50 mL of water. The solvent was removed under reduced pressure at 30°C to obtain the product as a dark orange solid: 17.4 g yield.

1H-NMR分析顯示約24%之4,5-二溴-2-羧酸甲酯與75%之4-溴-5-氯-2-羧酸甲酯。省略反應混合物在氬氣下過夜儲存,可使目標產物之分液增加 60至70%。然而,可比較之化學性質意指,僅在產物有重大損失時,可能耗乏約20至30%之副產物組分。 1 H-NMR analysis showed about 24% methyl 4,5-dibromo-2-carboxylate and 75% methyl 4-bromo-5-chloro-2-carboxylate. Omitting the overnight storage of the reaction mixture under argon increased the separation of the target product by 60 to 70%. However, comparable chemistry means that about 20 to 30% of the by-product components may be depleted only when there is a significant loss of product.

none

Figure 110136173-A0101-11-0001-3
Figure 110136173-A0101-11-0001-3

Claims (9)

一種用於製備通式( I)化合物之方法
Figure 03_image001
( I), 其中 R 1為COO(C 1-C 4)烷基, 其特徵在於通式( II)化合物
Figure 03_image003
( II), 其中 R 1係如上面之定義, 在1.0至1.8當量之氯化鋁 – 以通式( II)化合物為基準 – 與溴存在下反應以形成通式( III)化合物,
Figure 03_image005
( III) 其中 R 1係如上面之定義, 且係進一步與1.0至1.5當量之鋅和氯化銨反應以形成式( I)化合物。
A kind of method for preparing compound of general formula ( I )
Figure 03_image001
( I ), wherein R 1 is COO(C 1 -C 4 ) alkyl, which is characterized by a compound of general formula ( II )
Figure 03_image003
( II ), wherein R1 is as defined above, and 1.0 to 1.8 equivalents of aluminum chloride - based on the compound of general formula ( II ) - is reacted with bromine to form the compound of general formula ( III ),
Figure 03_image005
( III ) wherein R1 is as defined above, and is further reacted with 1.0 to 1.5 equivalents of zinc and ammonium chloride to form compounds of formula ( I ).
如請求項1之方法,其特徵在於通式( I)、( II)及( III)化合物中之基團的定義如下: R 1為COOCH 3、COOC 2H 5The method of claim 1, characterized in that the groups in the compounds of general formula ( I ), ( II ) and ( III ) are defined as follows: R 1 is COOCH 3 , COOC 2 H 5 . 如請求項1之方法,其特徵在於通式( I)、( II)及( III)化合物中之基團的定義如下: R 1為COOCH 3The method of claim 1, characterized in that the groups in the compounds of general formula ( I ), ( II ) and ( III ) are defined as follows: R 1 is COOCH 3 . 如請求項1至3中任一項之方法,其特徵在於使用1.3至1.4當量之氯化鋁,以通式( II)化合物為基準。 The method according to any one of claims 1 to 3, characterized in that 1.3 to 1.4 equivalents of aluminum chloride are used, based on the compound of general formula ( II ). 如請求項1至4中任一項之方法,其特徵在於使用1.9至2.2當量之溴,以通式( II)化合物為基準。 The method of any one of claims 1 to 4, characterized in that 1.9 to 2.2 equivalents of bromine are used, based on the compound of general formula ( II ). 如請求項1至5中任一項之方法,其特徵在於使用1.1至1.2當量之鋅,以通式( II)化合物為基準。 The method according to any one of claims 1 to 5, characterized in that 1.1 to 1.2 equivalents of zinc are used, based on the compound of general formula ( II ). 如請求項1至6中任一項之方法,其特徵在於使用2.8至3.2當量之氯化銨,以通式( II)化合物為基準。 The method according to any one of claims 1 to 6, characterized in that 2.8 to 3.2 equivalents of ammonium chloride are used, based on the compound of general formula ( II ). 如請求項1至7中任一項之方法,其特徵在於第一反應步驟中之溶劑為二氯甲烷。The method according to any one of claims 1 to 7, characterized in that the solvent in the first reaction step is dichloromethane. 如請求項1至8中任一項之方法,其特徵在於第二反應步驟中之溶劑為甲醇。The method according to any one of claims 1 to 8, characterized in that the solvent in the second reaction step is methanol.
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