CN115894498A - A kind of potential antiviral drug intermediate BL and its synthetic method - Google Patents

Abstract

其中，R₁为C1‑C6烷基、对甲基苯磺酰基或4‑甲氧基苯磺酰基，本发明工艺路线半缩醛中间体A在路易斯酸催化的条件下和TMSCN反应，得到很高的非对映体选择性的中间体B，另外本发明的工艺操作简单、收率高、产品质量纯度高、手性纯度高，适合放大生产的中间体BL工艺路线。The present invention relates to a kind of potential antiviral drug intermediate BL and its synthetic method, and the structural formula of described intermediate BL is:

Wherein, R ₁ is C1-C6 alkyl, p-toluenesulfonyl or 4-methoxybenzenesulfonyl, and the hemiacetal intermediate A of the technical route of the present invention reacts with TMSCN under the condition of Lewis acid catalysis, and obtains very Intermediate B with high diastereoselectivity. In addition, the process of the present invention is simple in operation, high in yield, high in product quality and high in chiral purity, and is suitable for the process route of intermediate BL in scale-up production.

Description

A potential antiviral drug intermediate BL and its synthesis method

Technical Field

The invention relates to a potential antiviral drug intermediate BL and a synthesis method thereof.

Background Art

Remdesivir is an antiviral drug. It was developed by Gilead Sciences for the treatment of Ebola virus disease and Marburg virus infection, and was later found to show reasonable antiviral activity against other related viruses (such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS).

In October 2020, the U.S. Food and Drug Administration (FDA) approved Gilead Sciences' antiviral drug remdesivir for the treatment of hospitalized COVID-19 patients, making it the first officially approved drug for the treatment of the new coronavirus in the United States.

The chemical structure of Remdesivir is as follows:

There are some synthetic methods for remdesivir intermediates in my country, but none of these methods modify the amino group on remdesivir 4-aminopyrrolo[2,1-f][1,2,4]triazine, and the intermediate obtained after modifying the amino group is expected to develop a new antiviral drug. Therefore, it is necessary to make certain improvements to the intermediates of remdesivir and develop new drug intermediates. The present invention develops a process route for preparing intermediate BL, the purpose of which is to provide a key intermediate BL for potential new antiviral compound drugs. The chemical structure of the intermediate BL is as follows:

The process route for preparing the intermediate BL is as follows:

Wherein, _R1 is C1-C6 alkyl, p-toluenesulfonyl or 4-methoxybenzenesulfonyl.

Summary of the invention

The purpose of the present invention is to provide a potential antiviral drug intermediate BL and a synthesis method thereof.

The purpose of the present invention is achieved through the following technical solutions:

A potential antiviral drug intermediate BL, its structural formula is as follows:

Wherein, _R1 is C1-C6 alkyl, p-toluenesulfonyl or 4-methoxybenzenesulfonyl.

The synthesis method of the potential antiviral drug intermediate BL comprises the following steps:

(1) Synthesis of intermediate A: SM (the synthesis of this compound refers to the disclosed invention patent CN102596979) and acyl chloride undergo acylation reaction of hydroxyl and amino groups to obtain intermediate A. The structural formulas of SM and intermediate A are:

(2) Synthesis of intermediate B: Intermediate A reacts with TMSCN in the presence of a Lewis acid boron trifluoride ether solution to obtain intermediate B. The structural formula of intermediate B is:

(3) Synthesis of intermediate BL: Intermediate B is debenzylated under the condition of Lewis acid BCl ₃ to obtain intermediate BL. The structural formula of intermediate BL is:

The specific reaction route is as follows:

Wherein, _R1 is C1-C6 alkyl, p-toluenesulfonyl or 4-methoxybenzenesulfonyl.

Compared with the prior art, the advantages of the present invention are:

1. Process Route of the Invention The hemiacetal intermediate A reacts with TMSCN under Lewis acid catalysis to obtain an intermediate B with high diastereomeric selectivity.

2. Provide an intermediate BL process route that is simple to operate, has high yield, high product quality purity, high chiral purity, and is suitable for scale-up production.

DETAILED DESCRIPTION

A potential antiviral drug intermediate BL, its structural formula is as follows:

Wherein, _R1 is C1-C6 alkyl, p-toluenesulfonyl or 4-methoxybenzenesulfonyl.

The preparation method of the potential antiviral drug intermediate BL comprises the following steps:

(1) Synthesis of intermediate A: SM and acyl chloride undergo acylation reaction of hydroxyl and amino groups to obtain intermediate A, wherein the structural formulas of SM and intermediate A are:

(2) Synthesis of intermediate B: Intermediate A reacts with TMSCN in the presence of a Lewis acid boron trifluoride ether solution to obtain intermediate B. The structural formula of intermediate B is:

(3) Synthesis of intermediate BL: Intermediate B is debenzylated in the presence of Lewis acid BCl ₃ to obtain intermediate BL.

Wherein, the specific operation method of step (1) is: under nitrogen protection, in a three-necked flask, add SM, 4-dimethylaminopyridine and dichloromethane mixed solution, add TEA, cool to -40 ~ 0 ° C (more preferably -10 ~ 0 ° C), add acyl chloride, stir for 10-15min, and then react at 20 ~ 70 ° C (more preferably 25 ~ 35 ° C) for 4 ~ 10h (more preferably 5 ~ 6h). TLC detection shows that the raw material basically disappears, water is added to quench, 1N dilute hydrochloric acid is adjusted to pH 6-7, liquid separation, the organic phase is adjusted to pH 7-8 with saturated sodium bicarbonate aqueous solution, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure, and dried to obtain intermediate A.

The molar ratio of SM: 4-dimethylaminopyridine: TEA: acyl chloride is 1: 0.01-0.10: 1.1-2.0: 1.1-2.0, and more preferably 1: 0.02: 1.2: 1.2.

Wherein, the specific operation method of step (2) is: under nitrogen protection, add intermediate A and DCM in a three-necked flask, after dissolving and clarifying, add TMSCN, and cool to -40-0°C (preferably -10-0°C). After stirring for 30 minutes, add boron trifluoride ether solution, raise the temperature to 20-50°C (preferably 25-30°C), and react under this temperature condition for 6-15h (preferably 8-10h). TLC detection shows that the raw material basically disappears, TEA is added to the reaction solution to quench the reaction, water is added, 1N dilute hydrochloric acid is adjusted to pH 6-7, the liquid is separated, the organic phase is adjusted to pH 7-8 with saturated sodium bicarbonate aqueous solution, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure, and dried to obtain intermediate B.

The molar ratio of the intermediate A:TMSCN:boron trifluoride etherate is 1:2-6:2-8, more preferably 1:4.5:5.

Wherein, the specific operation method of step (3) is: under nitrogen protection, add intermediate B and DCM in a three-necked flask, cool to -80 to -20°C (preferably -65 to -75°C), add 1M dichloromethane solution of boron trichloride, and react under this temperature condition for 1 to 6 hours (preferably 2 to 3 hours). TLC detection shows that the raw material basically disappears, then add methanol solution of triethylamine to quench the reaction, warm to room temperature, concentrate under reduced pressure, wash with n-hexane 3 times, then add 2-methyltetrahydrofuran to wash, wash with water, stir, stand, separate, collect organic phase layers, combine organic phase layers, wash organic phase layers with saturated brine, separate, concentrate the filtrate, and slurry the obtained filter cake with 2-methyltetrahydrofuran and methyl tert-butyl ether, filter and dry to obtain intermediate BL.

The molar ratio of the intermediate B to boron trichloride is 1:2-4, more preferably 1:3.5.

The present invention is described in detail below in conjunction with embodiments:

In the following examples, the intermediate A is named as intermediate _A1 to _An according to different examples, and the corresponding intermediate B and intermediate BL are also named according to this rule.

Example 1

1.1 Synthesis of Intermediate _A1 ( _When Intermediate A is Intermediate A1, _R1 is pivaloyl)

Under nitrogen protection, in a three-necked flask, add 55.2g (100mmol) SM, 0.24g (2mmol) 4-dimethylaminopyridine and 200ml dichloromethane mixed solution, add 12.1g (120mmol) TEA, cool to -10-0°C, add 14.5g (120mmol) pivaloyl chloride, stir for 10-15min, and then react at 25-35°C for 5-6h. TLC detection shows that the raw material has basically disappeared, add 200ml water to quench, adjust pH to 6-7 with 1N dilute hydrochloric acid, separate, adjust the organic phase to pH 7-8 with saturated sodium bicarbonate aqueous solution, wash with saturated sodium chloride aqueous solution, concentrate under reduced pressure, and dry to obtain 68.4g intermediate _A1 with a yield of 95.0%.

Nuclear magnetic analysis: ¹ H NMR (400MHz, DMSO-d ⁶ )δ9.84(s,1H),8.93(s,1H),7.25-7.35(m,15H),6.57-6.62(m,2H),4.92(d,1H),4.59-4.80(m,6H),4.30(q,1H),4.17(m,1H),3.65(m,2H),1.31(s,9H),1.16(s,9H)

1.2 Synthesis of Intermediate _B1 ( _When Intermediate B is Intermediate B1, _R1 is pivaloyl)

Under nitrogen protection, add 72.1g (0.1mol) of intermediate _A1 and 200ml of DCM to a three-necked flask. After dissolving and clarifying, add 44.6g (0.45mol) of TMSCN and cool to -10-0°C. After stirring for 30 minutes, add 71g (0.5mol) of boron trifluoride ether solution, raise the temperature to 25-30°C, and react at this temperature for 8-10h. TLC detection shows that the raw material has basically disappeared, then add 100ml of TEA to the reaction solution to quench the reaction, add water, adjust the pH to 6-7 with 1N dilute hydrochloric acid, separate the liquids, adjust the pH of the organic phase to 7-8 with saturated sodium bicarbonate aqueous solution, wash with saturated sodium chloride aqueous solution, concentrate under reduced pressure, and dry to obtain 53.3g of intermediate _B1 with a yield of 82.5%.

Nuclear magnetic analysis: ¹ H NMR (400MHz, DMSO-d ⁶ )δ9.86(s,1H),8.84(s,1H),7.27-7.38(m,15H),6.98-7.00(d,1H),6.84-6.86(d,1H),4.84(m,1H),4.60-4.80(m,6H),4.28(q,1H),4.14(m,1H),3.64(m,1H),3.50(m,1H),1.33(s,9H)

1.3 Synthesis of Intermediate BL ₁ (When Intermediate BL is Intermediate BL ₁ , R ₁ is pivaloyl)

Under nitrogen protection, 64.6g (0.1mol) of intermediate _B1 and 200ml DCM were added to a three-necked flask, cooled to -65--75°C), and 41.0g (0.35mol) of 1M dichloromethane solution of boron trichloride was added, and the reaction was carried out for 2-3h under this temperature condition. TLC detected that the raw material basically disappeared, and then 100ml of methanol solution of triethylamine was added to quench the reaction, the temperature was raised to room temperature, and the mixture was concentrated under reduced pressure. 100ml of n-hexane was added to wash 3 times, and then 100ml of 2-methyltetrahydrofuran was added to wash once, and 150ml of water was added to wash twice, stirred, allowed to stand, separated, the organic phase layer was collected, the organic phase layer was combined, the organic phase layer was washed with saturated brine, and then separated, the filtrate was concentrated, and the obtained filter cake was slurried with 100ml 2-methyltetrahydrofuran and 100ml methyl tert-butyl ether, filtered and dried to obtain 30.6g of intermediate _BL1 , with a yield of 81.6%.

Nuclear magnetic analysis: ¹ H NMR (400MHz, DMSO-d ⁶ ) δ10.41(s,1H),8.47(s,1H),7.18(d,1H),6.99(d,1H),6.23(d,1H) ,5.25(d,1H),4.92(t,1H),4.63(t,1H),4.10(q,1H),3.97(q,1H),3.66(m,1H),3.53(m,1H), 1.30(s,9H);

Embodiment 2:

2.1 Synthesis of Intermediate _A2 (When Intermediate A is Intermediate _A2 , _R1 is 4-methoxybenzenesulfonyl)

Under nitrogen protection, add 55.2g (100mmol) SM, 0.36g (3mmol) 4-dimethylaminopyridine and 200ml dichloromethane mixed solution in a three-necked flask, add 15.1g (150mmol) TEA, cool to -15～-10℃, add 24.8g (120mmol) 4-methoxybenzenesulfonyl chloride, stir for 10-15min, and then react at 35～45℃ for 8～9h. TLC detection shows that the raw material basically disappears, add 200ml water to quench, adjust pH to 6-7 with 1N dilute hydrochloric acid, separate, adjust pH to 7-8 with saturated sodium bicarbonate aqueous solution, wash with saturated sodium chloride aqueous solution, concentrate under reduced pressure, and dry to obtain 81.5g intermediate _A2 with a yield of 91.3%.

NMR analysis: ¹ H NMR (400MHz, DMSO-d ⁶ )δ11.3(s,1H),δ8.90(s,1H),7.03-7.80(m,23H),6.98(d,1H),6.88(d,1H),4.85(m,1H),4.53-4.80(m,6H),4.30(q,1H),4.15(t,1H),3.82(m,1H),3.80(s,3H),3.78(s,3H),3.68(m,1H)

2.2 Synthesis of Intermediate _B2 (When Intermediate B is Intermediate _B2 , _R1 is 4-methoxybenzenesulfonyl)

Under nitrogen protection, add 89.3g (0.1mol) of intermediate _A2 and 200ml DCM in a three-necked flask. After dissolving and clarifying, add 49.5g (0.5mol) of TMSCN and cool to -25--15°C. After stirring for 30 minutes, add 85.2g (0.6mol) of boron trifluoride ether solution, raise the temperature to 35-45°C, and react for 6-7h under this temperature condition. TLC detection shows that the raw material has basically disappeared, then add 150ml of TEA to the reaction solution to quench the reaction, add water, adjust the pH to 6-7 with 1N dilute hydrochloric acid, separate the liquids, adjust the pH of the organic phase to 7-8 with saturated sodium bicarbonate aqueous solution, wash with saturated sodium chloride aqueous solution, concentrate under reduced pressure, and dry to obtain 58.9g of intermediate _B2 with a yield of 80.6%.

Nuclear magnetic analysis: ¹ H NMR (400MHz, DMSO-d ⁶ )δ10.8(s,1H),δ8.73(s,1H),7.00-7.69(m,19H),6.86(d,1H),6.71(d,1H),4.96(d,1H),4.55-4.81(t,6H),4.28(q,1H),4.16(t,1H),3.79(s,3H),3.69(s,1H),3.54(m,1H)

2.3 Synthesis of Intermediate BL ₂ (When Intermediate BL is Intermediate BL ₂ , R ₁ is 4-methoxybenzenesulfonyl)

Under nitrogen protection, add 73.2g (0.1mol) of intermediate _B2 and 200ml DCM in a three-necked flask, cool to -50～-60℃), add 23.4g (0.2mol), 1M dichloromethane solution of boron trichloride, and react for 4～5h under this temperature condition. TLC detection shows that the raw material basically disappears, then add 100ml methanol solution of triethylamine to quench the reaction, warm to room temperature, concentrate under reduced pressure, wash 3 times with 100ml n-hexane, wash once with 100ml 2-methyltetrahydrofuran, wash twice with 150ml water, stir, stand, separate, collect organic phase layer, combine organic phase layer, wash organic phase layer with saturated brine, separate, concentrate filtrate, slurry the obtained filter cake with 100ml 2-methyltetrahydrofuran and 100ml methyl tert-butyl ether, filter and dry to obtain 36.1g intermediate _BL2 , with a yield of 78.4%.

Nuclear magnetic analysis: ¹ H NMR (400MHz, DMSO-d ⁶ ) δ10.6 (s, 1H), δ 8.86 (s, 1H), 7.64 (d, 2H), 7.02 (d, 2H), 6.88 (d, 1H),6.71(d,1H),5.14(d,1H),4.90(d,1H),4.83(t,1H),4.26(m,1H),4.20(t,1H),4.16(t,1H ),3.88(m,1H),3.78(s,3H),3.63(m,1H)

Embodiment three:

3.1 Synthesis of Intermediate A ₃ (When Intermediate A is Intermediate A ₃ , R ₁ is 4-methylbenzenesulfonyl)

Under nitrogen protection, in a three-necked flask, add 55.2g (100mmol) SM, 0.48g (4mmol) 4-dimethylaminopyridine and 200ml dichloromethane mixed solution, add 18.0g (180mmol) TEA, cool to -30～-20℃, add 28.6g (150mmol) 4-methylbenzenesulfonyl chloride, stir for 10-15min, and then react at 35～40℃ for 7～8h. TLC detection shows that the raw material basically disappears, add 200ml water to quench, adjust pH to 6-7 with 1N dilute hydrochloric acid, separate, adjust pH to 7-8 with saturated sodium bicarbonate aqueous solution for the organic phase, wash with saturated sodium chloride aqueous solution, concentrate under reduced pressure, and dry to obtain 77.6g intermediate A ₃ with a yield of 90.1%.

Nuclear magnetic analysis: ¹ H NMR (400MHz, DMSO-d ⁶ )δ10.9(s,1H),δ8.84(s,1H),7.25-7.80(m,23H),6.73(d,1H),6.56(d,1H),4.53-4.91(m,7H),4.28(m,1H),4.22(t,1H),3.79(m,1H),3.66(m,1H),2.4(d,6H)

3.2 Synthesis of Intermediate _B3 (When Intermediate B3 _is Intermediate B3, _R1 is 4-methylbenzenesulfonyl)

Under nitrogen protection, add 86.1g (0.1mol) of intermediate A ₃ and 200ml of DCM in a three-necked flask. After dissolving and clarifying, add 59.4g (0.6mol) of TMSCN and cool to -25--15°C. After stirring for 30 minutes, add 113.6g (0.8mol) of boron trifluoride ether solution, raise the temperature to 35-45°C, and react for 6-7h under this temperature condition. TLC detection shows that the raw material has basically disappeared, then add 200ml of TEA to the reaction solution to quench the reaction, add water, adjust the pH to 6-7 with 1N dilute hydrochloric acid, separate the liquids, adjust the pH of the organic phase to 7-8 with saturated sodium bicarbonate aqueous solution, wash with saturated sodium chloride aqueous solution, concentrate under reduced pressure, and dry to obtain 56.2g of intermediate B ₃ with a yield of 78.5%.

NMR analysis: ¹ H NMR (400MHz, DMSO-d ⁶ )δ10.6(s,1H),δ8.80(s,1H),7.80(d,2H),7.28-7.36(m,17H),6.84(d,1H),6.32(d,1H),5.00(m,1H),4.58-4.88(m,6H),4.34(m,1H),4.12(t,1H),3.56(m,1H),3.36(m,1H),2.42(s,3H)

3.3 Synthesis of Intermediate BL ₃ (When Intermediate BL is Intermediate BL ₃ , R ₁ is 4-methylbenzenesulfonyl)

Under nitrogen protection, add 71.6g (0.1mol) of intermediate B ₃ and 200ml DCM in a three-necked flask, cool to -25～-35℃), add 35.1g (0.3mol), 1M dichloromethane solution of boron trichloride, and react for 5～6h under this temperature condition. TLC detection shows that the raw material basically disappears, then add 100ml methanol solution of triethylamine to quench the reaction, warm to room temperature, concentrate under reduced pressure, wash 3 times with 100ml n-hexane, wash once with 100ml 2-methyltetrahydrofuran, wash twice with 150ml water, stir, stand, separate, collect organic phase layer, combine organic phase layer, wash organic phase layer with saturated salt water, separate, concentrate filtrate, slurry the obtained filter cake with 100ml 2-methyltetrahydrofuran and 100ml methyl tert-butyl ether, filter and dry to obtain 33.4g intermediate BL ₃ , with a yield of 75.1%.

Nuclear magnetic analysis: ¹ H NMR (400MHz, DMSO-d ⁶ ) δ10.8 (s, 1H), δ 8.90 (s, 1H), 7.80 (m, 2H), 7.30 (d, 2H), 6.80 (d, 1H),6.30(d,1H),5.14(d,1H),5.00(d,1H),4.46(t,1H),4.32(m,1H),4.22(t,1H),3.94(m,1H ),3.82(s,1H),3.68(m,1H),2.38(s,3H)

The upper and lower limit values and interval values of each raw material of the present invention can realize the present invention, and each raw material listed can realize the present invention, and the embodiments are not listed one by one here.

It should be noted that all documents or patents mentioned in the present invention are cited as references in this application, just as each article or patent is cited as a separate reference. In addition, it should be understood that the above is a specific embodiment and technical principle of the present invention. After reading the above content of the present invention, those skilled in the art can make various improvements and modifications to the present invention without departing from the scope of the present invention, and these equivalent forms also fall within the scope of the present invention.

Claims (5)

1. A potential antiviral drug intermediate BL, characterized by: the structural formula is as follows:

wherein R is ₁ Is C1-C6 alkyl, p-toluenesulfonyl or 4-methoxybenzenesulfonyl.

2. The method for synthesizing the latent antiviral drug intermediate BL as claimed in claim 1, wherein: it comprises the following steps:

step (1) synthesis of intermediate A: carrying out acylation reaction of hydroxyl and amino on SM and acyl chloride to obtain an intermediate A, wherein the structural formulas of SM and intermediate A are respectively as follows:

R ₁ is C1-C6 alkyl, p-toluenesulfonyl or 4-methoxybenzenesulfonyl;

step (2) synthesis of intermediate B: the intermediate A reacts with TMSCN under the condition of Lewis acid boron trifluoride ether solution to obtain an intermediate B, and the structural formula of the intermediate B is as follows:

R ₁ is C1-C6 alkyl, p-toluenesulfonyl or 4-methoxybenzenesulfonyl;

and (3) synthesizing an intermediate BL: intermediate B in Lewis acid BCl ₃ Under the condition of (3), obtaining an intermediate BL by debenzylation, wherein the structural formula of the intermediate BL is as follows:

R ₁ is C1-C6 alkyl, p-toluenesulfonyl or 4-methoxybenzenesulfonyl.

3. The method for synthesizing the intermediate BL of the potential antiviral drug according to claim 2, wherein: the specific operation method of the step (1) comprises the following steps:

Under the protection of nitrogen, adding a mixed solution of SM, 4-dimethylaminopyridine and dichloromethane into a three-necked bottle, adding TEA, cooling to-40-0 ℃, adding acyl chloride, stirring for 10-15min, and reacting for 4-10 h at 20-70 ℃; after TLC detection, adding water quenching, adjusting pH to 6-7 with 1N dilute hydrochloric acid, separating, adjusting pH of organic phase to 7-8 with saturated sodium bicarbonate water solution, washing with saturated sodium chloride water solution, concentrating under reduced pressure, and drying to obtain intermediate A;

wherein the mol ratio of SM, 4-dimethylaminopyridine, TEA and acyl chloride is 1:0.01 to 0.10: 1.1-2.0: 1.1 to 2.0.

4. The method for synthesizing the latent antiviral drug intermediate BL according to claim 2, wherein: the specific operation method of the step (2) is as follows: under the protection of nitrogen, adding the intermediate A and DCM into a three-necked flask, dissolving and clarifying, adding TMSCN, cooling to-40-0 ℃, stirring for 30 minutes, adding boron trifluoride diethyl etherate, heating to 20-50 ℃, reacting for 6-15h under the temperature condition, after TLC detection raw materials disappear, adding TEA into reaction liquid for quenching reaction, adding water, adjusting the pH to 6-7 by 1N diluted hydrochloric acid, separating liquid, adjusting the pH of an organic phase to 7-8 by saturated sodium bicarbonate aqueous solution, washing by saturated sodium chloride aqueous solution, concentrating under reduced pressure, and drying to obtain an intermediate B;

Wherein the molar ratio of the intermediate A to TMSCN to boron trifluoride diethyl etherate is 1:2 to 6:2 to 8.

5. The method for synthesizing the latent antiviral drug intermediate BL according to claim 2, wherein: the specific operation method of the step (3) is as follows: under the protection of nitrogen, adding the intermediate B and DCM into a three-necked bottle, cooling to-80-20 ℃, adding 1M dichloromethane solution of boron trichloride, reacting for 1-6 h under the temperature condition, adding methanol solution of triethylamine to quench the reaction after TLC detection raw materials disappear, heating to room temperature, concentrating under reduced pressure, adding n-hexane for washing for 3 times, adding 2-methyltetrahydrofuran for washing, washing with water, stirring, standing, separating, collecting an organic phase layer, combining the organic phase layer, washing the organic layer with saturated saline solution, separating, concentrating filtrate, pulping the obtained filter cake with 2-methyltetrahydrofuran and methyl tert-butyl ether, filtering and drying to obtain an intermediate BL;

the molar ratio of the intermediate B to the boron trichloride is 1.